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2022 - 2023
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First Year
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1 .
Liron Rosenkrantz
Bar Ilan University, Faculty of Medicine
Elucidating the neural mechanisms of enhanced rationality in autism
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| Background: Individuals with autism spectrum disorder (ASD) strikingly display a more rational and less biased decision-making process, conferring them with significant strengths over neurotypical counterparts (NT). However, as autism research mainly focused on deficits rather than strengths, the mechanisms of such enhanced rationality are poorly understood. The proposed project will use combined behavioral and neuroimaging (fMRI) techniques to elucidate the mechanisms of ASD enhanced rationality. Methods: Fifty ASD individuals and fifty age and gender-matched NT individuals will perform a well-characterized task examining the optimistic belief-updating bias, while being scanned in the MRI scanner. We will use neuroimaging to disentangle two competing hypotheses regarding the mechanisms of ASD enhanced rationality, establishing whether enhanced rationality is a product of bottom-up versus top-down processing. Implications: This study is the first to explore the neural basis of ASD enhanced rationality. Identifying pathways by which brain regions implicated in ASD may contribute to strengths, and not just deficits, will generate a more comprehensive understanding of ASD, and promote a strength-based approach to autism research. Furthermore, establishing information processing advantage in ASD may be harnessed to improve life with ASD, for example by developing better treatments for autistic individuals, or fostering their transition into the workforce. |
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2 .
Alon Shamir & Einat Madar, Mazor
The Technion, Faculty of Medicine
Pain and schizophrenia: Unraveling the molecular mechanism underling pain. Sensitivity of individuals with schizophrenia.
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| Numerous studies indicated that people with schizophrenia are hyposensitivity to pain. Very few studies have investigated the cause of pain hyposensitivity and whether these changes are part of the illness etiology and or adverse effects of the drug treatment. We used molecular and behavioral tools to test whether and how antipsychotic treatment (clozapine & haloperidol) affects pain transmission from the peripheral to the central nervous system in naïve rats. Preliminary results show that sub-chronic and chronic antipsychotic treatment of clozapine or haloperidol leads to a significant increase in mechanical and thermal sensitivity threshold. There was no change in the expression of TRPV1, TRPA1 pain receptors, and NAV1.8 / NAV1.7 voltage channels associated with sciatic nerve activity. In contrast, low c-Fos protein levels, a molecular marker of neural activity, were found in the anterior cingulate cortex and nucleus accumbens but not in the hippocampus. Here, we aim to explore- in more detail - the molecular mechanism of antipsychotic drugs on pain sensitivity using olanzapine and shed light on the relationship between pain and schizophrenia using a schizophrenia-like animal model. We will probe molecular changes, brain region/s, and neuronal systems involved in pain sensitivity in naïve and schizophrenia-like rats. Unraveling the molecular mechanism of pain sensitivity in individuals with schizophrenia might lead to a new neurobiological pain pathway and improve the knowledge about hypoalgesia in schizophrenia. |
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3 .
David Deutsch
University of Haifa, Department of Neurobiology
Characterizing deficits in social communication in Drosophila ASD models
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| Autism spectrum disorders (ASDs) are characterized by deficits in social interactions, language development, and repetitive behaviors. Because of its link to genetics and neural development, and the severe abnormalities in social interaction by which it is defined, autism offers the opportunity to study the neurobiological origin of social communication. From a clinical perspective, understanding the genetic and neurobiological disease mechanisms is critical for developing treatments.
Flies are widely used as models for ASD. With ~100K neurons, flies show a complex repertoire of social behaviors, including an elaborate mating ritual. Due to the available toolkit and knowledge in this model, scientists are able to identify the detailed circuitry responsible for specific behaviors. Using recent tools for fine characterization of social behaviors, we aim to determine the effect of ASD-linked mutations on social behaviors in male and female flies. We will quantify how social communication is modulated by specific mutants in three different experimental setups. Following the behavioral analysis, we will characterize how gene expression in specific cell types is causally linked to specific social deficits.
This study aims to present a new framework for understanding disease mechanisms for ASD, building on novel tools for quantification of complex social behaviors in flies.
Keywords: Social behaviors, acoustic communication, social deficits, autism spectrum disorders, ASD, neurogenetic disorders, neurodevelopment. |
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4 .
Niv Regev
Ben Gurion University, Psychology
The rewarding value of self-verifying information
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| The self-concept, how people understand themselves, guides many daily interactions. Individuals use the self-concept to create expectations regarding self-relevant information, including feedback from their peers and visceral reactions to actions that impact their self-image. Given recent findings showing that confirmation of (social) expectations is intrinsically rewarding, this proposal hypothesizes that confirming self-relevant expectations can also be rewarding. Preliminary findings support the rewarding value of such confirmation by showing that people forgo money to receive self-verifying rather than self-violating evaluations. We plan to examine whether such confirmation triggers a reward response using neuroimaging and behavioral studies. Study 1 (neuroimaging) will examine neural activity in the reward circuitry while people view information that verifies (or violates) their self-concept. Importantly, we will test whether the rewarding effect extends to confirmation of negative expectations (e.g., I am going to fail my test). To understand the mechanisms supporting self-relevant information processing, studies 2a (behavioral) and 2b (neuroimaging) will include confirmation and violations of expectations relevant to the self or a close individual. Together, the hypothesized findings can delineate how the self-concept is maintained and may also be relevant to clinical populations characterized by a negative self-concept, such as the clinically depressed or socially anxious individuals. |
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5 .
Ariel gilad
Hebrew University Jerusalem, Medical Neurobiology
Thalamo-cortico-amygdala network dysfunctions underlying sensory integration in ASD
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| Although much of autism research is focused on social impairment, recent evidence has highlighted sensory processing as a key dysfunction in autism spectrum disorder (ASD). The brain dynamics underlying impaired sensory integration in autism is still unknown. Three main brain structures are highly relevant to sensory integration deficits in ASD: thalamus, cortex and amygdala. Our research goal is to study aberrant interactions within this network in ASD during sensory integration. Using a mouse model for ASD, we combine for the first time wide-field cortical imaging with multi-fiber photometry to enable unprecedented access to a wide range of the thalamo-cortico-amygdala network. We will train ASD mice on a whisker-dependent task and measure calcium dynamics from the thalamo-cortico-amygdala network. A network analysis will detect dysfunctional interactions that are present in ASD. Next, the same mice will continue to learn and auditory discrimination task and we will compare network dysfunctions across the different sensory modalities. Finally, we will also continuously measure the same network as mice gradually learn each task and outline specific network patterns that are precluded during learning. Our general hypothesis is that ASD mice will exhibit thalamo-amygdala-cortical network dysfunction and these outcomes will aid in understanding sensory impairment in ASD |
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6 .
Keren Nitzan
The Open University, Psychology and Education
Anxiolytic and antidepressants’ effect of crataegus pinnatifida (Shan Zha) during and after Exposure to stress: effect on 5HT metabolism.
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| Depression and anxiety are two of the most common mental health conditions. The most common treatment for depression is selective serotonin reuptake inhibitors (SSRIs). SSRIs have many adverse effects that delay the clinical response and might reduce patients' adherence to therapy. Thus, there is a pressing need for a treatment with minimal side effects. We examined a novel herbal treatment (NHT; U.S. Patent No 9,320,772) consisting of four herbs - one of which is Crataegus pinnatifida (ShanZha; Israeli Patent No 275222) that demonstrated efficacy in pre-clinical studies when given during or after exposure to chronic stress. We recently published that Shan Zha is sufficient to produce an anxiolytic and antidepressant-like effect similar to NHT or Escitalopram through, without affecting the serotonin transporter and with activation of the 5-HT1A serotonin receptor. In a preliminary study, we saw that Shan-Zha treatment also changes serotonin metabolism when given after exposure to stress. This indicates a different mechanism than SSRI, which we further wish to understand. However, treatment during exposure to stress might have different effects than after the stress. We propose to evaluate the behavioral effects of Shan-Zha when given during exposure to chronic stress and explore its effect on Serotonin synthesis and metabolism. |
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7 .
Odaya Damri
Ben Gurion University, Clinical Biochemistry & Pharmacology
Does chronic exposure to high temperature, one of the factors of global warming, worsen Psychiatric illness prevalence and/or cause its exacerbation? A study in a mouse model of bipolar disorder.
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| Epidemiological and experimental studies found relationship between exposure to chronic heat and mental-health, but prospective studies are required to substantiate or disprove the conception that global warming threats to induce mental-health worsening. To execute such a study we will utilize our recently designed and reported novel bipolar-disorder mouse model based on low dose rotenone-induced mild mitochondrial dysfunction as robustly found in this disorder. We hypothesize that chronic exposure to hot ambient temperature (AT) by itself impaires mood-related behavioral and neurochemical parameters qualitatively and quantitatively in a gender-dependent mode, but protects from further detrimental effects (heat acclimation). We aim to find out (1) whether chronic exposure to hot AT affects mood-related behavioral indices, but protects against other detrimental interventions; (2) the consequences of such exposure at the level of mood-related brain neurochemical parameters possibly mediating the effects of heat; (3) whether the response to heat is gender-dependent. As described in the detailed proposal, by-and-large, our preliminary results are in favor of our hypothesis, e.g., exposing naive mice and mice exhibiting facets reminiscent of bipolar behavior and neurochemistry (our lab’s novel BD-like mouse model) to hot AT (28oC) for four weeks resulted in striking female/male temperature susceptibility difference in psychiatric–like characteristics. |
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8 .
Lilach Avitan
The Hebrew University of Jerusalem, ELSC
A mechanistic circuitry account for the he emergence of social behavior in the larval zebrafish
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| The ability to detect and understand movements of others is a hallmark of social cognition and interaction. Impaired interpretation of such biological motions has emerged as an early marker for autism in humans. The neural circuitry underlying human social cognition is established in utero, and therefore very little is known about its normal and pathological development and function. In contrast, the zebrafish provides an accessible nervous system from very early stages of development, and exhibits increasingly robust social behavior driven by recognition of movements of others over the course of development. In the current proposal, we will examine the neural processing of social information and its transformation into social actions. Subsequently, we will examine the neural circuitry driving the emergence of social behavior, and lastly we will unravel the mechanisms that underlie normal and abnormal social variability. This study will advance our contemporary understanding of social behavior, identifying key features of the developing neural code and their precise impact on measurable aspects of social behavior in the normal and the abnormal case. |
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9 .
Segal Zilka Mano
University of Haifa, Psychology
Identifying individual-specific mechanisms of change for major depressive disorder
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| Recent studies have defined biotypes (shared patterns of neural dysfunction in subgroups of patients) in major depressive disorder (MDD) and putative therapeutic mechanisms (brain changes associated with treatment efficacy), but no research has connected the two. Understanding the interrelations between biotypes and therapeutic mechanisms can provide deeper insight into MDD pathophysiology, identify necessary changes for treating MDD, facilitating rational treatment. We propose to identify MDD biotypes and test whether normalization of their features (biotype-concordant change) predicts subsequent MDD outcomes better than normalization of unrelated features (biotype-discordant change). We will analyze previously collected data from the EMBARC project (N=296). Multimodal data (MRI, clinical) were acquired at baseline and after one week of treatment with sertraline or placebo. First, we will identify multimodal MDD biotypes using machine learning approaches, and characterize their relations with therapeutic mechanisms (Aim 1). Second, we will assess whether biotype membership moderates treatment response to sertraline vs. placebo and whether distinct change in MDD biotypes occurs from baseline to week 1 in sertraline vs. placebo (Aim 2). The study will be the first to test a multimodal biotype-guided computation-based approach for guiding personalized interventions, demonstrating how diagnostic heterogeneity in MDD could guide personalized treatment. |
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10 .
Michael London
The Hebrew University of Jerusalem, Life science, Neurobiology, and ELSC
Abnormal dendritic excitability: a convergent mechanism in ASD
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| Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting social interactions and is associated with restricted and repetitive behaviors. Strong links were made between monogenetic mutations, dendritic structural abnormalities, and ASD. However, little attention was given to dendritic functional mechanisms (specifically dendritic spikes), which play critical roles in synaptic integration, plasticity, and cognitive functions. Here we set to test the hypothesis that dendriticexcitability is a convergent factor in ASD that may affect developmental stages and ongoing functions. We postulate that genetic factors can lead to dendritic excitability changes, causing alteredsynaptic formation and modification threshold. Using two-photon Ca2+ imaging in dendrites of mice, we will compare dendritic excitability in two models of ASD (SHANK3 and CNTNAP2) with WT mice. We will explore their spontaneous activity and response to sensory and social stimuli throughout development. Additionally, we will specifically test the role of the dendritic Ih ioniccurrent, which regulates dendritic excitability and thus can serve as a therapeutical target. Lastly, we and others have shown that dendritic Ih is modulated by alpha-2A adrenoceptors. Therefore, we will test if altered excitability in ASD mice models could be rectified by manipulating these systems. |
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11 .
Gali Umschweif-Nevo
The Hebrew University of Jerusalem, School of Pharmacy
CCL21 as a potential biomarker for depression and its treatments
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| Major depression disorder (MDD) is a common psychiatric disorder and the single most significant contributor to non-fatal health loss globally. Unfortunately, the lack of an available biomarker test to measure MDD severity leaves clinicians with only symptom-based diagnoses. Moreover, the efficacy evaluation of prescribed antidepressants takes weeks, which would be spared if an effective biomarker test was available. Over the years, the blood levels of inflammation factors and neurotransmitters have been linked to MDD. Specifically, the induced pro-inflammatory factors and the reduced γ-aminobutyric acid (GABA) were measured in MDD patients, but they offered only limited specificity to MDD. Here, we suggest studying a new biomarker candidate related to both inflammation and GABA, namely, CCL21. We found that this chemokine is selectively expressed by GABAergic neurons in a murine model of depression. As a secreted factor, CCL21 can be readily measured in the blood or cerebrospinal fluid. Thus, this proposal is designed to determine whether CCL21 can serve as a potential biomarker for (i) depression-related behaviors, (ii) vulnerability to depression, and (iii) determining the efficacy of antidepressants. Establishing a correlation between the CCL21 levels and effective behaviors will set the basis for clinical studies in MDD and other psychiatric conditions. |
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Second Year
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1 .
Jennifer Resnik
Ben-Gurion University, Life Science department
The neural underpinnings of sound processing and hypersensitivity in mice models of autism spectrum disorder
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| Autism spectrum disorder (ASD) is associated with altered sensory processing. Difficulties perceiving and understanding sensory stimuli can be uncomfortable and, in many cases, debilitating. One of the main sensory symptoms in individuals with ASD is hypersensitivity to sounds. Studies have suggested that atypical responses in primary auditory cortices could lead to the sound hypersensitivity observed in ASD. However, we still don’t know if and how changes in cortical activity modulate auditory sensitivity. To test if aberrant cortical activity modulates auditory sensitivity in ASD, we propose to 1) Develop an auditory perceptual task that asses auditory thresholds and sensitivity in wild type and ASD mouse models, 2) Combine 2-Photon imaging and behavior to identify the cell-type-specific difference in cortical sound processing between WT and ASD mice models and 3) Combine optical stimulation and 2-Photon imaging to manipulate the activity of specific inhibitory and excitatory cells to test their role in the modulation of auditory sensitivity. The results from the proposed project will allow us to elucidate the neural underpinnings of sound processing in ASD and determine whether there is a causal relationship between changes in cortical activity and altered auditory processing and hypersensitivity. |
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2 .
Silvi Frenkel-Toledo
Ariel University, School of Health sciences, Physiotherapy department
Human higher-order motor control: Neural correlates of imitation, pantomime, and tool-related actions, and the relationship between deficits in these skills and motor function following stroke.
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| The ability to imitate and pantomime gestures, and use tools are fundamental highorder motor skills that are executed in response to different inputs. These skills play an important role in motor learning and non-verbal social communication. Whereas much has been learned about the neural correlates of these skills, information about the hemispheric contribution, amount of network sharing, and relative contribution of regions of interest to these skills is lacking. The contribution of deficits in these skills to motor functioning also requires further clarification. My overall goal is to elucidate the neuroanatomical correlates of imitation, pantomime, and tool-related actions, and the clinical correlates of their deficits by pursuing two specific aims: (1a) Identify the cortical and white-matter substrates in each hemisphere where damage has a significant impact on these skills, using voxel-based lesion-symptom mapping; (1b) Identify the relative contribution of regions of interest to these skills, using a novel computational framework – multi-perturbation Shapley analysis; and (2) Elucidate how deficits in these skills relate to motor functioning following stroke. The results will have theoretical implications regarding brain organization of human praxis network and practical implications for prognosis and possible treatments of neurological patients with impairments in these skills or other motor disturbances. |
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3 .
Sarit Szpiro
University of Haifa, Special Education
Recovering Sensory Decline: Unlocking the Potential of Perceptual Learning across Modalities
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| Aging impacts perception significantly, leading to sensory declines in vision and audition. One of the most promising methods to offset sensory decline is perceptual learning (PL) -- the ability to improve performance on perceptual tasks with practice. Although PL is an effective behavioral intervention in vision and audition, separate bodies of research have addressed each modality. To effectively restore perception in aging, it is critical to develop training protocols that address the simultaneous declines in both modalities. The goals of the current research are: (1) To unravel the extent to which sensory plasticity is similar across modalities in vision and audition by examining both in young adults; (2) To examine whether and how sensory decline alters sensory plasticity across modalities in older adults; and (3) To test novel training protocols that are designed to efficiently yield learning and transfer in both vision and audition, leading to “double sensory learning”. The findings of the current research will provide the first steps in developing multi-modal learning protocols for older adults. |
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4 .
Michal Taler
Sheba, Tel Hashomer, The Pediatric Molecular Psychiatry Laboratory
The Role of Neuro-inflammation and Medical Burden in Schizophrenia: A Longitudinal Study on 22q11.2 Deletion Syndrome as a Model
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| The 22q11.2 Deletion Syndrome (22q11.2DS) is a neuro-genetic disorder caused by a microdeletion on the long arm of chromosome 22. Among its heterogeneous phenotype are cognitive deficits, immune disorders and high rates of psychiatric comorbidities that make it a genetic model for schizophrenia. In a previous study, we recruited psychotics and non-psychotic individuals with 22q11.2DS and healthy control. All participants underwent cognitive and psychiatry evaluation accompanied by biochemical analysis of immunological and blood-brain barrier (BBB) parameters. Our results showed that cognitive deficits in the 22q11.2DS participants were correlated with an upregulation of their immune system, specifically with interleukin 6 levels. Our findings are in line with studies in non-syndromic population that showed a correlation between immune activation at baseline and cognitive and psychiatry outcomes. In the proposed study we will conduct a longitudinal study that will allow us to examine the cognitive, psychotic and inflammatory states of the same cohort seven years after first evaluation. In addition to a reassessment of the same parameters, we will evaluate their medical history to find whether past adverse medical events contributed to the risk of psychosis development. To the best of our knowledge, we are the first to conduct this type of study in 22q11.2DS. We hypothesize that inflammation and BBB permeability will be identified as a central process in the pathophysiology of the 22q11.2DS phenotype and will allow opening a whole new world of possible treatments. |
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5 .
Haitham Amal
The Hebrew University of Jerusalem, Institute for Drug Research, School of Pharmacy, Faculty of Medicine
The role of CREB signalling via SNO-calcineurin in a mouse model of autism spectrum disorder (ASD).
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| Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by abnormalities in social interactions, deficits in communication, restricted interests, repetitive behavior, and sensory anomalies. No effective pharmacological treatment or preventive measures have been established for ASD to date. Recently, we have discovered that the mouse model of ASD based on InsG3680 mutation of the Shank3 gene led to a dramatic increase of nitric oxide (NO) formation and NO-related S-nitrosylation (SNO) of proteins. A significant amplification of the SNO-dependent CREB signaling pathway was also found in our study. We hypothesize that Shank3 mutation leads to amplification of the neuronal NO synthase (nNOS) activity and to molecular changes including SNO that affects CREB signaling. We will apply multi-level analysis including proteomics, bioinformatics, as well as conventional biochemical, pharmacological, and behavioral tools using the well-established InsG3680 Shank3 mouse model. The knowledge obtained from the current study will likely be applicable to a broader group of patients with genetically diverse but mechanistically related etiology. The proposed research plan will provide novel mechanistic insights into the contribution of NO and CREB in ASD, and will lead to the discovery of novel drug targets and therapeutic strategies.
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6 .
Boaz Barak
Tel Aviv University, The School of Psychological Sciences and Sagol school of Neuroscience
Elucidating the roles of microglia in the pathophysiology of Williams syndrome
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| Williams syndrome (WS) is a neurodevelopmental disorder caused by a heterozygous microdeletion of about 26 genes, characterized by hypersociability and unique neurocognitive abnormalities. Of the deleted genes, GTF2I has been linked to hypersociability in WS. Our previous findings from humans and mice identified myelination deficits, mediated by Gtf2i deletion specifically in forebrain excitatory neurons (Barak et al., Nature Neuroscience, 2019). These myelination deficits affected social behavior and motor capabilities that were normalized following treatment with FDA-approved drugs aimed to improve myelination and axonal conductivity properties.
Here, we seek to take advantage of this gained knowledge and expertise to further define whether WS-related abnormalities are associated with microglial functions. Our preliminary data show a significantly increased number of microglia and microglial activation in the mutant mouse cortex compared to controls. Based on these data, and using a mouse model for WS, we aspire to deepen the characterization of microglia properties and functions in WS, and test for a potential treatment based on IGF-1. Together, our findings will potentially discover novel pathophysiological mechanism in WS, mediated by microglia, and improve our understanding on the efficacy of a novel treatment in WS as an example of myelin dysfunction-related disorder. |
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7 .
Rama Novogrodsky & Natalia Meir
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Exploring the Use of Dual-Language Assessment for Bilingual Children with Autism Spectrum Disorder (ASD): Implications for Diagnosis and Treatment
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| Bilingual children show unequal competence across their two languages. According to the best practice guidelines recommended by professional bodies (APA, 2017; ASHA, 2004; IALP, 2011), assessment of bilingual children must be culturally and linguistically appropriate in order to obtain a complete picture of the child`s competences. However, today, bilingual children are mainly assessed in their Societal Language, disregarding their abilities in their Home Language. The proposed study will test bilingual children with ASD in both languages. The novelty of this study is a dual-language assessment approach with bilingual children. We will compare the performance of bilingual children with ASD in their Home Language (English / Russian) and in the Societal Language (Hebrew). Comparing the scores across the two languages of a bilingual child is expected to shed light on the effects of bilingualism on language skills as well as performance on diagnostic measures (e.g., ADOS). The study will develop a protocol with evidence-based guidance for the assessment of bilingual children with ASD providing scientific evidence for professionals and bilingual families with ASD regarding the assessment procedures with the ultimate goal of improving the quality of life of bilingual children with ASD, as well as that of their families. |
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8 .
Ravid Doron
The Open University, Education and Psychology Department
An ultra-low dose of ∆9-tetrahydrocannabinol for the treatment of Alzheimer’s Disease and the role of Sirtuin 1 and BDNF
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| Alzheimer’s disease (AD) is the most common form of dementia. AD has a physical, emotional, and economic impact on the patients and their families and society at large. More than a decade since its discovery, there is still no available treatment. ∆9-tetrahydrocannabinol (THC) is emerging as a promising therapeutic agent. Using THC in conventional-high doses may have deleterious effects. Therefore, we propose to use an ultra-low dose of THC (ULD-THC). We previously published that a single injection of ULD-THC elevated brain-derived neurotrophic factor (BDNF) and Sirtuin-1 (Sirt-1) levels in the brain and ameliorated cognitive functioning in several models of brain injuries as well as in naturally aging mice. Our working hypothesis suggests that ULD-THC can prevent and even reverse AD pathology and assumes the involvement of BDNF and Sirt1 in these processes. Following the experiments of the first year, we published that a single injection of ULD-THC alleviated cognitive impairments of 5xFAD mice, a mice model for AD. Our treatment also downregulated the truncated isoform of Tropomyosin receptor kinase B (TrkB) receptor, which acts as an inhibitory modulator of BDNF signaling. Here, we suggest treating AD male and female mice at different disease stages, examining cognitive functions and analyzing AD-related brain pathology, Sirt1, BDNF and BDNF receptors levels. Our work may establish the foundations for developing a pharmaceutical preparation for the treatment of AD patients. We believe that the pre-clinical results obtained in our proposed study will enable us to move forward quickly to clinical trials, as cannabis is already approved for the treatment of several diseases. |
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2021 - 2022
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First Year
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1 .
Haitham Amal
Hebrew University Jerusalem, Institute for Drug Research
The role of CREB signaling via SNO calcineurin in a mouse model of ASD.
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| Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by abnormalities in social interactions, deficits in communication, restricted interests, repetitive behavior, and sensory anomalies. No effective pharmacological treatment or preventive measures have been established for ASD to date. Recently, we have discovered that the mouse model of ASD based on InsG3680 mutation of the Shank3 gene led to a dramatic increase of nitric oxide (NO) formation and NO-related S-nitrosylation (SNO) of proteins. A significant amplification of the SNO-dependent CREB signaling pathway was also found in our study. We hypothesize that Shank3 mutation leads to amplification of the neuronal NO synthase (nNOS) activity and to molecular changes including SNO that affects CREB signaling. We will apply multi-level analysis including proteomics, bioinformatics, as well as conventional biochemical, pharmacological, and behavioral tools using the well-established InsG3680 Shank3 mouse model. The knowledge obtained from the current study will likely be applicable to a broader group of patients with genetically diverse but mechanistically related etiology. The proposed research plan will provide novel mechanistic insights into the contribution of NO and CREB in ASD, and will lead to the discovery of novel drug targets and therapeutic strategies. |
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2 .
Boaz Barak
Tel Aviv University, Psychology Sciences
Elucidating the roles of microglia in the pathophysiology of Williams syndrome.
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| Williams syndrome (WS) is a neurodevelopmental disorder caused by a heterozygous microdeletion of about 26 genes, characterized by hypersociability and unique neurocognitive abnormalities. Of the deleted genes, GTF2I has been linked to hypersociability in WS. Our previous findings from humans and mice identified myelination deficits, mediated by Gtf2i deletion specifically in forebrain excitatory neurons (Barak et al., Nature Neuroscience, 2019). These myelination deficits affected social behavior and motor capabilities that were normalized following treatment with FDA-approved drugs aimed to improve myelination and axonal conductivity properties.
Here, we seek to take advantage of this gained knowledge and expertise to further define whether WS-related abnormalities are associated with microglial functions. Our preliminary data show a significantly increased number of microglia and microglial activation in the mutant mouse cortex compared to controls. Based on these data, and using a mouse model for WS, we aspire to deepen the characterization of microglia properties and functions in WS, and test for a potential treatment based on IGF-1. Together, our findings will potentially discover novel pathophysiological mechanism in WS, mediated by microglia, and improve our understanding on the efficacy of a novel treatment in WS as an example of myelin dysfunction-related disorder. |
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3 .
Silvi Frenkel Toledo
Ariel University, School of health sciences
Human higher order control
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| The ability to imitate and pantomime gestures, and use tools are fundamental highorder motor skills that are executed in response to different inputs. These skills play an important role in motor learning and non-verbal social communication. Whereas much has been learned about the neural correlates of these skills, information about the hemispheric contribution, amount of network sharing, and relative contribution of regions of interest to these skills is lacking. The contribution of deficits in these skills to motor functioning also requires further clarification. My overall goal is to elucidate the neuroanatomical correlates of imitation, pantomime, and tool-related actions, and the clinical correlates of their deficits by pursuing two specific aims: (1a) Identify the cortical and white-matter substrates in each hemisphere where damage has a significant impact on these skills, using voxel-based lesion-symptom mapping; (1b) Identify the relative contribution of regions of interest to these skills, using a novel computational framework – multi-perturbation Shapley analysis; and (2) Elucidate how deficits in these skills relate to motor functioning following stroke. The results will have theoretical implications regarding brain organization of human praxis network and practical implications for prognosis and possible treatments of neurological patients with impairments in these skills or other motor disturbances. |
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4 .
Jennifer Resnik
Ben Gurion University, Life Sciences
The neural underpinnings of sound processing and hypersensitivity in mice models of ASD.
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| Autism spectrum disorder (ASD) is associated with altered sensory processing. Difficulties perceiving and understanding sensory stimuli can be uncomfortable and, in many cases, debilitating. One of the main sensory symptoms in individuals with ASD is hypersensitivity to sounds. Studies have suggested that atypical responses in primary auditory cortices could lead to the sound hypersensitivity observed in ASD. However, we still don’t know if and how changes in cortical activity modulate auditory sensitivity. To test if aberrant cortical activity modulates auditory sensitivity in ASD, we propose to 1) Develop an auditory perceptual task that asses auditory thresholds and sensitivity in wild type and ASD mouse models, 2) Combine 2-Photon imaging and behavior to identify the cell-type-specific difference in cortical sound processing between WT and ASD mice models and 3) Combine optical stimulation and 2-Photon imaging to manipulate the activity of specific inhibitory and excitatory cells to test their role in the modulation of auditory sensitivity. The results from the proposed project will allow us to elucidate the neural underpinnings of sound processing in ASD and determine whether there is a causal relationship between changes in cortical activity and altered auditory processing and hypersensitivity. |
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5 .
Sarit Szpiro and Hanin Karawani (Joint application)SAC: Hochstein,D.Sagi
Haifa university, Education and communication sciences and disorders
Recovering sensory decline; unlocking the potential of perceptual learning across modalities.
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| Aging impacts perception significantly, leading to sensory declines in vision and audition. One of the most promising methods to offset sensory decline is perceptual learning (PL) -- the ability to improve performance on perceptual tasks with practice. Although PL is an effective behavioral intervention in vision and audition, separate bodies of research have addressed each modality. To effectively restore perception in aging, it is critical to develop training protocols that address the simultaneous declines in both modalities. The goals of the current research are: (1) To unravel the extent to which sensory plasticity is similar across modalities in vision and audition by examining both in young adults; (2) To examine whether and how sensory decline alters sensory plasticity across modalities in older adults; and (3) To test novel training protocols that are designed to efficiently yield learning and transfer in both vision and audition, leading to “double sensory learning”. The findings of the current research will provide the first steps in developing multi-modal learning protocols for older adults. |
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6 .
Michal Taler
Sheba, SAC: Klein Pediatric moleculat psychiatry laboratory
The role of neuro inflammation and medical burden in Schizophrenia: A longitudinal studyd on 22q11.2 deletion syndrome as a model.
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| The 22q11.2 Deletion Syndrome (22q11.2DS) is a neuro-genetic disorder caused by a microdeletion on the long arm of chromosome 22. Among its heterogeneous phenotype are cognitive deficits, immune disorders and high rates of psychiatric
comorbidities that make it a genetic model for schizophrenia.
In a previous study, we recruited psychotics and non-psychotic individuals with 22q11.2DS and healthy control. All participants underwent cognitive and psychiatry evaluation accompanied by biochemical analysis of immunological and blood-brain barrier (BBB) parameters. Our results showed that cognitive deficits in the
22q11.2DS participants were correlated with an upregulation of their immune system, specifically with interleukin 6 levels. Our findings are in line with studies in nonsyndromic population that showed a correlation between immune activation at
baseline and cognitive and psychiatry outcomes.
In the proposed study we will conduct a longitudinal study that will allow us to examine the cognitive, psychotic and inflammatory states of the same cohort seven years after first evaluation. In addition to a reassessment of the same parameters, we will evaluate their medical history to find whether past adverse medical events contributed to the risk of psychosis development. To the best of our knowledge, we are the first to conduct this type of study in 22q11.2DS. We hypothesize that inflammation and BBB permeability will be identified as a central process in the pathophysiology of the 22q11.2DS phenotype and will allow opening a whole new world of possible treatments. |
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Second Year
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1 .
Rama Novogrodsky And
Dr. Natalia Meir
Haifa University, Bar Ilan University, English Literature and Linguistics, Communication sciences and disorders
Exploring the use of dual language assessment for bilingual children with ASD: Implications for diagnosis and treatment.
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| Bilingual children show unequal competence across their two languages. According to the best practice guidelines recommended by professional bodies (APA, 2017; ASHA, 2004; IALP, 2011), assessment of bilingual children must be culturally and linguistically appropriate in order to obtain a complete picture of the child`s competences. However, today, bilingual children are mainly assessed in their Societal Language, disregarding their abilities in their Home Language.
The proposed study will test bilingual children with ASD in both languages. The novelty of this study is a dual-language assessment approach with bilingual children. We will compare the performance of bilingual children with ASD in their Home Language (English / Russian) and in the Societal Language (Hebrew). Comparing the scores across the two languages of a bilingual child is expected to shed light on the effects of bilingualism on language skills as well as performance on diagnostic measures (e.g., ADOS).
The study will develop a protocol with evidence-based guidance for the assessment of bilingual children with ASD providing scientific evidence for professionals and bilingual families with ASD regarding the assessment procedures with the ultimate goal of improving the quality of life of bilingual children with ASD, as well as that of their families. |
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2 .
Vadim Axelrod
Vadim Axelrod, Gonda Multidisciplinary Brain Research Center
Gonda Multidisciplinary Brain Research Center
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| People mind-wander (or daydream) frequently. While some aspects of mind-wandering are likely beneficial
(e.g., creative incubation), negative repetitive self-focused thoughts (i.e., rumination) is clearly detrimental
and causes suffering. Rumination occurs in both healthy people and those across a wide spectrum of
pathologies, but the neural mechanisms of rumination are poorly understood. The proposed innovative
functional MRI project aims to shed light on neural mechanisms of rumination by comparing functional
connectomes of healthy participants with high vs. low propensity for rumination. Addressing limitations of
previous studies, we introduce a new experimental paradigms and new data analysis approach. Our main
hypothesis is that spontaneous activity and functional connectivity fingerprints contain information and
possibly determine rumination state. By employing state-of-the-art machine learning, graph theoretical and
dynamic connectivity analyses, we test that: a) rumination personal traits can be decoded from functional
connectivity fingerprints; b) ruminative state is characterized by increased integration within DMN and
decreased whole-brain integration; and c) rumination personal traits can be decoded from the durations of
dynamic network states. Overall, we believe that the present project constitutes a major leap in our
understanding of rumination in the brain. The present research also paves the way for future intervention
study. |
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3 .
Orit Elyon
Ariel University, Health Sciences
Extending haptic sense: Psychophysics and therapy method based on the “modra inspire” system.
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| The ease with which healthy individuals hold and lift objects without dropping or damaging them is not reflected in upper limb (UL) amputees with grip prosthesis or any other patient group with finger- grip disabilities (e.g. stroke patients, cervical cord injured patients.)
The proposed study is designed to develop training methods for these tasks, based on innovative technology. The “Mudra-Strap” ®, developed by “Wearable Devices”, identifies finger movements and measures of force elicited between defined fingers by receiving the neural activating signals from the nerve supply of individual fingers via embedded sensors within the wrist strap. The systems’ high sensitivity enables detection of single motor-neuron signals.
Psychophysical studies of visual/auditory modalities provided mathematical models of transformation-functions between physical light/tone features, and their subjective perception. Haptic sense has remained a neglected modality. Robotic and virtual reality interfaces have elicited the development of remote operating by “gestures” and haptics; “Mudra-inspire” presenting one of the most advanced devices.
We propose utilizing this technology in two study phases: 1 – Psychophysics of haptic-sense: detecting transformation-functions of finger-grip-force-skills in healthy participants. 2 – Developing a therapeutic-rehabilitation program based on this technology and visual-feedback, for UL amputees, incomplete spinal cord lesions, stroke patients and other finger-grip disabled persons.
Keywords:
Finger-grip, haptic sense, innovative technologies |
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4 .
Sveta Fichman
Hadassah Academic College, Hadassah Academic College
Stuttering and bilingualism: Cross linguistic aspects.
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| Developmental stuttering affects 5% of children in preschool, and its life-long effects
on academic, social, and emotional wellbeing are well-known. In bilingual children,
stuttering is manifested by dysfluency in both languages, but research on uniquely
bilingual features of stuttering and on cross-linguistic differences and similarities is
very limited. In the assessment of stuttering, Speech-Language Pathologists are
guided by speech norms developed for monolingual English-speaking children, which
are not adjusted for bilingual speech. The current proposal is designed to: i) identify
unique bilingual features of stuttering; ii) explore cross-linguistic manifestation of
stuttering; and iii) study the impact of language proficiency on speech disfluencies in
bilingual preschool children who stutter. The first goal will be achieved by comparing
frequency of disfluencies in English-Hebrew bilingual children who stutter and two
groups of monolingual children who stutter (monolingual speakers of English and
Hebrew). A second goal will be addressed by comparing the frequency, type and loci
of disfluencies across the two languages, within-subject comparisons for bilinguals
and between-subject comparisons for monolinguals. Finally, the relationship between
language proficiency (in both languages for bilinguals) and frequency of disfluencies
will be assessed in children who stutter.
Keywords: stuttering, bilingualism, cross-linguistic, disfluency |
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5 .
Tal Krasovsky
University of Hafia, Physical Therapy
Neural and behavioral correlates of coplex walking in people with anxiety disorders.
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| Objective: Anxiety is one of the most prevalent mental health disorders, with debilitating symptoms causing avoidance and decreased quality of life. The link between anxiety and balance is ubiquitous throughout the life span, resulting in a higher fall risk for people with anxiety disorders. However, understanding of central control of mobility, and specifically walking in people with anxiety, is still limited. This proposal examines the neural and behavioral correlates of complex walking performance in people with anxiety. Methods: Ninety people aged 40-65 will be recruited, N=60 clinically-diagnosed with anxiety disorder and N=30 controls. Participants will perform single- and dual-task walking trials (counting backwards (cognitive) or texting on a mobile phone (visuomotor)) and their task performance as well as prefrontal cortex (PFC) activation will be measured using behavioral and neural (functional near infrared spectroscopy) markers. People with anxiety disorders are hypothesized to walk slower and in a less stable manner and to demonstrate less PFC activation, due to reduced inhibitory PFC control. It is further hypothesized that the ability of anxious individuals to perform visuomotor dual-task walking will be reduced due to increased visual dependence. Impact: A better understanding of central mobility control can identify potential targets for individualized balance and fall prevention programs for people with anxiety.
Keywords: Dual task; functional Near Infrared Spectroscopy; Attention; Prefrontal cortex; Visual dependence; Executive function |
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6 .
Smadar Ovadia-Caro
University of Haifa, Cognitive Sciences
Developing novel, connectivity based tDCS stimulation Protocols to enhance the effects of visuomotor prismatic adaptation.
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| Unilateral neglect is a brain disorder where patients are unable to orient, respond to, or report
stimuli in the contra-lesional space. Prismatic adaptation (PA) – a visuomotor adaptation task
that induces a visual shift - is a commonly used rehabilitation technique in unilateral neglect
patients, aimed at re-balancing spatial attention. Although the behavioural effects of PA are
well documented, its mechanism of action, even in healthy subjects, is still debatable. In
addition, it is unclear whether it is possible to further augment PA effects, and thus promote
long-term clinical benefits. We propose here to use fMRI connectivity to study the underlying
neural mechanism associated with PA in healthy subjects, and identify relevant connections
mitigating its effects at the whole-brain level. We will further use transcranial direct current
stimulation (tDCS) to augment the effects of PA by targeting these specific connections. The
suggested project is aimed at the long-term goals of prompting our understanding of PA
mechanisms and devising stimulation protocols that can be later-on tested in unilateral neglect
patients.
Keywords: Prismatic adaptation, fMRI connectivity, resting-state fMRI, non-invasive
brain stimulation, Transcranial direct current stimulation, unilateral neglect |
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7 .
Noam Weinbach and Noga Cohen
University of Haifa, Psychology
How emotion regulation strategies influence the physiological reaction to food in women with Bullimia nervoa.
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| Bulimia nervosa (BN) is a psychiatric disorder characterized by recurrent episodes of binge eating followed by compensatory behaviors. Understanding the mechanisms that underlie bulimic symptoms may improve evidence-based interventions for BN. Research has shown that the use of maladaptive emotion regulation strategies and alterations in autonomic nervous system activity may serve as risk factors for bulimic symptoms. The goal of the current research is to assess the causal role played by emotion regulation strategies in modulating physiological reactions to food in patients with BN. In the study, patients with BN and a control group of women with high body dissatisfaction will complete tasks that include rumination induction (dwelling on symptoms of distress) and reappraisal induction (reinterpreting a situation to make it feel less negative). During the tasks, participants’ physiological response to high- and low-calorie food images will be monitored via pupil size. Additionally, participants' desire to eat will be assessed via self-report. The expectation is that rumination will intensify the arousing impact of high-calorie foods and the desire to eat these foods, while reappraisal will reduce these responses. The results should shed light on the processes through which emotion regulation strategies heighten or reduce the risk of bulimic symptoms.
Keywords: Eating disorders, bulimia nervosa, emotion regulation, rumination, reappraisal, pupil dilation. |
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8 .
Sigal Zilcha-Mano
University of Haifa, Psychology
Neural mechanisms of expectancy based effects in psychotherapy.
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| Bulimia nervosa (BN) is a psychiatric disorder characterized by recurrent episodes of binge eating followed by compensatory behaviors. Understanding the mechanisms that underlie bulimic symptoms may improve evidence-based interventions for BN. Research has shown that the use of maladaptive emotion regulation strategies and alterations in autonomic nervous system activity may serve as risk factors for bulimic symptoms. The goal of the current research is to assess the causal role played by emotion regulation strategies in modulating physiological reactions to food in patients with BN. In the study, patients with BN and a control group of women with high body dissatisfaction will complete tasks that include rumination induction (dwelling on symptoms of distress) and reappraisal induction (reinterpreting a situation to make it feel less negative). During the tasks, participants’ physiological response to high- and low-calorie food images will be monitored via pupil size. Additionally, participants' desire to eat will be assessed via self-report. The expectation is that rumination will intensify the arousing impact of high-calorie foods and the desire to eat these foods, while reappraisal will reduce these responses. The results should shed light on the processes through which emotion regulation strategies heighten or reduce the risk of bulimic symptoms.
Keywords: Eating disorders, bulimia nervosa, emotion regulation, rumination, reappraisal, pupil dilation. |
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2020 - 2021
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First Year
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1 .
Vadim Axelrod
Bar Ilan University, Gonda Multidisciplinary Brain Research Center
In quest of understanding neural mechanisms of rumination in non-clinical population
|
| People mind-wander (or daydream) frequently. While some aspects of mind-wandering are likely beneficial (e.g., creative incubation), negative repetitive self-focused thoughts (i.e., rumination) is clearly detrimental and causes suffering. Rumination occurs in both healthy people and those across a wide spectrum of pathologies, but the neural mechanisms of rumination are poorly understood. The proposed innovative functional MRI project aims to shed light on neural mechanisms of rumination by comparing functional connectomes of healthy participants with high vs. low propensity for rumination. Addressing limitations of previous studies, we introduce a new experimental paradigms and new data analysis approach. Our main hypothesis is that spontaneous activity and functional connectivity fingerprints contain information and possibly determine rumination state. By employing state-of-the-art machine learning, graph theoretical and dynamic connectivity analyses, we test that: a) rumination personal traits can be decoded from functional connectivity fingerprints; b) ruminative state is characterized by increased integration within DMN and decreased whole-brain integration; and c) rumination personal traits can be decoded from the durations of dynamic network states. Overall, we believe that the present project constitutes a major leap in our understanding of rumination in the brain. The present research also paves the way for future intervention study. |
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2 .
Boaz Barak
Tel Aviv University, Psychological Sciences and Neuroscience
Elucidating how prenatal Gtf2i deletion in myelinating glia affects behavioral, myelination and neurobiological properties
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| Williams syndrome (WS) is a neurodevelopmental disorder caused by a heterozygous microdeletion of about 26 genes, characterized by hypersociability and unique neurocognitive abnormalities. Of the deleted genes, GTF2I has been linked to hypersociability in WS. Our previous findings from humans and mice identified the first molecular and cellular evidences for myelination deficits, mediated by Gtf2i deletion specifically in forebrain excitatory neurons (Barak et al., Nature Neuroscience, 2019). These myelination deficits affected social behavior and motor capabilities that were normalized following treatment with FDA-approved drugs aimed to improve myelination and axonal conductivity properties.
Here, we seek to take advantage of this gained knowledge and expertise to further define whether myelination abnormalities can also be caused by Gtf2i-KO in myelinating glia, and by thus further study the roles of Gtf2i in different cell types. To study this, we will define how prenatal Gtf2i deletion in myelinating glia affects behavioral, myelination and neurobiological properties. This will be achieved by inducing homozygous embryonic deletion of Gtf2i in myelinating glia using the Cnp-Cre mouse, and investigating neurobiological outcomes. This will allow us to elucidate Gtf2i’s specific roles in regulating myelination, the neuron–oligodendrocyte (OL) interplay and the behavioral consequences when altering this interplay. |
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3 .
Livnat Brill
Hebrew University Jerusalem, Neurology, Hadassah Medical Center
Molecular and cognitive functions as predictors for multiple sclerosis outcome
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| Multiple sclerosis (MS) is an autoimmune neurodegenerative disease of the central nervous system. Due to heterogeneity of clinical course, rate of disability progression and cognitive dysfunction, a patient's disease course cannot be anticipated in the majority of patients, at diagnosis. Valid biomarkers with predictive value for clinical outcome are important for effective therapy and disability prevention.
Our aim is to identify biomarkers that would predict advance to the neurodegenerative stage of the disease (accumulation of motor and cognitive disabilities). We recently found that the co-inhibitory receptors, TIM-3 and LAG-3 expression levels at disease onset, together with paraclinical parameters correlate with MS motor disability, assessed by Expanded Disability Status Scale (EDSS).
The current proposal will examine whether circulating biomarker levels at diagnosis (collected in 2008-2011) can predict 10 years' cognitive impairment and brain atrophy in 40 MS patients (patients either mild or severe disease outcome will participate). In addition, in a separate group of patients (n=20) that underwent cognitive assessment at diagnosis, we will analyze if circulating blood biomarkers, together with brain volume change and cognitive assessment, may enable to build a predictive model of individual 10 year disease outcome. |
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4 .
Orit Elyon
Ariel University, Health Sciences
Extending haptic sense: Psychophysics and therapy method based on the “Mudra Inspire” system
|
| The ease with which healthy individuals hold and lift objects without dropping or damaging them is not reflected in upper limb (UL) amputees with grip prosthesis or any other patient group with finger- grip disabilities (e.g. stroke patients, cervical cord injured patients.)
The proposed study is designed to develop training methods for these tasks, based on innovative technology.
The “Mudra-Strap” ®, developed by “Wearable Devices”, identifies finger movements and measures of force elicited between defined fingers by receiving the neural activating signals from the nerve supply of individual fingers via embedded sensors within the wrist strap. The systems’ high sensitivity enables detection of single motor-neuron signals.
Psychophysical studies of visual/auditory modalities provided mathematical models of transformationfunctions between physical light/tone features, and their subjective perception. Haptic sense has remained a neglected modality. Robotic and virtual reality interfaces have elicited the development of remote operating by “gestures” and haptics; “Mudra-inspire” presenting one of the most advanced devices.
We propose utilizing this technology in two study phases: 1 – Psychophysics of haptic-sense: detecting transformation-functions of finger-grip-force-skills in healthy participants. 2 – Developing a therapeuticrehabilitation program based on this technology and visual-feedback, for UL amputees, incomplete spinal cord lesions, stroke patients and other finger-grip disabled persons. |
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5 .
Sveta Fichman
Hadassah Academic College, Jerusalem, Hadassah Academic College, Jerusalem
Stuttering and bilingualism: Cross linguistic aspects
|
| Developmental stuttering affects 5% of children in preschool, and its life-long effects on academic, social, and emotional wellbeing are well-known. In bilingual children, stuttering is manifested by dysfluency in both languages, but research on uniquely bilingual features of stuttering and on cross-linguistic differences and similarities is very limited. In the assessment of stuttering, Speech-Language Pathologists are guided by speech norms developed for monolingual English-speaking children, which are not adjusted for bilingual speech. The current proposal is designed to: i) identify unique bilingual features of stuttering; ii) explore cross-linguistic manifestation of stuttering; and iii) study the impact of language proficiency on speech disfluencies in bilingual preschool children who stutter. The first goal will be achieved by comparing frequency of disfluencies in English-Hebrew bilingual children who stutter and two groups of monolingual children who stutter (monolingual speakers of English and Hebrew). A second goal will be addressed by comparing the frequency, type and loci of disfluencies across the two languages, within-subject comparisons for bilinguals and between-subject comparisons for monolinguals. Finally, the relationship between language proficiency (in both languages for bilinguals) and frequency of disfluencies will be assessed in children who stutter. |
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6 .
Tal Krasovsky
University of Haifa, Physical Therapy
Neural and behavioral correlates of complex walking in people with anxiety disorders
|
| Objective: Anxiety is one of the most prevalent mental health disorders, with debilitating symptoms causing avoidance and decreased quality of life. The link between anxiety and balance is ubiquitous throughout the life span, resulting in a higher fall risk for people with anxiety disorders. However, understanding of central control of mobility, and specifically walking in people with anxiety, is still limited. This proposal examines the neural and behavioral correlates of complex walking performance in people 'Mth anxiety. Methods: Ninety people aged 40-65 will be recruited, N=60 clinically-diagnosed with anxiety disorder and N=30 contols. Participants will perform single- and dual-task walking trials (counting backwards (cognitive) or texting on a mobile phone (visuomotor)) and their task performance as well as prefrontal cortex (PFC) activation will be measured using behavioral and neural (functional near infrared spectroscopy) markers. People with anxiety disorders are hypothesized to walk slower and in a less stable manner and to demonstrate less PFC activation, due to reduced inhibitory PFC control. It is further hypothesized that the ability of anxious individuals to perform visuomotor dual-task walking will be reduced due to increased visual dependence. Impact: A better understanding of central mobility confrol can identify potential targets for individualized balance and fall prevention programs for people with anxiety |
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7 .
Tzuri Lifschytz
Hadassah Hebrew University Medical Center, Biological Psychiaty Lab
Maternal immune activation (MIA) combined with under expression of the Abelson-helper intergration site 1 (Ahi1) gene as risk factors to develop schizophrenia-related phenotypes, and the beneficial effect of preventive of early antipsychotic treatment on these phenotypes.
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| Schizophrenia, one of the most devastating forms of mental illness, causes severe human suffering and has significant societal impact. Understanding the complex interactions between genetic vulnerability and environmental stressors is an important challenge. Advances in this understanding could be pivotal in the process of developing new and more effective treatments. In this research we will evaluate the biological effects of the combined occurrence of genetic vulnerability - reduced expression of the Abelson Helper Integration Site 1 (Ahi1), a gene whose under-expression is putatively associated with schizophrenia - and prenatal exposure to maternal immune activation (MIA). We will further study the prevention of these effects by antipsychotic pharmacotherapy. The Ahi1 gene was found to be associated in humans with increased susceptibility to schizophrenia and mutant mice heterozygous for a knockout mutation of this gene (Ahi1+/-) were shown to display aberrant behavioral responses compared to wild type (Ahi1+/+) mice. In this project, we will first determine the optimal time point during pregnancy in which MIA (Poly I:C model) should be implemented, then we will study the effects of the a combination of MIA and reduced Ahi1 expression on schizophrenia-like behavioral, imaging, histological and molecular phenotypes. Thereafter we will study the efficacy of early pharmacological intervention (the antipsychotic drug clozapine) in preventing these effects. Our findings could further understanding of the pathogenesis of schizophrenia, the role Ahi in susceptibility and of the justification for prophylactic treatment with antipsychotic drugs in young people at high genetic risk for the disorder. |
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8 .
Smadar Ovadia-Caro
University of Haifa, Cognitive Sciences
Developing novel, connectivity-based tDCS stimulation protocols to enhance the effects of visuomotor prismatic adaptation.
|
| Unilateral neglect is a brain disorder where patients are unable to orient, respond to, or report stimuli in the contra-lesional space. Prismatic adaptation (PA) – a visuomotor adaptation task that induces a visual shift - is a commonly used rehabilitation technique in unilateral neglect patients, aimed at re-balancing spatial attention. Although the behavioural effects of PA are well documented, its mechanism of action, even in healthy subjects, is still debatable. In addition, it is unclear whether it is possible to further augment PA effects, and thus promote long-term clinical benefits. We propose here to use fMRI connectivity to study the underlying neural mechanism associated with PA in healthy subjects, and identify relevant connections mitigating its effects at the whole-brain level. We will further use transcranial direct current stimulation (tDCS) to augment the effects of PA by targeting these specific connections. The suggested project is aimed at the long-term goals of prompting our understanding of PA mechanisms and devising stimulation protocols that can be later-on tested in unilateral neglect patients. |
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9 .
Noam Weinbach and Noga Cohen
University of Haifa, Psychology
How emotion regulation strategies influence the physiological reaction to food in women with Bulimia nervosa.
|
| Bulimia nervosa (BN) is a psychiatric disorder characterized by recurrent episodes of binge eating followed by compensatory behaviors. Understanding the mechanisms that underlie bulimic symptoms may improve evidence-based interventions for BN. Research has shown that the use of maladaptive emotion regulation strategies and alterations in autonomic nervous system activity may serve as risk factors for bulimic symptoms. The goal of the current research is to assess the causal role played by emotion regulation strategies in modulating physiological reactions to food in patients with BN. In the study, patients with BN and a control group of women with high body dissatisfaction will complete tasks that include rumination induction (dwelling on symptoms of distress) and reappraisal induction (reinterpreting a situation to make it feel less negative). During the tasks, participants’ physiological response to high- and low-calorie food images will be monitored via pupil size. Additionally, participants' desire to eat will be assessed via self-report. The expectation is that rumination will intensify the arousing impact of high-calorie foods and the desire to eat these foods, while reappraisal will reduce these responses. The results should shed light on the processes through which emotion regulation strategies heighten or reduce the risk of bulimic symptoms. |
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10 .
Sogal Zilcha-Mano
University of Haifa, Psychology
Neural mechanisms of expectancy based effects in psychotherapy
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| Background: Patient expectancy of therapeutic improvement is associated with psychotherapy efficacy, but its mechanisms are poorly understood. The proposed study will employ a novel trial design that for the first time manipulates expectancy in psychotherapy with integrated functional magnetic resonance imaging (fMRI) to examine neural mediators of expectancy.
Method: One hundred and twenty outpatients with major depressive disorder (MDD) will participate in a randomized controlled trial, assigned to high- vs. low-expectancy conditions before entering 8-week therapeutic sessions. fMRI scans will be acquired before and after the expectancy manipulation (before the start of treatment), while participants perform a masked emotional face task. We will investigate the neural signature underlying expectancy effects in psychotherapy, testing whether normalization of the amygdala hyper-activation in response to sad stimuli significantly mediates the effect of expectancy manipulation on treatment response.
Implications: Results from this interdisciplinary study, the first randomized control trial designed to identify neural mechanisms of expectancy-based effects in psychotherapy, will identify pathways by which expectancy alters the course of MDD. Identifying such pathways can help elucidate some of the pathophysiology of MDD and the mechanisms of action of treatments, helping develop methods for optimizing expectancy effects and improving the treatment of MDD. |
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2019 - 2020
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First Year
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1 .
Uri Hertz
Haifa University, Department of Cognitive Sciences
Motivations for information sharing in social anxiety disorder.
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| Being asked to give an advice can serve as an opportunity for an individual to increase his social status, as it allows him to share his unique point of view, but it also conveys a social risk if his perspective turns out to be wrong. People suffering from social anxiety disorder (SAD), the most common anxiety disorder, are characterized by social avoidance behaviour and increased sensitivity to evaluation by others which is at the heart of information sharing. While some models provided a cognitive description of SAD, experimental evaluation of the motivational basis of SAD, is lacking. In this proposal I built on my previous investigation of neural and cognitive mechanisms of social influence (Hertz et al. 2017), to study the social motivation basis of SAD. I will examine participants diagnosed with SAD while playing an advice-giving task. I will measure social motivations using explicit measures, such as the willingness to exert effort to achieve social = goals. In addition, I will use computational modeling and model-based neuroimaging to evaluate neural signals associated with task related rewards. The results from this project will provide a computational-mechanistic model of the motivational basis of SAD, which could be used for the development of new treatment protocols and diagnostic tools. |
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2 .
Maria Lev
Bar Ilan University, School of Optometry & Vision Science, Life Sciences,
Effect of medications on visual processing and perceptual learning in ADHD participants.
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| Attention deficit hyperactivity disorder (ADHD) is characterized by inappropriate levels of inattention, hyperactivity, and impulsivity; It is a very common neurobehavioral disorder in children and in adults.
The symptoms may be linked to dopamine synaptic modulation, which is involved in the reward system and in learning. Stimulant medications are the most common treatment for ADHD and have been shown to be effective in improving classroom manageability rather than in improving academic performance.
Our working hypothesis is that ADHD involves an atypical learning process and impaired visual processing. Thus, we seek to explore whether medications affect visual learning and to determine whether the visual processing is normal. ADHDs and matched controls will undergo a thorough assessment including psychiatric assessments, followed by a wide-range investigation of visual functions.
Our preliminary results indicate that there is an atypical pattern of learning in ADHD, a high degree of crowding, and reduced collinear facilitation. The impairments cannot be attributed to inattentional aspects. Thus, ADHD adults exhibit a pattern of results similar to that of young children. Therefore, revealing the nature of the impairments in ADHD can pave the way to improved treatment’s efficacy, offering optimal phase for medication intervention, thus improving the lives of ADHDs. |
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3 .
Moran Rubinstein
Tel Aviv University, Sagol School of Neuroscience
Identification of early behavioral deficit in Dravet Syndrome.
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| Dravet syndrome (Dravet) is intractable childhood-onset epilepsy. Following the onset of seizures, Dravet patients develop cognitive deterioration leading to severe mental retardation, hyperactivity, autistic-like behaviors and ataxia. The underlying genetic defect is genetic mutations of the SCN1A gene. Dravet diagnosis is usually confirmed following the presentation of severe developmental delay, around two years of age. By that time Dravet patients have had countless spontaneous seizures and multiple episodes of status epilepticus, which are likely to contribute to the poor cognitive prognosis. We propose to develop novel early diagnostic tools, able to predict Dravet before the presentation of developmental delay. Utilize two SCN1A mutant mouse models, with varying severity of epilepsy, comparing their performance in multiple behavioral tests, together with in vivo and ex vivo electrophysiological recordings, we will identify the onset of each of the associated comorbidities. Ultimately, our results will provide a novel, early diagnostic tool that can confirm diagnosis of Dravet at the onset of epilepsy. Prompt and aggressive treatment might improve the cognitive outcome of Dravet patients. |
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4 .
Shai Sabbah
Hebrew University, Department of Medical Neurobiology
Dissecting brain circuits that mediate a direct effect of light on mood.
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| Light impacts mood in ways we are only beginning to recognize. Although phototherapy is being used successfully, we know shockingly little about the mechanisms mediating the effects of light on mood. The recent demonstration that a novel retino-thalamo-frontocortical (RTFC) pathway plays a key role in the induction of depression by abnormal lighting places us in a unique position to resolve this mystery. Beyond its key role in linking light to mood, virtually nothing is known about the pathway’s synaptic input or broader behavioral significance. I recently found that light intensity directly modulates frontal cortex activity in mice and humans. Here, I propose to further explore this system and test the hypothesis: depression is induced when there is a mismatch between the amount of light in the environment and the amount predicted by the circadian clock. My aims are to: (1) elucidate the ability of the RTFC pathway to carry information about the ambient light intensity, an essential property if it is to detect a mismatch between lighting and circadian signals; and (2) explore the effect of abnormal lighting on mood and activity in the RTFC pathway. The mechanistic insights obtained will promote the development of treatments for light-dependent mood disorders. |
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5 .
Alon Shamir
The Technion, Faculty of Medicine
The impact of maternal immune activation (MIA) on the neuregulin-ErbB signaling in an animal model and in Schizophrenia patients.
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| Maternal infection during pregnancy is associated with a higher incidence of mental disorders, in general, and in schizophrenia, in particular, in the offspring in later life. However, it is unclear how this stimulus results in neurological and behavioral abnormalities that emerge at different stages of life. Given the accumulating evidence of the role played by the ErbB signaling pathway in embryonic brain development, in the biology of the dopaminergic and GABAergic systems and in schizophrenia, the hypothesis of the current proposed project is that the ErbB pathway is associated with neurodevelopmental mechanisms underlying the pathogenesis of neuro-inflammation-based neurodevelopmental diseases including schizophrenia. In the proposed study, we wish to investigate the impact of maternal immune activation (MIA) at a late gestational time point on the expression and function of the ErbB and the dopamine D2 signaling pathways across the lifespan of the offspring. Specifically, the project will focus on the underlying spatial and temporal alterations of these pathways. The project will also address the question whether changes in the ErbB signaling modulate proinflammatory markers release and expression in brain-immune cells in rodents and in microglia-like cells derived from schizophrenia patients and healthy controls. It is anticipated that the results of the current proposal will shed new light on the neurodevelopmental vulnerability induced by MIA and will offer a novel biomarker and/or treatment target for neurodevelopmental conditions of schizophrenia. |
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6 .
Ido Tavor
Tel Aviv University, Department of Anatomy
A rush of blood to the head – can we increase our brain’s capacity for neuroplasticity By improving the brain’s blood supply?
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| Neuroplasticity, our brain’s capacity to change in reaction to stimuli, is crucial for normal cognition1.
Vascular dementia, cognitive impairment and stroke are medical diagnoses that take time to evolve and erupt. Blood vessel inflammation and clogging begin decades before these diseases manifest2,3. Early detection of cerebrovascular pathology could help treat and prevent these horrible diseases.
Recently, we demonstrated that short-term learning-related gray-matter changes can be detected using diffusion MRI, providing a novel objective biomarker for plasticity in-vivo4. Our study aims to use this biomarker in order to detect early cerebrovascular changes.
We study a unique human model - patients with severe Carotid Artery Stenosis (CAS) who have compromised blood flow to their brain which puts them at risk of stroke and cognitive impairment5–9. They undergo carotid artery stenting which restores brain blood flow, improves cognition and prevents strokes10–13.
We hypothesize that compromised blood flow diminishes brain tissue’s learning-related plasticity. We employ diffusion MRI to investigate CAS patients’ learning-related plasticity measures in response to a cognitive task, before and after carotid artery stenting. Increased plasticity following vascular repair would support a tight link between blood supply and neuroplasticity, and may provide a novel approach for early diagnosis of cerebrovascular conditions. |
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Second Year
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1 .
Roee Admon
University of Haifa, Psychology
Towards enhancement of stress resiliency: Facilitating cognitive and emotional function under stress in humans via Upregulation of mineralocorticoid receptors.
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| Stress exposure may carry profound, often detrimental, effects on cognitive and emotional function that may last long after the stress has terminated, and, for some individuals, may result in psychopathology. In recent years, ample preclinical and clinical studies highlighted a critical role for mineralocorticoid receptors (MR) in mediating adequate stress response. The current study will test, for the first time, whether exogenous upregulation of MR can facilitate cognitive and emotional function under stress in humans, thus enhancing stress resiliency. For that, 120 healthy participants will be randomly assigning via a 2×2 double-blind, placebo-controlled design, into four experimental groups: receiving either placebo or a single dose of the MR agonist fludrocortisone (0.5mg), and undergoing a psychological stress induction or a non-stressful control task. Participants’ cognitive and emotional function under stress (or no-stress) will be assessed via designated tasks. We hypothesize that stress will impair cognitive and emotional function yet that MR upregulation would counter such effects, yielding enhanced stress resiliency. Given the ubiquity of stress in military and civilian settings and the importance of adequate cognitive and emotional function in maintaining quality of life and mental health, improving cognitive and emotional resiliency to stress may carry prominent societal and clinical implications. |
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2 .
ran Bar-Kalifa
Ben Gurion University, Psychology
Capitalization deficits in the intimate bonds of individuals with social anxiety: A biopsychosocial model of challenge and threat.
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| Despite the inherent interpersonal nature of social anxiety (SA), a surprisingly sparse literature addresses the interpersonal processes occurring within the committed romantic relationships of SA individuals. The current proposal aims to begin filling this gap, by focusing on deficits among individuals with SA in one key relational process – capitalization, defined as the receipt of responsive reactions from one’s partner when disclosing personal positive experiences. Specifically, using the framework of the biopsychosocial model of challenge and threat, I suggest that due to their emotional suppression, limited selfdisclosure, and fear of any social (positive or negative) feedback, individuals with SA exhibit a threat physiological response (i.e., the simultaneous activation of the SAM and HPA axes) when involved in capitalization interactions. As a result, they and their partners are caught in maladaptive dyadic transactions, missing the opportunity to harness the myriad documented relational and personal benefit associated with adaptive capitalization processes. To test this prediction, 100 romantically involved couples will be observed while one partner discloses a recent positive experience. Partners’ cardiovascular activity and cortisol levels will be monitored during the dyadic interaction. I expect that the results of this study will help practitioners address deficits in the intimate relationships of SA individuals. |
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3 .
Ravid Doron
The Open University, Education & Psychology
A Herbal treatment with a fast-onset anxiolytic effect
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| Try to imagine you have pill that can disappear your depression after few hours. This proposal tries to do the natural step for this future. Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for anxiety. Nevertheless, they are characterized by low success rate and slow onset. Adverse side effects and delay in clinical response might be critical and may reduce patients’ adherence to therapy. Thus, there is a pressing need for fast onset anxiolytics with minimal side-effects. We have recently found that 3-week treatment with the Shan-zha herb effectively reduced anxiety-like behavior while precluding sexual dysfunction and weight gain. However, Shan-zha’s anxiolytic effect was not immediate. Here, we propose the Uncaria Rhynchophylla (Japanese herb; JH) herb as a candidate treatment that can hasten the effect of herbal and conventional anxiolytics. The aim of the current research is to examine the anxiolytic effect’s temporal profile as well as side-effects induced by JH in combination with Shan-zha and SSRIs. Additionally, we aim to examine the mechanisms underlying the anxiolytic effect induced by the combined treatments. We found that JH treatment in combination with our novel herbal treatment (of which Shan-zha is the dominant component) and the SSRI induced fast-onset and sustained anxiolytic effect |
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4 .
Yafit Gabay, Avi Mendelsohn
University of Haifa, Special Education Department & Neurobiology Department
Exploring the role of feedback timing on acquisition and consolidation Of procedural learning in ADHD
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| Attention-Hyperactivity Deficit Disorder (ADHD) has been associated primarily with executive function deficits. Emerging findings suggest, however, that procedural feedback-based learning may be compromised as well. To this effect, we recently showed that feedback-based procedural learning is selectively impaired in ADHD, results that coincide with dopaminergic alterations associated with ADHD. Key questions, however, remain unresolved, among which are the learning conditions that may improve procedural learning skills in ADHD, and how learning conditions might affect long-term consolidation of skills over time. Using behavioral and neuroimaging tools, we propose a study that examines feedback-based procedural learning during conditions that engage procedural and explicit learning systems to different degrees, depending on immediate and delayed feedback timing, respectively. This will be examined across acquisition and long-term retention, thereby investigating how consolidation is affected in ADHD. Our preliminary results show that immediate, but not delayed feedback harms learning in ADHD, emphasizing the importance of tailoring learning conditions that favor the recruitment of explicit learning systems. Understanding how different feedback settings may influence the learning and consolidation of procedural learning will advance our understanding of the nature of ADHD and will direct future evidenced-based approaches to support efficient learning.
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5 .
Itai Horowitz
Rambam Medical Center, Child and Adolescent Psychiatry
Dynamic brain patterns in youths with ADHD and the effects of Methylpehindate: An EEG connectivity study.
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| Recent studies have provided evidence of distinct electroencephalography (EEG) signature in ADHD. To date only local EEG reponses are clinically measured for diagnosis and treatment with moderate success, whereas integrative global-network EEG analysis has not yet been applied for ADHD management. Global-network analysis integrates diverse EEG parameters across time and space and thus unifies neurobiological variables. Here, we aim at characterizing global-network dynamics associated with the clinical aspects of ADHD in children and youth and the normalizing effects of stimulant on these network dynamics. EEG will be measured during the execution of cognitive tasks before and after methylphenidate treatment in a doubleblind placebo-controlled crossover study. We conducted a preliminary pilot study with a single cognitive task which demonstrated a significant difference between methylphenidate vs placebo on network metrics in frontal region. Clustering coefficient measured after task restest was normalized after methylphenidate. We hypothesize that global network metrics in youth with ADHD will differ from healthy subjects in specific time windows. Furthermore, we hypothesize that these network metrics will show normalization after methylphenidate. Such novel translational approach can lead to the characterization of global-network patterns related to the symptoms of ADHD and to the effects of treatment. Our proposed global analysis may offer an integrative framework for the numerous well-established but fragmented ADHD spectral EEG findings and develop a neuroscientific diagnostic platform, as well as ways to assess treatment response. |
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6 .
Amit Lotan
Hebrew University, Psychiatry Hadassah Medical Center
Hebrew University
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| Based on data gathered and analyzed so far, in the 2nd part of the project we intend to perform convergent studies in both mice and humans aimed at validating the hypotheses outlined above. More specifically, we would like to assess more directly whether adverse childhood events (ACEs) indeed bring about long-lasting resistance to the salutary effects of FGF2 on the heart, and if so, is it mediated via post-natal methylation, and consequent underexpression, of the FGFR1 receptor. To this end, we plan to conduct the following studies:
Follow-up of the same cohort – as outlined above, following recruitment of patients presenting with STEMI, we focused on 18 patients with MDD and 18 matched controls. We measured serum levels of relevant growth factors, correlated these with cardiac markers (CPK and ejection fraction at discharge) and tested whether depression and/or self-reported childhood trauma moderated these relationships. As patients have been recruited during July 2014 – December 2017, long-term follow-up should now be feasible. Specifically, we intend to contact these 36 individuals, and obtain updated data relating to subsequent coronary events. Based on these data, we will calculate survival plots, and test whether, FGF2, depression and childhood trauma, alone or in combination, could predict long-term outcome. By doing so, we intend to further explore the long-term relevance of FGF2 signaling in the context of early adversity and ischemic heart disease. |
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7 .
Gilly Wolf
Hadassah Hebrew University Medical Center, Biological Psychiatry Lab
Effects of cerebrovascular insufficiency on iron deposition and ferroptosis: Affective and cognitive aspects, lesions to the deep white matter, neurogenesis and glial activation.
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| Increased human lifespan has been accompanied by elevated risk for the development of neurodegenerative and neuropsychiatric disorders of late life. Cerebrovascular disease is a common cause of age-related cognitive impairment and dementia (known as Vascular Dementia [VaD]). In this disorder, cerebral vessel disease results in cerebral hypoperfusion which causes white matter lesions (WMLs). Currently, there are no specific treatments for VaD. Given the current treatment gap, the investigation of animal models is important. Recently, a mouse model of chronic cerebral hypoperfusion following bilateral carotid artery stenosis (BCAS) was introduced. However, direct mechanistic links explaining how hypoperfusion triggers oligodendrocyte death have yet to be found. Excess iron is a potent source of oxidative damage, possibly through ferroptosis (iron-dependent cell death). Iron deposition has been demonstrated in several neurodegenerative disorders, suggesting it is most likely also a factor in VaD. The current study aims to address the hypothesis that cerebral hypoperfusion induces iron elevation and ferroptosis, resulting in cognitive impairment. This hypothesis will be tested by combining the BCAS procedure, cognitive-affective phenotyping, structural imaging and laser ablationinductively coupled plasma-mass spectrometry. The results will improve our mechanistic understanding of VaD and provide a basis for developing novel treatments of ferroptosis inhibitors. |
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8 .
Florina Yuzphosbski
Ben Gurion University, Psychology
The role of puberty and sex hormones in autism symptomology.
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| Autism Spectrum Disorder (ASD; autism) is a relatively frequently occurring neurodevelopmental disorder associated with difficulties in social communication and restrictive interests and behaviors. Boys are diagnosed with autism more often than girls (4:1 ratio), and prenatal exposure to testosterone has been implicated in the etiology of autism. Most of the research in the area has focused on early manifestations of autism and the biological mechanisms that govern them, and later stages of development have been largely neglected. Even though autism is early appearing, it changes throughout development and 3-25% of children outgrow the diagnosis, while others may improve, deteriorate or remain stable. The current proposal aims to investigate puberty as a critical developmental period, characterized by hormonal surges, physical changes, and accompanied by behavioral transformation. More specifically, I will measure puberty stages and circulating levels of testosterone, estradiol and dehydroepiandrosterone (DHEA) in 160 youths (10-16 year-olds) with and without an autism diagnosis. In addition, autistic symptoms and social cognition will be rigorously assessed in order to unravel the relationship between autism-specific biological and behavioral changes during a hitherto neglected, but crucial period of development. |
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2018 - 2019
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First Year
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1 .
Mor Nahum & Itai Berger
Hebrew University Hadassah Medical Center, School of OT, Faculty of Medicine, Hebrew University & Pediatrics
Neural correlates and everyday manifestation of emotion dysregulation in youth with ADHD
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| Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder afflicting 5-7% of adolescents. Emotion dysregulation (ED), inability to modulate emotional experience in order to reach one's goals, is highly prevalent in ADHD. Central theories propose that ED stems from abnormal executive control (EC), which cause reduced moderation of emotion by top-down processes. However only a few studies to date have examined the link between ED and EC directly. The goal of the current proposal is to further understand the mechanisms of ED in ADHD by studying the interaction between emotion and EC in ecological settings. We will measure emotional
interference using EEG, and continuously track emotional states and EC performance in real-life using a novel mobile application. Specifically, we propose to: (1) Identify the neural correlates of emotional interference; (2) Profile the temporal variability of emotional states and of EC performance in ecological settings; (3) Measure the dynamics of ED in ecological settings; and (4) Determine the predictability of neural-based profiling on ED in daily life. In addition to advancing our knowledge regarding the ED mechanism and its manifestation in ecological context, this project could potentially lead to the development of cost-effective and ecological assessment and treatment tools for ADHD. |
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2 .
Eran Bar-Kalifa
Ben-Gurion University of the Negev, Psychology
Capitalization deficits in the intimate bonds of individuals with social anxiety: A biopsychosocial model of challenge and threat
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| Despite the inherent interpersonal nature of social anxiety (SA), a surprisingly sparse literature addresses the interpersonal processes occurring within the committed romantic relationships of SA individuals. The current proposal aims to begin filling this gap, by focusing on deficits among individuals with SA in one key relational process – capitalization, defined as the receipt of responsive reactions from one’s partner when disclosing personal positive experiences. Specifically, using the framework of the biopsychosocial model of challenge and threat, I suggest that due to their emotional suppression, limited self-disclosure, and fear of any social (positive or negative) feedback, individuals with SA exhibit a threat physiological response (i.e., the simultaneous activation of the SAM and HPA axes) when involved in capitalization interactions. As a result, they and their partners are caught in maladaptive dyadic transactions, missing the opportunity to harness the myriad documented relational and personal benefit associated with adaptive capitalization processes. To test this prediction, 100 romantically involved couples will be observed while one partner discloses a recent positive experience. Partners’ cardiovascular activity and cortisol levels will be monitored during the dyadic interaction. I expect that the results of this study will help practitioners address deficits in the intimate relationships of SA individuals. |
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3 .
Segev Barak
Tel Aviv University, School of Psychological Sciences& Sagol school for Neuroscience
Role of fibroblast growth factor receptor 1 (FGFR1) in alcohol use disorder
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| Alcohol use disorder has severe impacts on society, however, pharmacotherapy is very limited. Fibroblast growth factor 2 (FGF2) plays a role in the development and maintenance of dopaminergic neurons, and we recently characterized a positive feedback loop between alcohol and FGF2 in the dorsomedial striatum (DMS). Thus, alcohol increases Fgf2 mRNA expression, and FGF2 infusion enhances excessive alcohol consumption1, whereas blocking FGF2 activity in the DMS reduces alcohol consumption1. FGF2 binds mainly to FGF receptor 1 (FGFR1)2, which is highly expressed in the striatum pathways3,4. Moreover, our preliminary results show that alcohol exposure increases the expression of Fgfr1 in several striatal brain regions, including the DMS. Thus, the present study aims to elucidate the role of FGFR1 in alcohol-drinking behaviors, and to characterize the brain circuitry that
control the FGFR1-alcohol interaction. Specifically, we aim to 1. Determine whether systemic and/or focal administration of FGFR1 antagonists suppresses alcohol drinking behaviors. 2. Identify the striatal cellular pathway that mediates the effects of FGFR1 activation on alcohol-drinking behavior. The project is expected to shed light on the role of FGFR1 in alcohol use disorder, and to promote development of new potential therapeutic targets for this devastating disorder. |
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4 .
Ravid Doron
The Academic College - Tel Aviv Jaffa, School of Behavioral Sciences
An herbal treatment with a fast-onset anxiolytic effect
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| Try to imagine you have pill that can disappear your depression after few hours. This proposal tries to do the natural step for this future. Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for anxiety. Nevertheless, they are characterized by low success rate and slow onset. Adverse side effects and delay in clinical response might be critical and may reduce patients’ adherence to therapy. Thus, there is a pressing need for fastonset anxiolytics with minimal side-effects. We have recently found that 3-week treatment with the Shan-zha herb effectively reduced anxiety-like behavior while precluding sexual dysfunction and weight gain. However, Shan-zha’s anxiolytic effect was not immediate. Here, we propose the Uncaria Rhynchophylla (UR) herb as a candidate treatment that can hasten the effect of herbal and conventional anxiolytics. The aim of the current research is to examine the anxiolytic effect’s temporal profile as well as side-effects induced by UR in combination with Shan-zha and SSRIs. Additionally, we aim to examine the mechanisms underlying the anxiolytic effect induced by the combined treatments. We found that UR treatment in combination with our novel herbal treatment (of which Shan-zha is the dominant component) and the SSRI induced fast-onset and sustained anxiolytic effect. |
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5 .
Yafit Gabay & Avi Mendelsohn
University of Haifa, Sagol Department of Neurobiology, Brain and Learning Disabilities
Exploring the role of feedback timing on acquisition and consolidation of procedural learning in ADHD
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| Attention-Hyperactivity Deficit Disorder (ADHD) has been associated primarily with executive function deficits. Emerging findings suggest, however, that procedural feedback-based learning may be compromised as well. To this effect, we recently showed that feedback-based procedural learning is selectively impaired in ADHD, results that coincide with dopaminergic alterations associated with ADHD. Key questions, however, remain unresolved, among which are the learning conditions that may improve procedural learning skills in ADHD, and how learning conditions might affect long-term consolidation of skills over time. Using behavioral and neuroimaging tools, we propose a study that examines feedback-based procedural learning during conditions that engage procedural and explicit learning systems to different degrees, depending on immediate and delayed feedback timing, respectively. This will be examined across acquisition and long-term retention, thereby investigating how consolidation is affected in ADHD. Our preliminary results show that
immediate, but not delayed feedback harms learning in ADHD, emphasizing the importance of tailoring learning conditions that favor the recruitment of explicit learning systems. Understanding how different feedback settings may influence the learning and consolidation of procedural learning will advance our understanding of the nature of ADHD and will direct future evidenced-based approaches to support efficient learning. |
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6 .
Dana Ekstein
Hebrew University, Neurology, Hadassah Medical Center
Games of Troy: Modulating neuroinflammation in epilepsy by targeting the cannabinoid system of monocytes
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| Epilepsy, affecting 1% of the population, is associated with impaired quality of life, increased risk of premature death, and psychiatric symptoms as comorbidity and as adverse events of medications, particularly in the 30% of patients with pharmacoresistance. The pathophysiology of epilepsy also involves non-neuronal components, specifically myeloid cells - microglia and peripheral monocytes that penetrate from the circulation and mediate focal neuroinflammation. The aim of this proposal is to investigate the function of the endocannabinoid system in epilepsy and the effects of this system on myeloid cells activity. We will study the profile of endocannabinoids in plasma, monocytes and brains of patients with drug-resistant epilepsy and in a well-established rodent model of epilepsy. We will then investigate ex vivo the effects of endocannabinoid manipulations on rodent and human myeloid cells, and the influences of such manipulated cells on the disease process in vivo. This study will pave the road to new approaches for treatment of epilepsy, aimed to overcome drug-resistance and to mitigate psychiatric symptoms. Beyond epilepsy, this research will contribute to the understanding of the endocannabinoids-dependent function of systemic and CNS myeloid cells, therefore promoting knowledge and eventually new therapeutic options for other neurological and neuropsychiatric diseases.
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7 .
Itai Horowitz
Beer Yaakov–Ness Ziona Mental Health Center, Department of Child & adolescent Psychiatry
Dynamic brain patterns in youth with ADHD and the effects of Methylpehindate: An EEG connectivity study
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| Many studies have provided evidence of distinct electroencephalography (EEG) signature in ADHD. To date only local EEG correlates are clinically applied for ADHD management with limited success. Recent global network analysis enables to integrate diverse EEG parameters across time and space and thus to unify neurobiological variables. Here, we aim at characterizing global-network dynamics associated with the clinical aspects of ADHD in youth and the normalizing effects of psychostimulant on these network dynamics. Preliminary findings of ADHD patients demonstrated a significant effect of methylphenidate on network metrics during task in frontal region. EEG will be thus measured during the execution of three cognitive tasks before and after methylphenidate treatment in a double-blind placebo-controlled crossover study. We hypothesize that global network metrics in youth with ADHD will differ from healthy subjects in specific time windows. Furthermore, we hypothesize that these network metrics will show normalization after methylphenidate. Such novel translational approach can lead to the characterization of global-network patterns related to the symptoms of ADHD and to the effects of treatment. Our proposed global analysis may further promote an integrative framework for the numerous well established but fragmented ADHD spectral EEG findings and enhance the developpment of a diagnostic platform. |
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8 .
Moshe Isserles
Hebrew University, Psychiatry, Hadassah Medical Center
Intramuscular Ketamine with Ultra-Brief Exposure for Treatment Resistant PTSD - Clinical Effects and fMRI Correlates
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| Post-traumatic stress disorder (PTSD) is an anxiety disorder that develops at the aftermath of trauma. About a third of those affected retain symptoms despite psychopharmacological and / or trauma focused psychological treatments. Ketamine, a widely-used anesthetic has shown promising results in treating depression, and recent evidence indicates that it might effectively treat patients suffering from PTSD. In the current study, we aim to test the preliminary efficacy and fMRI correlates of a single intramuscular sub-anesthetic dose of ketamine followed by exposure to a brief, individual trauma-narrative based script among 20 resistant PTSD patients. We intend to study the specific effect of this intervention on intrusive recollection scores as well as on reducing total PTSD symptom severity. Ketamine's potential mechanistic impact in modulating the reconsolidation of evoked traumatic memory traces and/or facilitating the extinction of the fear response will be investigated with fMRI before and after the ketamine-script administration. Resting state functional connectivity analysis and an emotional activation task will be utilized to search for baseline or treatment-emergent biomarkers of response.
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9 .
Amir Krivoy
Geha Mental Health Center, Psychiatry
Investigation of the role of glutamatergic mechanisms in response and resistance of schizophrenia patients to clozapine
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| Clozapine-resistant schizophrenia represents a subset of patients with the most pressing unmet need for therapeutic options. Data suggest that stratifying schizophrenia patients according to treatment response denotes distinct biological processes. In line with that, previous studies, as well as ours, link clinical response to dopamine-blocking agents with hyperdopaminergic states, while response to clozapine may be associated with hyperglutamatergic states.
In the current proposal, we wish to validate, in a comprehensive preclinical and clinical prospective longitudinal project, the possible association of clozapine response and glutamate. We will assess a cohort of patients before commencing clozapine treatment (as indicated) and following a substantial period of treatment by which response to the drug is clear. We will assess serum glutamatergic components as putative indicators for response. Complementary, we will attempt to decipher clozapine resistance mechanisms through a mouse model of the response to clozapine in a pharmacological model of schizophrenia, based on glutamate NMDA antagonism. We will compare the most treatment-resistant and the most treatment-responsive mice with regard to relevant biochemical and neuropathological assays. Identification of putative mechanisms and targets of clozapine response and resistance can enable development of novel therapeutic approaches for clozapine-resistant schizophrenia.
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10 .
Anan Moran
Tel Aviv University, Neurobiology
Revealing the primary abnormalities of ApoE4 and their role in Alzheimer’s disease using implicit memory tests
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ApoE4 is the most prevalent genetic risk factor of Alzheimer’s disease (AD), yet it
primary-impairments that lead to AD are not clear. A recent hypothesis suggests
vesicular transportation malfunction to be the culprit of ApoE4 impairment, which
implies ApoE4 primary-impairments are task-dependent, rather than location
(hippocampus) specific, and should be detected at early age in non-hippocampal
memory systems. To test this hypothesis we will check whether young transgenic
ApoE4 mice and rats are impaired in conditioned taste aversion (CTA) learning and
extinction; memory systems that are not hippocampus-dependent.
Preliminary behavior results have indeed confirmed our hypothesis showing severe
acquisition and extinction of CTA in transgenic ApoE4 mice and rats.
To further expose the underpinning of the ApoE4 impairments we will utilize a
combined molecular and electrophysiological approach in behaving ApoE4 mice and
rats. The molecular study will aim to portray the molecular deficits in the nuclei that
subserve CTA learning and extinction (primarily the gustatory cortex [GC] and the
basolateral-amygdala [BLA]) and compare them to known hippocampal aberrations.
The in-vivo electrophysiology recordings will test the synaptic rigidity caused by the
ApoE4 in the GC-BLA network. Better understanding the ApoE4 primaryimpairments
may promote early diagnosis and invention of new targeted treatments.
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11 .
Limor Shtoots
Interdisciplinary Center, Herzliya, School of Psychology
Enhancing Consolidation of Conceptual Learning via EEG Neurofeedback
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| Memory consolidation is the transformation over time of experience-dependent internal representations and their neurobiological underpinnings. Consolidation of newly formed memories is readily disrupted, but can it be enhanced? While sleep provides the most commonly studied framework for such consolidation processes, post-learning modulation of oscillatory brain activity may also impact on plasticity processes. Previous studies in which I was involved revealed that upregulating post-
learning theta power using EEG neurofeedback (NFB) significantly contributed to immediate and delayed procedural and episodic memory performance, since theta enhancement may provide optimal conditions for stabilization of new memories. A promising possibility is that these memory effects of NFB may also strengthen semantic memory. I will use NFB to enable young and older adult participants to selectively increase EEG theta power following semantic knowledge learning, and test their subsequent memory performance over time compared with control groups. If found effective, this intervention could benefit various memory-challenged populations, such as traumatic brain injury patients who may have sustained frontal lobe damage, as well as healthy older adults.
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Second Year
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1 .
Roee Admon
University of Haifa, Psychology
Towards enhancement of stress resiliency: facilitating cognitive and emotional function under stress in humans via upregulation of mineralocorticoid receptors
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| Humans’ response to stress involve a complex interaction of physiological and psychological
processes. Unfortunately, for a significant amount of the population stress exposure may lead to the
development of long-term mental illness. The current study will rely on extensive scientific work that
highlighted a specific endocrinological pathway as essential to maintain adaptive response to stress. To
this end, we will test whether upregulation of mineralocorticoid receptors via an acute pharmacological
manipulation may lead to improved cognitive and emotional function under stress among healthy
individuals. Taken together, our study may provide vital information towards the ultimate goal of
enhancing stress resiliency. |
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2 .
Adi Aran
Shaare Zedek Medical Center, Pediatrics, Pediatric Neurology unit
Cannabinoids for behavioral problems in autism spectrum disorder: A randomized, double-blind, placebo-controlled, three-arm crossover study
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| Background: It is very common for children and youth with autism spectrum disorder (ASD) to manifest
severe behavioral difficulties, including tantrums, noncompliance, aggression, and self-injury. Animal
studies and our clinical experience suggest a therapeutic role for cannabinoids in ASD.
Objective: To investigate the value of medical marijuana in cases of drug resistant disruptive behavior
associated with ASD.
Brief Study Design 120 participants with ASD and behavioral problems, will be randomly assigned to
receive: pure cannabinoids, whole plant extract or placebo.
After 12 weeks, each participant will be blindly assigned to receive one of the 2 remaining compounds
for another 12 weeks. |
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3 .
Ayelet Ben-Sasson
University of Haifa, Occupational Therapy, Faculty of Social Welfare and Health Sciences
Sensory over-responsivity in OCD as a factor of slow habituation
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| Individuals with obsessive compulsive disorder (OCD) suffer from irritating sensations, e.g. sensitivity to
noises, smells, or touch. This study will characterize sensory over-responsivity's (SOR) role in OCD and
examine its neurological basis.
SOR symptoms will be mapped in adults with or without OCD. Recording continuous skin conductance
during the presentation of bothering versus neutral sounds will test whether in OCD it takes longer to
get used to bothering sounds.
This study will help understand the underlying mechanism of these debilitating sensations, draw clinical
attention to SOR in OCD, and facilitate the design of objective sensory measures. |
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4 .
Bat-Sheva Hadad&Maya Benish-Weisman &Miriam Fink Lavi
University of Haifa, Faculty of Education; Brain Research Center
Perceptual sensitivity as the missing link in the relations between gene-environment interactions and anxiety
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| People differ in the amount of anxiety they develop as a response to adversity. Dozens of studies point
to ‘sensitive genes’, but who are these sensitive individuals, and how do they differ from others? We will
examine the perceptual profile of individuals with varied anxiety outcomes and determine how these
profiles are related to specific genetic makeup. Our findings will lead to an integrated perspective on
the interplay between gene-environment interactions (GXE) and perception in determining anxiety,
with the potential to be translated into perceptual markers that can later be used for early diagnosis in
populations at risk. |
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5 .
Amir Hadanny
Asaf Harofe Medical Center, Center for Hyperbaric Medicine & Research
The application of hyperbaric oxygen therapy for substance usage related cognitive impairment
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| Illicit drugs use can cause brain injury associated with cognitive function impairment. After drug use
discontinuation, cognitive dysfunction may remain in some. Patients after stroke and traumatic brain
injury improved significantly after high pressure (hyperbaric) and oxygen therapy (HBOT). We aim to
evaluate this therapy among drug users.
Three months following discharge from a rehabilitation institute (Kfar Izun), those with cognitive
problems (questionaire), will be further evaluated at Ashaf Harofe by using computerized cognitive
tests and brain imaging. Included patients will be treated by HBOT and re-evaluated post treatment.
This pilot novel non-invasive and safe intervention among drug-users have potental for helping millions |
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6 .
Liat Helpman
Tel Aviv Sourasky Medical Center, Psychiatric Research Unit
Neurofeedback as an adjunctive treatment for dissociation, flashbacks, and sleep disturbance for women with PTSD following childhood sexual abuse
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| Posttraumatic stress disorder (PTSD) following childhood sexual abuse (CSA) is a debilitating disturbance,
affecting mostly women and presenting with intrusive memories, traumatic dreams, flashbacks, and
dissociations. The current treatments are often less effective for chronic, CSA-related PTSD than for
other types of PTSD. We suggest adding neurofeedback, a non-invasive treatment training patients to
control the brain’s emotional response, to the usual treatment. We will test the effect of treatment on
symptoms, as well as brain function. We believe that this may prove to be a useful and effective means of
treating individuals who have not been sufficiently helped by existing interventions. |
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7 .
Eyal Kalanthroff
Hebrew University of Jerusalem, Psychology
Personalized inhibitory control training for compulsive behavior change
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| Obsessive-compulsive disorder (OCD) is a severe mental illness characterized by repetitive behaviors
that a person feels compelled to perform. It has been demonstrated that stimuli in the environment
can trigger the compulsive urge, perpetuating the OCD cycle. The main goal of the current proposal,
which is based on exciting pilot data, is to test a novel computerized training program to create an
association between OCD-related stimuli, which typically trigger the compulsive urge, and the brain
system responsible for stopping. The idea is that once this system is triggered, it will be easier for
patients to stop the compulsive urge. |
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8 .
Dina Safina
University of Haifa, The Institute for the Study of Affective Neuroscience
The role of hippocampal neurogenesis and neuroinflammation in
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| emotional complications of chronic pain Chronic pain is often associated with mood disorders. Being able
to reduce the emotional suffering of patients will contribute significantly to improving their condition.
We will examine potential mechanisms that may underlie emotional aspects of chronic pain: in particular,
inflammation and impaired generation of new neurons, since those processes were separately shown to
be associated with depression and chronic pain. However, whether these alterations cause emotional
complications is still unclear. Finding a causal-link between inflammation, reduced generation of neurons
and co-occurrence of depression and chronic pain will help to propose novel therapeutic targets for
managing “emotional pain”. |
| close |
|
|
|
9 .
Roy Salomon
Bar-Ilan University, Gonda Brain Research Center
The neurocognitive representation of the self in psychosis
|
| Psychosis includes many symptoms which indicate a confusion between the self and others. For example,
in passivity symptoms patients feel that someone else is controlling their actions. A fundamental
mechanism of self-other demarcation is sensorimotor prediction in which the brain compares the
predicted outcomes of actions with the real sensory consequences, and if they correspond the action is
attributed to the self. In this project we will test, using virtual reality and EEG how psychosis patients and
healthy controls attribute their own actions to themselves and how this relates to clinical symptoms and
the spread of information in the brain. |
| close |
|
|
|
10 .
Florina Uzefovsky
Ben Gurion University of the Negev, Psychology
The role of puberty and sex-hormones in autism symptomology
|
| Autism affects ~1% of children and is characterized by difficulties in social communication and
restrictive interests. Autism is more frequently diagnosed in boys than in girls, and sex-hormones such
as testosterone have a role in the underlying biology of autism. Puberty marks a period of hormonal
change, but its influence on autism is unclear. The proposed research will measure hormone levels
during puberty and investigate their relationship to symptoms of autism, and social-cognition. Findings
promise to unveil the effects of puberty on autism, and suggest possible intervention avenues at a
period of development that has not been studied thoroughly yet. |
| close |
|
|
|
11 .
Gilly Wolf
Hebrew University, Biological Psychiatry Laboratory, Hadassah Medical Center
Effects of cerebrovascular insufficiency on iron deposition and ferroptosis: Affective and cognitive aspects, lesions to the deep white matter, neurogenesis and glial activation.
|
| The dark side of increased average human lifespan is elevated risk of cerebrovascular disease in late life,
a common cause of age-related neurodegeneration and cognitive impairment that is termed vascular
dementia (VaD). Currently, there are no specific treatments for VaD. Moreover, the mechanism explaining
how hypoperfusion triggers VaD has to be addressed. Demonstrated in several neurodegenerative
diseases, high iron concentration in the brain may provide such mechanism. The current study tests
the hypothesis that hypoperfusion induces iron elevation, resulting in brain damage and cognitive
impairment. The results will improve the mechanistic understanding of VaD and provide a basis for
developing novel treatments. |
| close |
|
|
|
12 .
Adam Zaidel
Bar Ilan University, Gonda Brain Research Center
Multisensory integration of visual and vestibular cues for self-motion perception in Parkinson’s disease
|
| Parkinson's disease (PD) is classically characterized by its motor symptoms, which have garnered the
most research attention. However, sensory disturbances are also becoming recognized as a major part
of PD. But, sensory dysfunction is less observable, and can therefore go unnoticed if not tested directly.
Here we will investigate perception of self-motion in PD, and test whether multisensory information
from visual and vestibular cues is appropriately integrated. Results from this study will improve our
understanding of PD, particularly regarding gait and balance disorders, which are tightly related to
visual and vestibular perception, but not well understood or treated in PD. |
| close |
|
|
|
13 .
Inna Gaisler-Salomon
University of Haifa, Department of Psychology
Therapeutic potential of cannabinoids in a rat model of schizophrenia
|
| Social and cognitive deficits are a key component of schizophrenia (SZ) symptomatology but are poorly
addressed by currently available medications. Preliminary studies indicate that modulation of the
endogenous cannabinoid system (i.e., cannabis based treatment) may provide a novel treatment venue.
Here, we will determine whether enhancing endocannabinoids can reverse social and cognitive deficits
in male and female rats. This study will provide a putative mechanism for the effects of endocannabinoids
on prefrontal cortex function, which is disrupted in SZ, and provide insight into the development of
novel strategies for prevention and therapeutic interventions for SZ. |
| close |
|
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2017 - 2018
|
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|
First Year
|
1 .
Roee Admon
Psychology, University of Haifa
Towards Enhancement of Stress Resiliency: Facilitating Cognitive and Emotional Function Under Stress in Humans via Upregulation of Mineralocorticoid Receptors
|
| Humans response to stress involve a complex interaction of physiological and psychological processes. Unfortunately, for a significant amount of the population stress exposure may lead to the development of long-term mental illness. The current study will rely on extensive scientific work that highlighted a specific endocrinological pathway as essential to maintain adaptive response to stress. To this end, we will test whether upregulation of mineralocorticoid receptors via an acute pharmacological manipulation may lead to improved cognitive and emotional function under stress among healthy individuals. Taken together, our study may provide vital information towards the ultimate goal of enhancing stress resiliency. |
| close |
|
|
|
2 .
Adi Aran
Pediatrics, Pediatric Neurology unit, Shaare Zedek Medical Center
Cannabinoids for behavioral problems in autism spectrum disorder: A randomized, double-blind, placebo-controlled, three-arm crossover study.
|
| Background: It is very common for children and youth with autism spectrum
disorder (ASD) to manifest severe behavioral difficulties, including tantrums,
noncompliance, aggression, and self-injury. Animal studies and our clinical
experience suggest a therapeutic role for cannabinoids in ASD.
Objective: To investigate the value of medical marijuana in cases of drug resistant
disruptive behavior associated with ASD.
Brief Study Design 120 participants with ASD and behavioral problems, will be
randomly assigned to receive: pure cannabinoids, whole plant extract or placebo.
After 12 weeks, each participant will be blindly assigned to receive one of the 2
remaining compounds for another 12 weeks.
|
| close |
|
|
|
3 .
Ayelet Ben-Sasson
Occupational Therapy, Faculty of Social Welfare and Health Sciences, University of Haifa
Sensory over-responsivity in OCD as a factor of slow habituation
|
| Individuals with obsessive compulsive disorder (OCD) suffer from irritating sensations, e.g. sensitivity to noises, smells, or touch. This study will characterize sensory over-responsivity's (SOR) role in OCD and examine its neurological basis.
SOR symptoms will be mapped in adults with or without OCD. Recording continuous skin conductance during the presentation of bothering versus neutral sounds will test whether in OCD it takes longer to get used to bothering sounds.
This study will help understand the underlying mechanism of these debilitating sensations, draw clinical attention to SOR in OCD, and facilitate the design of objective sensory measures.
|
| close |
|
|
|
4 .
Bat-Sheva Hadad & Maya Benish-Weisman & Miriam Fink Lavi
Education, Brain Research Center, University of Haifa
Perceptual sensitivity as the missing link in the relations between gene-environment interactions and anxiety
|
| People differ in the amount of anxiety they develop as a response to adversity. Dozens
of studies point to ‘sensitive genes’, but who are these sensitive individuals, and how do they differ from others? We will examine the perceptual profile of individuals with varied anxiety outcomes and determine how these profiles are related to specific
genetic makeup. Our findings will lead to an integrated perspective on the interplay
between gene-environment interactions (GXE) and perception in determining anxiety,
with the potential to be translated into perceptual markers that can later be used for
early diagnosis in populations at risk.
|
| close |
|
|
|
5 .
Amir Hadanny
Center for Hyperbaric Medicine & Research, Asaf Harofe Medical Center
The application of Hyperbaric Oxygen Therapy for substance usage related cognitive impairment
|
| Illicit drugs use can cause brain injury associated with cognitive function impairment. After drug use discontinuation, cognitive dysfunction may remain in some. Patients after stroke and traumatic brain injury improved significantly after high pressure (hyperbaric) and oxygen therapy (HBOT). We aim to evaluate this therapy among drug users.
Three months following discharge from a rehabilitation institute (Kfar Izun), those with cognitive problems (questionnaire), will be further evaluated at Asaf Harofe by using computerized cognitive tests and brain imaging. Included patients will be treated by HBOT and re-evaluated post treatment. This pilot novel non-invasive and safe intervention among drug-users have potential for helping millions. |
| close |
|
|
|
6 .
Liat Helpman
Psychiatric Research Unit, Sourasky Medical Center Tel Aviv
Neurofeedback as an adjunctive treatment for dissociation, flashbacks, and sleep disturbance for women with PTSD following childhood sexual abuse
|
| Posttraumatic stress disorder (PTSD) following childhood sexual abuse (CSA) is a
debilitating disturbance, affecting mostly women and presenting with intrusive memories, traumatic dreams, flashbacks, and dissociations. The current treatments are often less effective for chronic, CSA-related PTSD than for other types of PTSD. We suggest adding neurofeedback, a non-invasive treatment training patients to control the brain’s emotional response, to the usual treatment. We will test the effect of treatment on symptoms, as well as brain function. We believe that this may prove to be a useful and effective means of treating individuals who have not been sufficiently helped by existing interventions.
|
| close |
|
|
|
7 .
Eyal Kalanthroff
Psychology, Hebrew University of Jerusalem
Personalized Inhibitory Control Training for Compulsive Behavior Change
|
| Obsessive-compulsive disorder (OCD) is a severe mental illness characterized by repetitive behaviors that a person feels compelled to perform. It has been demonstrated that stimuli in the environment can trigger the compulsive urge, perpetuating the OCD cycle. The main goal of the current proposal, which is based on exciting pilot data, is to test a novel computerized training program to create an association between OCD-related stimuli, which typically trigger the compulsive urge, and the brain system responsible for stopping. The idea is that once this system is triggered, it will be easier for patients to stop the compulsive urge.
|
| close |
|
|
|
8 .
Dina Safina
The Institute for the Study of Affective Neuroscience, University of Haifa
The role of hippocampal neurogenesis and neuroinflammation in emotional complications of chronic pain
|
| Chronic pain is often associated with mood disorders. Being able to reduce the
emotional suffering of patients will contribute significantly to improving their
condition. We will examine potential mechanisms that may underlie emotional aspects
of chronic pain: in particular, inflammation and impaired generation of new neurons,
since those processes were separately shown to be associated with depression and
chronic pain. However, whether these alterations cause emotional complications is
still unclear. Finding a causal-link between inflammation, reduced generation of
neurons and co-occurrence of depression and chronic pain will help to propose novel
therapeutic targets for managing “emotional painâ€.
|
| close |
|
|
|
9 .
Roy Salomon
Gonda Brain Research Center, Bar-Ilan University
The neurocognitive representation of the self in psychosis
|
| Psychosis includes many symptoms which indicate a confusion between the self and others. For example, in passivity symptoms patients feel that someone else is controlling their actions. A fundamental mechanism of self-other demarcation is sensorimotor prediction in which the brain compares the predicted outcomes of actions with the real sensory consequences, and if they correspond the action is attributed to the self. In this project we will test, using virtual reality and EEG how psychosis patients and healthy controls attribute their own actions to themselves and how this relates to clinical symptoms and the spread of information in the brain.
|
| close |
|
|
|
10 .
Florina Uzefovsky
Psychology, Ben Gurion University of the Negev
The role of puberty and sex-hormones in autism symptomology
|
| Autism affects ~1% of children and is characterized by difficulties in social communication and restrictive interests. Autism is more frequently diagnosed in boys than in girls, and sex-hormones such as testosterone have a role in the underlying biology of autism. Puberty marks a period of hormonal change, but its influence on autism is unclear. The proposed research will measure hormone levels during puberty and investigate their relationship to symptoms of autism, and social-cognition. Findings promise to unveil the effects of puberty on autism, and suggest possible intervention avenues at a period of development that has not been studied thoroughly yet. |
| close |
|
|
|
11 .
Gilly Wolf
Biological Psychiatry Laboratory, Hadassah Medical Center, Hebrew University of Jerusalem
Effects of cerebrovascular insufficiency on iron deposition and ferroptosis: Affective and cognitive aspects, lesions to the deep white matter, neurogenesis and glial activation.
|
| The dark side of increased average human lifespan is elevated risk of cerebrovascular disease in late life, a common cause of age-related neurodegeneration and cognitive impairment that is termed vascular dementia (VaD). Currently, there are no specific treatments for VaD. Moreover, the mechanism explaining how hypoperfusion triggers VaD has to be addressed. Demonstrated in several neurodegenerative diseases, high iron concentration in the brain may provide such mechanism. The current study tests the hypothesis that hypoperfusion induces iron elevation, resulting in brain damage and cognitive impairment. The results will improve the mechanistic understanding of VaD and provide a basis for developing novel treatments. |
| close |
|
|
|
12 .
Adam Zaidel
Gonda Brain Research Center, Bar-Ilan University
Multisensory integration of visual and vestibular cues for self-motion perception in Parkinson’s disease
|
| Parkinson's disease (PD) is classically characterized by its motor symptoms, which have garnered the most research attention. However, sensory disturbances are also becoming recognized as a major part of PD. But, sensory dysfunction is less observable, and can therefore go unnoticed if not tested directly. Here we will investigate perception of self-motion in PD, and test whether multisensory information from visual and vestibular cues is appropriately integrated. Results from this study will improve our understanding of PD, particularly regarding gait and balance disorders, which are tightly related to visual and vestibular perception, but not well understood or treated in PD. |
| close |
|
|
|
13 .
Inna Gaisler-Salomon
Department of Psychology, University of Haifa
Therapeutic potential of cannabinoids in a rat model of schizophrenia
|
| Social and cognitive deficits are a key component of schizophrenia (SZ) symptomatology but are poorly addressed by currently available medications. Preliminary studies indicate that modulation of the endogenous cannabinoid system (i.e., cannabis based treatment) may provide a novel treatment venue. Here, we will determine whether enhancing endocannabinoids can reverse social and cognitive deficits in male and female rats. This study will provide a putative mechanism for the effects of endocannabinoids on prefrontal cortex function, which is disrupted in SZ, and provide insight into the development of novel strategies for prevention and therapeutic interventions for SZ. |
| close |
|
|
|
Second Year
|
1 .
Ravid Doron & Efrat City
School of Behavioral Sciences, The Academic College Tel Aviv Yaffo and Faculty of Health, Technion
The Chinese herb Shan-zha for the treatment of Anxiety disorders; efficiency, safety and biological correlates
|
| Anxiety disorders are among the ten most important public health concerns, which in recent years reached epidemic proportions. Current treatments are of limited efficacy and are associated with a wide variety of side-effects. Therefore, the need for further examination of alternative pharmacological agents is evident. In the current proposal, we will study the molecular mechanism and the therapeutic efficacy, safety, and tolerability of Shan-zha administration in a controlled clinical trial, and test our hypothesis that treatment with Shan-zha will reduce anxiety symptoms in mice and human study’s. |
| close |
|
|
|
2 .
Idit Golani
Biotechnology, ORT Braude College, Natania
Enhancement of neuroleptic drugs’ delivery across the Blood Brain Barrier using Trojan Horse nanoparticles
|
| About 1% of the population suffers from schizophrenia, a mental disorder affecting the most fundamental human attributes. The primary schizophrenia treatment is antipsychotic drugs.
Schizophrenic patients often go off their medication, mainly because of major side effects such as: weight gain, diabetes and cardiac dysfunction.
In this study a nano-scale drug delivery system is developed. These nanoparticles,loaded with drug, will include a protein that will act as a “Trojan Horse†which can transfer the drug into the brain.This strategy could potentially reduce the drug dose needed to achieve therapeutic effect, thus reducing the side effects associated with these drugs. |
| close |
|
|
|
3 .
Ayelet N. Landau
Psychology,, The Hebrew University of Jerusalem
Attentional sampling within and between modalities
|
| Attention is the ability to select relevant sensory inputs, such as a conversation we are holding and ignore parts of our environment that do not advance our goal, such as the passing traffic sounds that are in the background. It is a crucial cognitive ability without which the system would be in constant stimulus overload. In past research I discovered that attention is a rhythm. In order to be able to make use of this finding in the clinic for individuals suffering from impairments in attention, it is pivotal to generalize my findings beyond the visual modality. |
| close |
|
|
|
4 .
Yulia Lerner
Neurology and Brain Imaging Center, Sourasky Medical Center
Brain plasticity following physical training in individuals with mild cognitive impairment: Neuroimaging study
|
| The proposed study aims to explore the nature of brain changes following physical training in individuals who suffer of a-MCI and are at high risk of conversion to dementia. Findings in 'aerobic' group are compared to results in a group receiving non-aerobic exercises. In our research we use advanced techniques of brain imaging (fMRI). Participants are engaged in individual physical training for 4 months. Evaluations before and after the training include fMRI testing, cognitive assessment and blood tests of physiological markers related to improvement in brain function. The results of this study may have tremendous scientific and clinical significance for persons who are at the initial stages of Alzheimer’s disease. |
| close |
|
|
|
5 .
Yoni Pertzov
Psychology, Hebrew University of Jerusalem
Quantification and modulation of atypical gaze scanning of complex social scenes in individuals with anxiety disorder and autism symptoms
|
| Administration of the hormone oxytocin enhances visual attention to social cues. For
example, when viewing faces, oxytocin administration increases gaze to the eye-region, the part of the face most informative of a person’s intention. To date, research examining the effects of oxytocin on visual attention (via eye tracking) has been
limited to static pictures of faces. The proposed research will test if oxytocin effects
extend to complex natural scenes which are more ecologically valid. Since individuals
with anxiety disorders and autism symptoms show aberrations when scanning social
scenes, oxytocin administration may be useful in remediating social-cognitive skills in
these populations. |
| close |
|
|
|
6 .
Shaul Lev-Ran
Psychiatry, Sheba Medical Center and Psychiatry, Sackler Faculty of Medicine, Tel Aviv University
The effect of intra-nasal oxytocin on craving and withdrawal symptoms among individuals with cannabis dependence
|
| Cannabis is the most common illicit drug used worldwide, with about 10% of users developing addiction. To-date, there are no effective medical interventions for this disorder. Craving and withdrawal symptoms are major factors contributing to continuous use in addiction. Oxytocin has been shown to be effective in attenuating craving in individuals suffering from addiction to cannabis, though these data are preliminary. We propose exploring the effect of oxytocin on craving and withdrawal symptoms among individuals with cannabis dependence. We believe that oxytocin will reduce craving and withdrawal symptoms as well as reduction and abstinence rates in individuals with cannabis addiction. |
| close |
|
|
|
7 .
Avi Priel
The Institute for Drug Research (IDR)- Pharmacology section, Faculty of Medicine, The Hebrew University of Jerusalem
Cannabinoid-induced analgesia: elucidating the cellular and behavioral roles of TRPA1
|
| Chronic pain is defined as a pain that persists beyond the usual healing period. Continuous or intermittent, it can consume all aspects of a person's life, making it a massive socio-economic burden for the community. Cannabinoids (such as ‘medical marijuana’) are effective treatment for patients suffer from chronic pain, through a yet to be defined mechanism(s). Here, we propose to elucidate how cannabinoids target the pain system. We will use pharmacological tools we recently identified to define the role of a specific pain receptor in the cannabinoid induced analgesia. Our findings would facilitate rational design of novel and specific analgesics. |
| close |
|
|
|
8 .
Michal Taler & Ehud (Udi) Mekori
The Biological Psychiatry Laboratory, Felsenstein Medical Resaerch Center,Tel-Aviv University and The Child Psychiatry Unit, Sheba Medical Center., Tel-Aviv University
The Role of Neuroinflammation in Schizophrenia: 22q11.2 Deletion Syndrome as a Model
|
| Individuals with the genetic disorder 22q11.2 deletion syndrome (22q11.2DS) suffer from a variety of conditions including immune disorders and high rates of schizophrenia. It was suggested that neuroinflammation is involved in the pathophysiology of schizophrenia in people with and without 22q11.2DS. Thus making 22q11.2DS a perfect model for schizophrenia, as it entails both hight rates of schizophrenia and immune disorders. In a preliminary study, we have shown high blood levels of a general marker of inflammation (c-reactive protein) in psychotic subjects with 22q11.2DS. We intend to evaluate the association between immune factors and schizophrenia in patients with 22q11.2DS and in a mouse model of the syndrome. To the best of our knowledge, we are the first to conduct such a kind of study |
| close |
|
|
|
9 .
Ariel Tankus
Neurology and Neurosurgery, Sourasky Medical Center
Phonetic and phonological representations by single neurons in the human subthalamic nucleus and their impairment by Parkinson’s disease
|
| In the first year of the grant, we found how vowels are represented in the subthalamic
nucleus during speech production, perception and imagery. We discovered
mechanisms of degradation of this representation due to Parkinsonian speech
disorders, and a suboptimal compensatory mechanism. The results were recently
submitted for publication. In the second year, we aim to find out whether the
aforementioned representations are at the acoustic, phonetic or phonological levels,
and thus uncover the place of the underlying brain structures in the hierarchy of
language representation. Preliminary results indicate that thalamic neurons represent
vowel phonemes as logical units rather than acoustic properties. |
| close |
|
|
|
2016 - 2017
|
|
|
First Year
|
1 .
David Anaki
Psychology & Gonda Interdisciplinary Brain Research Center, Bar-Ilan University
The Effects of Neurofeedback Treatment on Obsessive-Compulsive Disorder
|
| Neurofeedback is a non-invasive treatment that helps a patient change his abnormal brain patterns. This treatment was proven as efficient for various disorders, such as ADD/ADHD, anxiety, depression, addictions, dementia and more. In this research, we aim to explore the effectiveness of neurofeedback treatment for obsessive-compulsive disorder.
Our main goals in this research are: 1) Studying and characterizing the brain patterns of OCD patients, 2) Designing a neurofeedback protocol for OCD and investigating the short and long-term effectiveness of neurofeedback as a treatment for OCD compared to CBT treatment, 3) Exploring the effect of neurofeedback treatment on specific brain activity components in OCD, that are suggested today as a biological markers for this disorder.
|
| close |
|
|
|
2 .
Ravid Doron & Efrat City
School of Behavioral Sciences and Faculty of Health, The Academic College Tel Aviv Yaffo and Technion
The Chinese herb Shan-zha for the treatment of Anxiety disorders; efficiency, safety and biological correlates
|
| Anxiety disorders are among the ten most important public health concerns, which in recent years reached epidemic proportions. Current treatments are of limited efficacy and are associated with a wide variety of side-effects. Therefore, the need for further examination of alternative pharmacological agents is evident. In the current proposal, we will study the molecular mechanism and the therapeutic efficacy, safety, and tolerability of Shan-zha administration in a controlled clinical trial, and test our hypothesis that treatment with Shan-zha will reduce anxiety symptoms. |
| close |
|
|
|
3 .
Idit Golani
Biotechnology, ORT Braude College, Natania
Enhancement of neuroleptic drugs’ delivery across the Blood Brain Barrier using Trojan Horse nanoparticles
|
| About 1% of the population suffers from schizophrenia, a mental disorder affecting
the most fundamental human attributes. The primary schizophrenia treatment is
antipsychotic drugs.
Schizophrenic patients often go off their medication, mainly because of major side
effects such as: weight gain, diabetes and cardiac dysfunction.
In this study a nano-scale drug delivery system is developed. These
nanoparticles,loaded with drug, will include a protein that will act as a “Trojan
Horse†which can transfer the drug into the brain.This strategy could potentially
reduce the drug dose needed to achieve therapeutic effect, thus reducing the side
effects associated with these drugs. |
| close |
|
|
|
4 .
Keren Grosman Kaplan
Psychiatry, Emek Medical Center, Afula
The role of the microbiome in Obsessive-compulsive disorder
|
| Obsessive-compulsive disorder (OCD) is a disabling condition with low to moderate response to treatment and a poorly understood mechanism. Preliminary studies suggest that gut bacteria play an important role in anxiety disorders. In this study we explore the role of the microbiota in OCD by comparing the induction of OCD behaviors in "germ free" mice with no intestinal bacteria to "normal" mice. Furthermore, we will characterize the microbiome of children with OCD and perform fecal transplants from children with OCD to GF mice and examine the outcomes. The findings can influence the design of new treatment strategies in OCD. |
| close |
|
|
|
5 .
Mati Joshua
Brain Sciences, The Hebrew University of Jerusalem
The role of subcortical networks in learning from sensory errors and rewards.
|
| How do we learn new actions? Two important neural structures, the basal ganglia and
cerebellum, are essential for learning. However, these structures are rarely studied in
conjunction and their role in different types of learning is unknown. This project is
designed to examine neural activity in both the basal ganglia and cerebellum while
animals are learning to choose an action that will yield a reward or adapt a movement
in a changing environment. The overarching goal is to unify research on the basal
ganglia and cerebellum to understand where and how different types of learning are
implemented in the brain. |
| close |
|
|
|
6 .
Ayelet N. Landau
Psychology, The Hebrew University of Jerusalem
Attentional sampling within and between modalities
|
| Attention is the ability to select relevant sensory inputs, such as a conversation we are holding and ignore parts of our environment that do not advance our goal, such as the passing traffic sounds that are in the background. It is a crucial cognitive ability without which the system would be in constant stimulus overload. In past research I discovered that attention is a rhythm. In order to be able to make use of this finding in the clinic for individual suffering from impairments in attention, it is pivotal to generalize my findings beyond the visual modality. |
| close |
|
|
|
7 .
Yulia Lerner
Neurology and Brain Imaging Center, Sourasky Medical Center
Brain plasticity following physical training in individuals with mild cognitive impairment: Neuroimaging study
|
| The proposed study aims to explore the nature of brain changes following physical training in individuals who suffer of a-MCI and are at high risk of conversion to dementia. Findings in 'aerobic' group will be compared to results in group receiving non-aerobic exercises. We will detect the changes using advanced techniques of brain imaging (fMRI). Participants will be engaged in individual physical training for four months. Evaluations before and after the training will include fMRI testing, cognitive assessment and blood tests of physiological markers related to improvement in brain function. The results of the current study may have tremendous scientific and clinical significance for persons who are at the initial stages of Alzheimer’s disease. |
| close |
|
|
|
8 .
Yoni Pertzov
Psychology, The Hebrew University of Jerusalem
Quantification and modulation of atypical gaze scanning of complex social scenes in individuals with anxiety disorder and autism symptoms
|
| Administration of the hormone oxytocin enhances visual attention to social cues. For example, when viewing faces, oxytocin administration increases gaze to the eye-region, the part of the face most informative of a person’s intention. To date, research examining the effects of oxytocin on visual attention (via eye tracking) has been limited to static pictures of faces. The proposed research will test if oxytocin effects extend to complex natural scenes which are more ecologically valid. Since individuals with anxiety disorders and autism symptoms show aberrations when scanning social scenes, oxytocin administration may be useful in remediating social-cognitive skills in these populations.
|
| close |
|
|
|
9 .
Shaul Lev-Ran
Psychiatry,Sackler Faculty of Medicine, Sheba Medical Center and Tel Aviv University
The effect of intra-nasal oxytocin on craving and withdrawal symptoms among individuals with cannabis dependence
|
| Cannabis is the most common illicit drug used worldwide, with about 10% of users
developing addiction. To-date, there are no effective medical interventions for this
disorder. Craving and withdrawal symptoms are major factors contributing to
continuous use in addiction. Oxytocin has been shown to be effective in attenuating
craving in individuals suffering from addiction to cannabis, though these data are
preliminary. We propose exploring the effect of oxytocin on craving and withdrawal
symptoms among individuals with cannabis dependence. We believe that oxytocin
will reduce craving and withdrawal symptoms as well as reduction and abstinence
rates in individuals with cannabis addiction. |
| close |
|
|
|
10 .
Avi Priel
The Institute for Drug Research (IDR)- Pharmacology section, Faculty of Medicine,, The Hebrew University of Jerusalem
Cannabinoid-induced analgesia: elucidating the cellular and behavioral roles of TRPA1
|
| Chronic pain is defined as a pain that persists beyond the usual healing period. Continuous or intermittent, it can consume all aspects of a person's life, making it a massive socio-economic burden for the community. Cannabinoids (such as ‘medical marijuana’) are effective treatment for patients suffer from chronic pain, through a yet to be defined mechanism(s). Here, we propose to elucidate how cannabinoids target the pain system. We will use pharmacological tools we recently identified to define the role of a specific pain receptor in the cannabinoid induced analgesia. Our
findings would facilitate rational design of novel and specific analgesics. |
| close |
|
|
|
11 .
Michal Taler & Ehud (Udi) Mekori
The Biological Psychiatry Laboratory, Felsenstein Medical Resaerch Center and The Child Psychiatry Unit, Tel-Aviv University and Sheba Medical Center.
The Role of Neuroinflammation in Schizophrenia: 22q11.2 Deletion Syndrome as a Model
|
| Individuals with the genetic disorder 22q11.2 deletion syndrome (22q11.2DS) suffer from a variety of conditions including immune disorders and high rates of schizophrenia. It was suggested that neuroinflammation is involved in the pathophysiology of schizophrenia in people with and without 22q11.2DS. Thus making 22q11.2DS a perfect model for schizophrenia , as it entails both hight rates of schizophrenia and immune disorders. In a perliminary study we have shown high blood levels of a general marker of inflammation (c-reactive protein) in psychotic subjects with 22q11.2DS. We intend to evaluate the association between immune factors and schizophrenia in 22q11.2DS . To the best of our knowledge, we are the first to conduct such a kind of study.
|
| close |
|
|
|
12 .
Ariel Tankus
Neurology and Neurosurgery, Sourasky Medical Center
Phonetic and phonological representations by single neurons in the human subthalamic nucleus and their impairment by Parkinson’s disease
|
| Speech is one of the most fundamental forms of human communication. How is speech generated in the human brain? Very little is known about this at the level of single neurons. Therefore, the goal of the proposed project is to understand how speech constructs, such as phonemes, syllables or acoustic features of speech, are represented by the activity of single neurons in the human brain. In a unique clinical setup, we will work, intra-operatively, with Parkinson's disease patients undergoing implantation of deep brain stimulator for clinical reasons. We will also explore the deterioration of speech due to Parkinson's disease. |
| close |
|
|
|
13 .
Omer Zarchi
The Intraoperative Neurophysiology Unit, Rabin Medical Center
The neural activity underling auditory phantom perception and its modulation by means of adaptive neurostimulation
|
| Phantom limb pain and phantom auditory perception (tinnitus) are well-known
phenomena but the neural mechanisms which underlie them are largely unknown.
Both phantom pain and auditory phantom arise from injury to the peripheral nervous
system and inner ear, respectively, leading to a reorganization of the central nervous
system. Severely affecting about 5% of the population, individuals with auditory
phantom experience great amount of psychological distress, while effectiveness of
current therapies is limited. The proposed study aims to investigate the neural circuits
which mediates phantom auditory perception and the modulation of their function by
means of electrical stimulation. Results will promote our understanding of the neural
encoding of the phantom phenomena and can shed light on the prospective benefits of
neuro-stimulation therapies. |
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Second Year
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1 .
Sharon Anavi-Goffer
Department of Behavioral Sciences, Ariel University
Role of cannabinoid CB2 receptor agonists in a mouse model for schizophrenia
|
| Schizophrenia is one of the most important forms of psychiatric illness, affecting young
people. This disease is associated with social withdrawal and cognitive dysfunction. We have
evaluated the contribution of the cannabinoid CB2-receptor to disease etiology and found that
CB2-receptor stimulators are effective in reversing schizophrenia-like behavior. Here, we will
characterize the effects of selected CB2-receptor stimulators on (1) social behavior; (2)
cognitive function and (3) the behavior of mice lacking the cannabinoid receptors. This study
will support the development of a new class of drugs to treat schizophrenia, improving life
quality of schizophrenic patients. |
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2 .
Ami Citri
Department of Biological Chemistry, The Hebrew University of Jerusalem
Electrophysiological and Functional Investigation of the Role of the Claustrum in Attention, as a Model for ADHD
|
| Attention Deficit Disorder (ADHD) is one of the most prevalent childhood disorders.
Symptoms of ADD include difficulty to maintain attention and control behavior, as
well as hyperactivity. Causative mechanisms for ADHD have not yet been identified.
We present a working hypothesis and preliminary evidence supporting a role
for a brain region called the claustrum in maintaining attention. We will study the role
of the claustrum in attention, and characterize its communication with other brain
regions important for maintaining attention. Our work is expected to develop a new
mouse model for ADHD, and define potential underlying causes of this disease. |
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3 .
Joshua Goldberg
Department of Medical Neurobiology, The Hebrew University of Jerusalem
Adaptations in dendritic excitability of striatal cholinergic interneurons in in a mouse model of Huntington’s disease
|
| Huntington’s disease (HD) is a devastating neurodegenerative disease that affects
1:10,000 individuals. HD patients suffer from insufficient striatal levels of acetylcholine. This is puzzling because the autonomous activity of the striatal neurons that release acetylcholine does not change in HD, even though the sodium current that drives the autonomous pacemaking does. We hypothesize that the up-regulation of this current is restricted to subcellular regions that are important for integration of afferent inputs but not for pacemaking. We will combine electrophysiology and imaging to study the distribution of this and other currents in these acetylcholine-releasing neurons in transgenic HD mice. |
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4 .
Orli Kehat
ISAN, University of Haifa
Risk and resilience to stress – differentiating associated inhibitiory factors in the dentate gyrus
|
| While most individuals are able to cope with a traumatic stressor and maintain or regain homeostasis, a significant minority fail to recover and exhibit prolonged and abnormal behavior. This failure to recover can be manifested as symptoms of various anxiety-related psychopathologies, including PTSD. Recent studies suggest that control of inhibitory activity in the dentate gyrus region may be of particular importance for determining the outcome of stressful experiences and a potentially important point of intervention. In the current study, we plan to identify specific factors in the dentate gyrus that are involved in stress processing, while making a distinction between pathology-related factors and resilience-related factors. |
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5 .
Lee Koren
Faculty of Life Sciences, Bar-Ilan University
An experimental study on wildlife risk-taking behavior: does testosterone help overcome anxiety-related behaviors in males and females?
|
| Male risk-taking behavior is often linked to testosterone levels. Females also take risks, and have testosterone, yet their link is ambiguous. In this study we will compare anxiety-related and risk-taking behaviors and their relationship with testosterone and cortisol in both sexes in a natural setting. We will introduce potential predators to artificial food patches and record behaviors and steroids in wild gerbils. Then, we will examine the effect of testosterone implants on behavior and cortisol. Together, we will test a potential mechanism mediating anxiety-related and risk-taking behaviors, and a possible treatment approach for fear and anxiety related disorders.
|
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6 .
Yonatan Kupchik
Department of Medical Neurobiology, The Hebrew University of Jerusalem
Glutamatergic input to a novel nucleus accumbens cell population and its role in cocaine addiction
|
| Addictive behavior is driven by glutamatergic input to two subgroups of neurons in
the nucleus accumbens (NAc) that differ in the way they connect to dopaminergic
brain regions. Recently, I discovered a third subgroup of NAc neurons that shows
output patterns contrary to current thinking. This proposal will examine using state of
the art electrophysiological and optogenetic tools the glutamatergic input patterns to
this new subgroup of NAc neurons and their relevance to cocaine addiction. Completion of this project may reveal a novel circuit that participates in the
generation of addictive behavior. |
| close |
|
|
|
7 .
Moshe Parnas
Department of Physiology and Pharmacology, Tel Aviv University
A novel multifaceted approach to study the neural mechanisms underlying the functional effects of human genes associated with Schizophrenia using Drosophila
|
| Schizophrenia, a highly heritable disease, is subject to intensive study. Yet, the
genetic and neuronal mechanisms underlying this disorder are poorly understood. The
efficacy of current drugs is poor for many patients. The disorder poor understanding
hinders development of novel drugs. Over 1000 genes are associated with
schizophrenia. Using current vertebrate model systems, screening the function of so
many genes is extremely difficult. However, the fruit-fly model system offers the
ability to perform large scale genetic screens. I propose to develop the fruit-fly as a
model system to schizophrenia and to examine the effects these genes have on neural
activity. |
| close |
|
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|
8 .
Lior Shmuelof
Brain and Cognitive Sciences Department, Ben-Gurion University
The neural basis of model-based and model-free motor learning in response to a visuomotor rotation
|
| A prominent distinction in motor learning is between learning from successes and learning from errors. I showed that error-based learning lead to quick changes in behavior that are also quickly forgotten, whereas learning from successes is much slower but also retains for longer. I hypothesize that these mechanisms will have different neuronal substrates, and suggest to examine this hypothesis using functional MRI. Subjects will make reaching movements under consistent or contradictory error and success signals and the neural correlates of the learning will be examined. This research attempts to understand the driving forces of motor learning and their neural structures. |
| close |
|
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|
9 .
Tal Shomrat
School of Marine Sciences and Dept. of Neurobiology, The Ruppin Academic Center, Michmoret and The Hebrew University
Long and short term effects of SSRIs on learning processes in octopuses: Simple system for the investigation of SSRIs mechanism of action
|
| The octopus uniquely combines vertebrate advanced behavior with a relatively simple invertebrate brain. Our previous work showed a possible role for serotonin as a reward signal, allowing reinforcement learning. In the proposed project, octopuses will be exposed to Selective Serotonin Reuptake Inhibitor (SSRI, used as antidepressant drug in humans). Due to these drugs’ high selectivity to serotonin, alteration in the octopus learning process will reveal the role of serotonin in learning. Additionally, we will investigate neurophysiological effects of SSRIs. Therefore, besides contributing to the field of learning and memory, this project can advance understanding of SSRI drugs’ mechanism of action. Thereby providing clinical implications for humans. |
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|
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10 .
Oren Tene
mbulatory Psychiatric Department, Tel Aviv Medical Center
Deep transcranial magnetic stimulation (dTMS) for the treatment of premenstrual dysphoric disorder (PMDD)
|
| Premenstrual dysphoric disorder (PMDD) is a hormone-dependent mental condition that causes significant suffering in 5% of women of reproductive age worldwide. The prominent symptoms are depressed mood, irritability, mood lability and anxiety. Treatment options for PMDD are limited with 40% nonresponders.
Deep transcranial magnetic stimulation (dTMS) is a novel therapeutic technique, which is based on modulating neural activity by inducing an electric field in the brain. To date, dTMS was found to be an effective treatment for depression, which is highly comorbid with PMDD.
We propose to study the effect of dTMS on PMDD patients in a prospective treatment study. |
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11 .
Gal Shoval
Geha Mental Health Center affiliated to Sackler School of Medicine, Tel Aviv University
Exo-cannabinoids for the treatment of depression and anxiety in a rat model
|
| Cannabidiol (CBD) is the major component of Cannabis that does not cause negative symptoms. Studies suggest that CBD may be reduce depression and anxiety symptoms. The proposed study will test the effects of CBD and similar synthetic compounds on depression- and anxiety-like behaviors in a rat model. We expect that CBD derivatives will be more potent than CBD, allowing for improved treatment options and examination of mechanisms. Rats will receive different dosages of the compounds and we will employ behavioral tests and measurement of stress hormone levels. This research will also allow for future examination of biological mechanisms. |
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2015 - 2016
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First Year
|
1 .
Renana Eitan (Tauber)
Department of Psychiatry, Hadassah Medical Center, Hebrew University Jerusalem
Can Deep Brain Stimulation Normalize Pathological Electrical Activity in the Subthalamic Nucleus of Human Patients with Intractable Obsessive-Compulsive Disorder?
|
| Recently, sub-thalamic nucleus (STN) deep brain stimulation (DBS) has been introduced as a novel therapy for treatment-resistant obsessive-compulsive disorder (OCD) patients. We hypothesize that the emotional and cognitive area of the STN of OCD patients has distinct electrophysiological properties that reflect the pathologic neural signature in OCD.
In this project, we intend to explore the neural signature of the emotional-cognitive areas of the STN in a large scale multicentered European study for STN DBS in 60 human OCD patients (n=60). The DBS group of Hadassah medical center will recruit at least ten patients and will design, implement and analyze the ancillary electrophysiological study of all patients in the study. A unique aspect of this study is the opportunity to monitor the changing neural activity throughout different phases of the disease. The novel Medtronic's implantable DBS system with sensing capability will allow long term electrophysiological recordings of the limbic STN. We anticipate that this study will provide better management of OCD patients treated with DBS. |
| close |
|
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2 .
Joshua Goldberg
Department of Medical Neurobiology, Hebrew University Jerusalem
Adaptations in dendritic excitability of striatal cholinergic interneurons in in a mouse model of Huntington’s disease
|
| Huntington’s disease (HD) is a devastating neurodegenerative disease that affects
1:10,000 individuals. HD patients suffer from insufficient striatal levels of acetylcholine. This is puzzling because the autonomous activity of the striatal neurons that release acetylcholine does not change in HD, even though the sodium current that drives the autonomous pacemaking does. We hypothesize that the up-regulation of this current is restricted to subcellular regions that are important for integration of afferent inputs but not for pacemaking. We will combine electrophysiology and imaging to study the distribution of this and other currents in these acetylcholine-releasing neurons in transgenic HD mice. |
| close |
|
|
|
3 .
Orli Kehat (Tauber)
ISAN, University of Haifa
Risk and resilience to stress – differentiating associated inhibitiory factors in the dentate gyrus
|
| Huntington’s disease (HD) is a devastating neurodegenerative disease that affects
1:10,000 individuals. HD patients suffer from insufficient striatal levels of acetylcholine. This is puzzling because the autonomous activity of the striatal neurons that release acetylcholine does not change in HD, even though the sodium current that drives the autonomous pacemaking does. We hypothesize that the up-regulation of this current is restricted to sub cellular regions that are important for integration of afferent inputs but not for pacemaking. We will combine electrophysiology and imaging to study the distribution of this and other currents in these acetylcholine-releasing neurons in transgenic HD mice. |
| close |
|
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4 .
Anna Alkelai
Biological Psychiatry Laboratory, Hadassah - Medical Center, Hebrew University Jerusalem
Seaking Biomarkers of Susceptibility to Antipsychotic-Induced Parkinsonism.
|
| Movement disorders induced by antipsychotic drugs are a significant clinical problem, particularly among patients treated with first generation antipsychotic drugs. There is considerable evidence that genetic factors play a significant role in susceptibility to drug induced movement disorders. In the proposed project, we are looking for novel genetic factors strongly predisposing to develop parkinsonian features when patients with psychiatric disorders are treated with antipsychotic drugs. In the proposed project, we will implement whole exome sequencing to identify rare coding variants with clear functional impact. This project has the unique advantage of a large, already collected, carefully phenotyped sample with DNA available and thus strong potential to yield meaningful, clinically relevant results. |
| close |
|
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5 .
Sharon Anavi-Goffer
Department of Behavioral Sciences, Ariel University
Role of cannabinoid CB2 receptor agonists in a mouse model for schizophrenia
|
| Schizophrenia is one of the most important forms of psychiatric illness, affecting young people. This disease is associated with social withdrawal and cognitive dysfunction. We have evaluated the contribution of the cannabinoid CB2-receptor to disease etiology and found that CB2-receptor stimulators are effective in reversing schizophrenia-like behavior. Here, we will characterize the effects of selected CB2-receptor stimulators on (1) social behavior; (2) cognitive function and (3) the behavior of mice lacking the cannabinoid receptors. This study will support the development of a new class of drugs to treat schizophrenia, improving life quality of schizophrenic patients. |
| close |
|
|
|
6 .
Ami Citri
Department of Biological Chemistry, Hebrew University Jerusalem
Electrophysiological and Functional Investigation of the Role of the Claustrum in Attention, as a Model for ADHD
|
| Attention Deficit Disorder (ADD) is one of the most prevalent childhood disorders. Symptoms of ADD include difficulty to maintain attention and control behavior, as well as hyperactivity. Causative mechanisms for ADD have not yet been identified. We present a working hypothesis and preliminary evidence supporting a role for a brain region called the claustrum in maintaining attention. We will study the role of the claustrum in attention, and characterize its communication with other brain regions important for maintaining attention. Our work is expected to develop a new mouse model for ADD, and define potential underlying causes of this disease. |
| close |
|
|
|
7 .
Lee Koren (Tauber)
Faculty of Life Sciences, Bar Ilan University
An experimental study on wildlife risk-taking behavior: does testosterone help overcome anxiety-related behaviors in males and females?
|
| Male risk-taking behavior is often linked to testosterone levels. Females also take risks, and have testosterone, yet their link is ambiguous. In this study we will compare anxiety-related and risk-taking behaviors and their relationship with testosterone and cortisol in both sexes in a natural setting. We will introduce potential predators to artificial food patches and record behaviors and steroids in wild gerbils. Then, we will examine the effect of testosterone
implants on behavior and cortisol. Together, we will test a potential mechanism mediating anxiety-related and risk-taking behaviors, and a possible treatment approach for fear and anxiety related disorders. |
| close |
|
|
|
8 .
Yonatan Kupchik
Department of Medical Neurobiology, Hebrew University Jerusalem
Glutamatergic input to a novel nucleus accumbens cell population and its role in cocaine addiction
|
| Addictive behavior is driven by glutamatergic input to two subgroups of neurons in the nucleus accumbens (NAc) that differ in the way they connect to dopaminergic brain regions. Recently, I discovered a third subgroup of NAc neurons that shows output patterns contrary to current thinking. This proposal will examine using state of the art electrophysiological and optogenetic tools the glutamatergic input patterns to this new subgroup of NAc neurons and their relevance to cocaine addiction.
Completion of this project may reveal a novel circuit that participates in the
generation of addictive behavior. |
| close |
|
|
|
9 .
Amit Lotan
Dept. of Adult Psychiatry and the Biological Psychiatry Laboratory, Hadassah Medical Center, Hebrew University Jerusalem
Monocyte platelet and microvesicle microRNA and transcriptional profiling among depressed and non-depressed coronary patients
|
| Heart attacks are a leading cause of morbidity and mortality worldwide. In recent years, emerging data suggest that clinically significant depressive symptoms pose a critical, independent risk factor for the development and exacerbation of ischemic heart disease (IHD). Therefore, it is reasonable to assume that at least some of the mechanisms underlying depression and IHD share biological similarities. However, such mutual links have not been systematically explored. By screening patients who undergo emergency coronary interventions for depressive symptoms at the Hadassah-Hebrew University Medical Center, we expect to identify some patients who are very depressed and other patients who show no depressive symptomatology. By comparing gene expression profiles between these two extreme patient groups using cutting-edge molecular and bioinformatic tools, we believe that we may be able to elucidate more clearly the biological mechanisms that link depression and heart disease. Such understanding is of tremendous clinical importance, as it may offer novel therapeutic approaches for ameliorating the detrimental physical effects exerted by depression |
| close |
|
|
|
10 .
Moshe Parnas
Department of Physiology and Pharmacology, Tel Aviv University
A novel multifaceted approach to study the neural mechanisms underlying the functional effects of human genes associated with Schizophrenia using Drosophila
|
| Schizophrenia, a highly heritable disease, is subject to intensive study. Yet, the
genetic and neuronal mechanisms underlying this disorder are poorly understood. The
efficacy of current drugs is poor for many patients. The disorder poor understanding
hinders development of novel drugs. Over 1000 genes are associated with schizophrenia. Using current vertebrate model systems, screening the function of so
many genes is extremely difficult. However, the fruit-fly model system offers the
ability to perform large scale genetic screens. I propose to develop the fruit-fly as a
model system to schizophrenia and to examine the effects these genes have on neural
activity. |
| close |
|
|
|
11 .
Lior Shmuelof
Brain and Cognitive Sciences Department, Ben-Gurion University
The neural basis of model-based and model-free motor learning in response to a visuomotor rotation
|
| A prominent distinction in motor learning is between learning from successes and learning from errors. I showed that error-based learning lead to quick changes in behavior that are also quickly forgotten, whereas learning from successes is much slower but also retains for longer. I hypothesize that these mechanisms will have different neuronal substrates, and suggest to examine this hypothesis using functional MRI. Subjects will make reaching movements under consistent or contradictory error and success signals and the neural correlates of the learning will be examined. This research attempts to understand the driving forces of motor learning and their neural structures. |
| close |
|
|
|
12 .
Tal Shomrat
The Ruppin Academic Center, School of Marine Sciences, Michmoret Dept. of Neurobiology, Hebrew University Jerusalem
Long and short term effects of SSRIs on learning processes in octopuses: Simple system for the investigation of SSRIs mechanism of action
|
| The octopus uniquely combines vertebrate advanced behavior with a relatively simple invertebrate brain. Our previous work showed a possible role for serotonin as a reward signal, allowing reinforcement learning. In the proposed project, octopuses will be exposed to Selective Serotonin Reuptake Inhibitor (SSRI, used as antidepressant drug in humans). Due to these drugs’ high selectivity to serotonin, alteration in the octopus learning process will reveal the role of serotonin in learning. Additionally, we will investigate neurophysiological effects of SSRIs. Therefore, besides contributing to the field of learning and memory, this project can advance understanding of SSRI drugs’ mechanism of action. Thereby providing clinical implications for humans. |
| close |
|
|
|
13 .
Oren Tene
Ambulatory Psychiatric Department, Tel Aviv Medical Center
Deep transcranial magnetic stimulation (dTMS) for the treatment of premenstrual dysphoric disorder (PMDD)
|
| Premenstrual dysphoric disorder (PMDD) is a hormone-dependent mental condition that causes significant suffering in 5% of women of reproductive age worldwide. The prominent symptoms are depressed mood, irritability, mood lability and anxiety. Treatment options for PMDD are limited, with 40% non-responders.
Deep transcranial magnetic stimulation (dTMS) is a novel therapeutic technique, which is based on modulating neural activity by inducing an electric field in the brain. To date, dTMS was found to be an effective treatment for depression, which is highly comorbid with PMDD.
We propose to study the effect of dTMS on PMDD patients in a prospective treatment study. |
| close |
|
|
|
Second Year
|
1 .
Gabi Aisenberg Romano
Psychiatric Service, Sourasky Medical Center, Tel Aviv University
Oxytocin and brief dyadic intervention in the treatment of women suffering from postpartum depression: A randomized, controlled fMRI clinical trial.
|
| Postpartum depression (PPD) is a highly prevalent disorder causing severe maternal distress, functional disability, and impaired mother-infant bonding with deleterious long-term consequences for infant development. Known effective pharmacological and psychological treatments have failed to show a significant improvement in mother-child interaction quality and infant development. We will treat women suffering from PPD with the hormone oxytocin plus mother-infant psychotherapy. We expect to find an advantage for the treatment combination in improving depressive symptoms, mother–infant interactions, and in the baby’s development. The brain's empathy and attachment neuronal systems will be studied by magnetic resonance imagery (fMRI) to help us learn about the biological aspects of condition and the intervention. |
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2 .
David Arkadir
Department of Neurology, Hadassah Medical Center, Hebrew University Jerusalem
Altered corticostriatal plasticity leads to risk-taking behavior in DYT1 dystonia.
|
| Humans learn to choose the best action, in response to environmental stimulus, based on their previous experience. Theoretical models assume that the neuronal substrate that shapes this choice is the dynamic weakening or strengthening of synapses between the brain cortex and the striatum. In the absence of a biological model to test this assumption, however, it is mainly based on observations that were made in isolated brain slices of animals. We suggest here that dystonia, a human genetic movement disorder, can serve as a biological model to test the neuronal substrate for choice behavior. Moreover, the same biological process may link choice behavior and the motor symptoms of dystonia. |
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3 .
Karen Banai
Communication Sciences & Disorders, University of Haifa
Listener, stimulus and procedural factors in the perceptual learning of time compressed speech and its generalization.
|
| Speech perception difficulties persist even after years of non-canonical listening (e.g., among individuals with hearing impairment or in non-native speakers). These difficulties could suggest that non-optimal listening experiences make listeners less able to generalize their experiences to novel situations. To test this idea, we propose a series of experiments on the perceptual learning of time-compressed speech, an acoustic distortion intended to mimic non-optimal listening circumstances. Factors that are hypothesized to influence generalization (e.g., training-set size, training procedure) will be manipulated and the effects on learning and generalization will be compared across listeners with diverse listening experiences. |
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4 .
Segev Barak
Psychological Sciences, Tel Aviv University
Role of fibroblast growth factor 2 (FGF2) in alcohol use and abuse disorders.
|
| Alcohol use and abuse disorders have severe impacts on society, however, the brain processes underlying these disorders are poorly understood, and available medications are limited. Long-term alcohol consumption induces long-lasting brain changes that promote the development of addiction-related behaviors. Levels of the protein FGF2 have been shown to increase following exposure to stimulants (e.g., cocaine). The present project will elucidate the role of FGF2 in alcohol addiction using rodent models. We will test whether brain FGF2 levels are altered following excessive alcohol consumption, and whether administration of FGF2 attenuates alcohol-drinking behaviors. |
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5 .
Tziona Ben Gedalya
Biochemistry and Molecular Biology, Medicine, Hebrew University Jerusalem
Does an aging associated decline in cyclophilin folding activity underlie the misfolding and aggregation of AD inked protein presenilin 1?
|
| Late-onset neurodegenerative disorders, such as Alzheimer’s (AD) and prion diseases, share a common feature; stemming from aberrant protein aggregation. Although it is unknown why these disorders emerge late in life, recent studies indicate that aging actively suppresses mechanisms that protect the young, exposing the aged organism to disease. We propose to study whether the protective activity of chaperone proteins that ensure correct, non-aggregative folding of other proteins is down-regulated by aging, enabling the onset of neurodegenerative disorders. Studying the mechanisms linking aging and neurodegeneration will open new avenues for the development of novel therapies based on manipulation of aging. |
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6 .
Sara Eyal
Drug Research, School of Pharmacy, Hebrew University Jerusalem
The role of altered function of uptake transporters at the blood-brain barrier in the CNS effects of epilepsy and antiepileptic drugs.
|
| Epilepsy affects sixty five million individuals worldwide. Patients with uncontrolled epilepsy suffer from impaired quality of life and have increased risk of premature death. Here we suggest evaluating the effects of epilepsy and antiepileptic drugs on the expression and activity of relevant protein pumps which carry drugs, hormones and nutrients into the brain. We hope to contribute to the understanding of drug resistance and behavioral issues in patients with epilepsy and to promote more selective and appropriate use of medications for these patients. In addition, this project will hopefully contribute to designing new drug delivery approaches for this patient population. |
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|
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7 .
Hagit Friedman
Nursing, University of Haifa
Computerized detection and analysis of early autistic signs in infant neuromotor development.
|
| Children with Autism show typical motor early signs. Identifying them will enable early treatment and better development. We aim to use computerized sampling and analysis of early movements of Autism in young premature infants, a population with a high risk for Autism,.
We use a novel non intrusive method based on video recording by depth camera and a tracking software. Preliminary results show successful automatic follow-up of infant movements, successful computerized analysis of infant's movements, and successful computer calculated parameters. Autism will be diagnosed when the infants are 1.5 years. Our
findings may improve early diagnosis of Autism, for the benefit of infants at risk. |
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8 .
Libi Hertzberg
Psychiatry, Shalvata Mental Health Center
Major depressive disorder (MDD) – the molecular signature of the response to electro convulsive therapy (ECT).
|
| Despite the numerous medications for depression, about 30% will not respond well. Electro Convulsive Therapy (ECT) is a powerful alternative, but many patients are reluctant to take this path.
Recent studies measure gene expression in patients' blood, trying to predict their response to medications, but the results so far are not consistent enough. To our best knowledge, no such studies were done for ECT. We will measure gene expression and other molecules, and incorporate biological knowledge to find potential biomarkers.
This will assist in 1) A diagnostic tool that will help direct patients to ECT; 2) Better understanding of the biology underlying the response to ECT; 3) The development of new treatments. |
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9 .
Adrian Israelson
Physiology and Cell Biology, Ben-Gurion University
Determining the contribution of misfolded SOD1 accumulation and the candidate chaperone MIF in familial ALS.
|
| Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterize by the loss of motor neurons, causing progressive paralysis. It has been 20 years since
the finding that mutant SOD1 causes ALS; however, the mechanism for toxicity remains unknown. Several groups have shown that a proportion of these mutants are
misfolded and bound to spinal cord mitochondria, but how this association occurs, remains unclear. We have identified a protein that can inhibit accumulation of misfolded SOD1. I propose to determine how this protein functions and the echanism by which these misfolded mutants lead to cell death selectively in affected tissues. |
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10 .
Nava Levit-Binnun
Applied Neuroscience, School of Psychology, IDC, Herzliya
Assessing vulnerability of Schizophrenia and healthy-sibling networks to TMS perturbations and their relation to neurological syptoms.
|
| Numerous external and internal stimulations impact and challenge our neuronal network moment by moment. A healthy network is expected to cope with disturbances. However, the schizophrenia network, due to its abnormal connectivity, is expected to exhibit more susceptibility to perturbations. Based on our previous work and recent pilot results we suggest to compare responses of schizophrenia networks to perturbations with the reponses of networks of healthy and unaffected siblings. We also suggest to investigate the relation between vulnerability to perturations and occurrence of neurological endophenotypes. This approach will assist in the development of novel interventions aimed at increasing network resilience. |
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11 .
Hadas Okon-Singer
Psychology, University of Haifa
Identifying neuro-cognitive abnormalities in individuals at high familial risk to develop essential hypertension.
|
| Threatening stimuli prototypically trigger activation of the autonomic nervous system and facilitate adaptive motor behavior. However, there is evidence that exaggerated reactions to stress, e.g. reactions that exceed those needed for relevant behavior, serve as a risk factor for future development of hypertension. Importantly, hypertension – high blood pressure with no underlying known cause – affects 50% of the population above 55 years in industrial societies, and is the most important risk factor for cerebro- and cardiovascular diseases. In contrast to the classic view, according to which hypertension starts from peripheral abnormalities in the vascular system, recent works suggest that brain abnormalities may exist prior to development of hypertension. The proposed study addresses the hypothesis that brain abnormality in emotion control systems mediates excessive reactions to aversive stimuli, which might predisposes to hypertension. During the last year, we demonstrated that individuals at high risk show abnormally-exaggerated blood pressure reactions to highly-aversive pictures. For the next year, in order to identify abnormal brain networks, we propose performing functional magnetic resonance imaging (fMRI), while simultaneously measuring peripheral blood pressure in the MR scanner. We speculate that structural and functional neural abnormality is related to exaggerated blood pressure reactions, and will be found in individuals at high genetic risk. Furthermore, we propose to examine whether cognitive training is effective in reducing these enhanced reactions. In the long term, elucidating mechanisms leading to hypertension should help initiating a paradigm shift from hypertension treating to prevention. In a broader perspective, these findings may be relevant to other populations showing enhanced reactions to stress, such as anxious individuals. |
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12 .
Ahikam Olmer
Department B, Beer Yaakov Mental Health Center
Are interferon gamma (IFN- )gene polymorphism and exposure to toxoplasma gondi joint risk factors for Schizophrenia in males?
|
| Toxoplasma gondii (TG) is an intracellular parasite. TG latent infection causes behavioral changes in rodents and humans. TG infected rats lose their fear reaction to cats' odor. TG increases dopamine levels (a key neurotransmitter in psychosis) in rodents. Rates of TG infection in schizophrenia patients are higher than in the general population.
IFN-γ is an immunological substance which transforms TG into a dormant form. The lowproduction form of IFN-γ correlates with a higher risk of schizophrenia in males. We hypothesize that this low-production form enables TG activity in the hosts' brain, alters neuron function and promote risk for schizophrenia. |
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13 .
Asya Rolls (Tauber)
Science & Engineering of Neuronal Systems Center, The Technion
Extracellular matrix involvement in the consolidation of fear memory during sleep: implications for PTSD and phobia.
|
| Following trauma, people learn to fear the cues that are associated with this event. With time, this memory trace is attenuated but in some cases, as in posttraumatic stress disorder (PTSD), the traumatic memory is over-stabilized and does not attenuate, limiting the capacity to cope with the trauma. Sleep plays a key role in memory stabilization. Here, we propose to explore a novel mechanism of sleepdependent memory consolidation testing the hypothesis that changes in the matrix surrounding neurons occur during sleep and support memory stabilization. Understanding this process introduce a novel therapeutic target to prevent the development of PTSD. |
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14 .
Aviv Weinstein
Behavioral Sciences, Ariel University
The effects of synthetic cathinone and synthetic cannabis on executive function and related brain activity.
|
| In Israel, there is a growing use of "designer drugs" such as “Hagigat†(synthetic
cathinone) and "Mr. nice guy" (synthetic cannabis). Clinical studies have shown that chronic use of these synthetic drugs can induce paranoid psychosis and hypomanic illness with grandiose delusions. The purpose of the study is to assess our hypothesis, that chronic use of these drugs is causing impairment to cognitive, motor, and executive functions using behavioral tests, as well as reduced activity in concommitant brain regions established by functional MRI findings. This may have major implications for our understanding of the long-term consequences of these designer drugs. |
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2014 - 2015
|
|
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First Year
|
1 .
Gabi Aisenberg Romano
Psychiatric Service, Sourasky Medical Center, Tel Aviv University
Oxytocin and brief dyadic intervention in the treatment of women suffering from postpartum depression: A randomized, controlled fMRI clinical trial.
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| Postpartum depression (PPD) is a highly prevalent disorder causing severe maternal distress, functional disability, and impaired mother-infant bonding with deleterious long-term consequences for infant development. Known effective pharmacological and psychological treatments have failed to show a significant improvement in mother-child interaction quality and infant development. We will treat women suffering from PPD with the hormone oxytocin plus mother-infant psychotherapy. We expect to find an advantage for the treatment combination in improving depressive symptoms, mother–infant interactions, and in the baby’s development. The brain's empathy and attachment neuronal systems will be studied by magnetic resonance imagery (fMRI) to help us learn about the biological aspects of condition and the intervention. |
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2 .
David Arkadir
Neurology, Hadassah University Hospital, Hebrew University of Jerusalem
Altered corticostriatal plasticity leads to risk-taking behavior in DYT1 dystonia.
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| Humans learn to choose the best action, in response to environmental stimulus, based on their previous experience. Theoretical models assume that the neuronal substrate that shapes this choice is the dynamic weakening or strengthening of synapses between the brain cortex and the striatum. In the absence of a biological model to test this assumption, however, it is mainly based on observations that were made in isolated brain slices of animals. We suggest here that dystonia, a human genetic movement disorder, can serve as a biological model to test the neuronal substrate for choice behavior. Moreover, the same biological process may link choice behavior and the motor symptoms of dystonia. |
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3 .
Karen Banai
Communication Sciences & Disorders, Haifa University
Listener, stimulus and procedural factors in the perceptual learning of time compressed speech and its generalization.
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| Speech perception difficulties persist even after years of non-canonical listening (e.g., among individuals with hearing impairment or in non-native speakers). These difficulties could suggest that non-optimal listening experiences make listeners less able to generalize their experiences to novel situations. To test this idea, we will conduct a series of experiments on the perceptual learning of time-compressed speech, an acoustic distortion intended to mimic non-optimal listening circumstances. Factors that are hypothesized to influence generalization (e.g., training-set size, training procedure) will be manipulated and the effects on learning and generalization will be compared across listeners with diverse listening experiences. |
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4 .
Segev Barak
Psychological Sciences, Tel Aviv University
Role of fibroblast growth factor 2 (FGF2) in alcohol use and abuse disorders.
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| Alcohol use and abuse disorders have severe impacts on society, however, the brain processes underlying these disorders are poorly understood, and available medications are limited.
Long-term alcohol consumption induces long-lasting brain changes that promote the
development of addiction-related behaviors. Levels of the protein FGF2 have been shown to increase following exposure to stimulants (e.g., cocaine). The present project will elucidate the role of FGF2 in alcohol addiction using rodent models. We will test whether brain FGF2 levels are altered following excessive alcohol consumption, and whether administration of FGF2 attenuates alcohol-drinking behaviors. |
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5 .
Tziona Ben Gedalya
Biochemistry and Molecular Biology, Medicine Faculty, Hebrew University of Jerusalem
Does an aging associated decline in cyclophilin folding activity underlie the misfolding and aggregation of AD inked protein presenilin 1?
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| Biochemistry and Molecular Biology, Medicine Faculty, Hebrew U
Does an aging associated decline in cyclophilin folding activity underlie the misfolding and aggregation of AD inked protein presenilin 1?
Late onset neurodegenerative disorders, such as Alzheimer’s (AD) and prion diseases, share a common feature; stemming from aberrant protein aggregation. Although it is unknown why these disorders emerge late in life, recent studies indicate that aging actively suppresses mechanisms that protect the young, exposing the aged organism to disease. We propose to study whether the protective activity of chaperone proteins that ensure correct, non-aggregative folding of other proteins is down-regulated by aging, enabling the onset of neurodegenerative disorders. Studying the mechanisms linking aging and neurodegeneration will open new avenues for the development of novel therapies based on manipulation of aging. |
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6 .
Hadas Okon-Singer (Tauber)
Psychology, Haifa University
Identifying neuro-cognitive abnormalities in individuals at high familial risk to develop essential hypertension.
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| Threatening stimuli prototypically trigger activation of the autonomic nervous system and facilitate adaptive motor behavior. However, there is evidence that exaggerated reactions to stress, e.g. reactions that exceed those needed for relevant behavior, serve as a risk factor for future development of hypertension. Importantly, hypertension – high blood pressure with no underlying known cause – affects 50% of the population above 55 years in industrial societies, and is the most important risk factor for cerebro- and cardiovascular diseases. In contrast to the classic view, according to which hypertension starts from peripheral abnormalities in the vascular system, recent works suggest that brain abnormalities may exist prior to development of hypertension. The proposed study addresses the hypothesis that brain abnormality in emotion control systems mediates excessive reactions to aversive stimuli, which might predisposes to hypertension. Individuals at high/low genetic risk (due to having two parents with/without hypertension) will be asked to ignore highly-aversive pictures and focus on a different task. To identify abnormal brain networks, we will perform functional magnetic resonance imaging (fMRI), while simultaneously measuring peripheral blood pressure in the MR scanner. We speculate that structural and functional neural abnormality is related to exaggerated blood pressure reactions to stress, and will be found in individuals at high genetic risk. In the long term, elucidating mechanisms leading to hypertension should help initiating a paradigm shift from hypertension treating to prevention. In a broader perspective, these findings may be relevant to other populations showing enhanced reactions to stress, such as anxious individuals.
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7 .
Sara Eyal
Drug Research, School of Pharmacy, Hebrew University of Jerusalem
The role of altered function of uptake transporters at the blood-brain barrier in the CNS effects of epilepsy and antiepileptic drugs.
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| Epilepsy affects sixty million individuals worldwide. Patients with uncontrolled epilepsy suffer from impaired quality of life and have increased risk of premature death. Here we suggest evaluating the effects of epilepsy and antiepileptic drugs on the expression and activity of relevant protein pumps which carry drugs, hormones and nutrients into the brain. We hope to contribute to the understanding of drug resistance and behavioral issues in patients with epilepsy and to promote more selective and appropriate use of medications for these patients. In addition, this project will hopefully contribute to designing new drug delivery approaches for this patient population. |
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8 .
Adrian Israelson
Physiology and Cell Biology, Ben-Gurion University
Determining the contribution of misfolded SOD1 accumulation and the candidate chaperone MIF in familial ALS.
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| Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized
by the loss of motor neurons, causing progressive paralysis. It has been 20 years since
the finding that mutant SOD1 causes ALS; however, the mechanism for toxicity
remains unknown. Several groups have shown that a proportion of these mutants are
misfolded and bound to spinal cord mitochondria, but how this association occurs,
remains unclear. We have identified a protein that can inhibit accumulation of
misfolded SOD1. I propose to determine how this protein functions and the
mechanism by which these misfolded mutants lead to cell death selectively in affected
tissues. |
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9 .
Nava Levit-Binnun
Applied Neuroscience, School of Psychology,, IDC, Herzliya
Assessing vulnerability of Schizophrenia and healthy-sibling networks to TMS perturbations and their relation to neurological syptoms.
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| Numerous external and internal stimulations impact and challenge our neuronal network moment by moment. A healthy network is expected to cope with disturbances. However, the schizophrenia network, due to its abnormal connectivity, is expected to exhibit more susceptibility to perturbations. Based on our previous work and recent pilot results we suggest to compare responses of schizophrenia networks to perturbations with the reponses of networks of healthy and unaffected siblings. We also suggest to investigate the relation between vulnerability to perturations and occurrence of neurological endophenotypes. This approach will assist in the development of novel interventions aimed at increasing network resilience. |
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10 .
Hagit Friedman
Nursing, Haifa University
Computerized detection and analysis of early autistic signs in infant neuromotor development.
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| Children with Autism show typical motor early signs. Identifying them will enable early treatment and better development.
We aim to use computerized sampling and analysis of early movements of Autism in young premature infants, a population with a high risk for Autism.
We use a novel non intrusive method based on video recording by depth camera and a
tracking software. Preliminary results show successful automatic follow-up of infant
movements, successful computerized analysis of infant's movements, and successful
computer calculated parameters. Autism will be diagnosed when the infants are 1.5 years. Our findings may improve early diagnosis of Autism, for the benefit of infants at risk. |
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11 .
Asya Rolls (Tauber)
Science & Engineering of Neuronal Systems Center, Technion Haifa
Extracellular matrix involvement in the consolidation of fear memory during sleep: implications for PTSD and phobia.
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| Following trauma, people learn to fear the cues that are associated with this event. With time, this memory trace is attenuated but in some cases, as in posttraumatic stress disorder (PTSD), the traumatic memory is over-stabilized and does not attenuate, limiting the capacity to cope with the trauma. Sleep plays a key role in memory stabilization. Here, we propose to explore a novel mechanism of sleep-dependent memory consolidation testing the hypothesis that changes in the matrix surrounding neurons occur during sleep and support memory stabilization. Understanding this process introduce a novel therapeutic target to prevent the development of PTSD. |
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12 .
Aviv Weinstein
Behavioral Sciences, Ariel University
The effects of synthetic cathinone and synthetic cannabis on executive function and related brain activity.
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| In Israel, there is a growing use of "designer drugs" such as “Hagigat†(synthetic cathinone) and "Mr. nice guy" (synthetic cannabis). Clinical studies have shown that chronic use of these synthetic drugs can induce paranoid psychosis and hypomanic illness with grandiose delusions. The purpose of the study is to assess our hypothesis that chronic use of these drugs is causing impairment to cognitive, motor, and executive functions using behavioral tests, as well as reduced activity in concommitant brain regions established by functional MRI findings. This may have major implications for our understanding of the long-term consequences of these designer drugs. |
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13 .
Libi Hertzberg
Psychiatry, Shalvata Mental Health Center
Major depressive disorder (MDD) – the molecular signature of the response to electro convulsive therapy (ECT).
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| Despite the numerous medications for depression, about 30% will not respond well. Electro Convulsive Therapy (ECT) is a powerful alternative, but many patients are reluctant to take this path.
Recent studies measure gene expression in patients' blood, trying to predict their response to medications, but the results so far are not consistent enough. To our best knowledge, no such studies were done for ECT. We will measure gene expression and other molecules, and incorporate biological knowledge to find potential biomarkers.
This will assist in 1) A diagnostic tool that will help direct patients to ECT; 2) Better understanding of the biology underlying the response to ECT; 3) The development of new treatments. |
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14 .
Ahikam Olmer
Department B, Beer Yaakov Mental Health Center
Are interferon gamma (IFN- )gene polymorphism and exposure to toxoplasma gondi joint risk factors for Schizophrenia in males?
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| Toxoplasma gondii (TG) is an intracellular parasite. TG latent infection causes behavioral changes in rodents and humans. TG infected rats lose their fear reaction to cats' odor. TG increases dopamine levels (a key neurotransmitter in psychosis) in rodents. Rates of TG infection in schizophrenia patients are higher than in the general population.
IFN-γ is an immunological substance which transforms TG into a dormant form. The low-production form of IFN-γ correlates with a higher risk of schizophrenia in males. We hypothesize that this low-production form enables TG activity in the hosts' brain, alters neuron function and promote risk for schizophrenia. |
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15 .
Gal Shoval (Tauber)
, Geha Mental Health Center
Exo-cannabinoids for the treatment of depression and anxiety in a rat model.
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| Cannabidiol (CBD) is the major component of Cannabis that does not cause negative symptoms. Studies suggest that CBD may be reduce depression and anxiety symptoms. The proposed study will test the effects of CBD and similar synthetic compounds on depression- and anxiety-like behaviors in a rat model. We expect that CBD derivatives will be more potent than CBD, allowing for improved treatment options and examination of mechanisms. Rats will receive different dosages of the compounds and we will employ behavioral tests and measurement of stress hormone levels. This research will also allow for future examination of biological mechanisms. |
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2013 - 2014
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First Year
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1 .
Yair Ben Chaim
Natural & Life Sciences, Open University
Does the allosteric binding site play a pivotal role in governing the voltage sensitivity of the m2 muscarinic receptor?
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| Cells sense the environment and communicate with each other largely by translating chemical signals into cellular functions. G-protein coupled receptors (GPCRs) mediate such processes, and thus their importance in many physiological functions. Recently we found that GPCRs can be modulated by electric signals, the same signals that allow nerve cells to communicate with each other. Experimental results alluded to the surprising possibility that a site in the receptor that modulates the affinity of the receptor (allosteric site) may play a role in that voltage sensitivity. We propose to study this possibility using the m2 muscarinic receptor as a case study. |
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2 .
Roy Luria
Psychology, Tel Aviv University
Neural mechanisms for representing complex objects in working-memory.
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| Visual working-memory is a cognitive meeting point for high and low cognitive functions, and information that is represented in working memory is likely to affect behavior, as indicated by the correlations between working-memory capacity and important capabilities such as intelligence and scholastic aptitudes. To date, the underlying mechanisms that support complex object representations in visual working memory are poorly understood. The goal of this proposal is to investigate these mechanisms, using an electrophysiological marker sensitive to the amount of
information that is being represented in this visual workspace. |
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3 .
Anat Maril
Psychology, Hebrew University
Neural correlates of semantic influences on episodic encoding.
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4 .
Dalit Sela-Donenfeld
Robert Smith Faculty of Agriculture, Hebrew University, Rehovot
Deciphering the development program and molecular cues of the Chochlear circuitry in the embryonic brainstem.
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| Hearing is achieved when sounds are transmitted from the inner-ear to the cochlear nucleus (CN) in the brainstem, followed by traveling of information to the upper-brain. Interneurons are important cells that generate the CN in the brainstem embryonic precursor, the hindbrain. They are formed during embryogenesis and acquire unique identities and wiring. Defects in their formation/function are associated with hearing disorders of clear psychobiology impacts, including deafness. Despite their importance, knowledge on CN-interneurons is limited. Here we will decipher how their networks are developed. Discovering novel aspects of CN development will help elucidate mechanisms of hearing-related disorders. |
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5 .
Gal Sheppes
Psychology, Tel Aviv University
Emotion regulation control: Promoting healthy adaptation by overriding default regulation strategies
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| Under many affective states individuals seek to control or regulate their emotions in ways that offer immediate relief. However, healthy adaptation requires overriding these immediate relief regulatory options in favor of other regulatory options that provide long term benefits.
Importantly, psychopathologies such as anxiety disorders involve a breakdown of this healthy adaptation feature. While clearly important, empirical findings have been lacking. In a set of two studies, I will shed light on the behavioral and electrophysiological consequences of this feature of healthy adaptation when regulating positive emotional states as compared with negative emotional states. Findings will further our understanding of the contribution of emotion regulation to adaptive functioning, and to the development of psychopathologies such as anxiety disorders, where insufficient overriding of the strong tendency to disengage
from emotional processing inhibits engagement in regulatory responses that would offer longer term benefits. |
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6 .
Michal Taler
Felsenstein Medical Center, Tel Aviv University
Evaluation of the metabolic parameters of a novel antipsychotic agent "PGW5" in a rat model of a typical antipsychotics induced metabolic side-effect. Determination of brain peptides associated with appetite regulation
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| Schizophrenia is a chronic, debilitating disease affecting about 1% of the population. Existing agents has a variety of side effects including weight gain and the associated medical co morbiditie, atherosclerosis, hypertension, dyslipidemia, diabetes and eating disorders that limit their use. We developed a female rat model that represents the weight gain associated with antipsychotic therapy. In a preliminary study we found that a novel analogue of olanzapine (PGW5) developped in our lab was not associated with weight gain at variance from olanzapine. The study is aimed to confirm the initial results and clarify the differential mechanism of olanzapine and PGW5. |
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7 .
Rami Yaka
Drug Research, Hebrew University
Earasing cocaine conditioned cues in the nucleus accumbens by inactivation of PKMz.
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| One of the main problems in drug addiction is the high rate of relapse or drug reuse following cesation of drug intake. Most drug users that quit using the drug will undergo relapse very soon after withdrwal. While the molecular basis of this phenomena remains unclear, recent studies point out that part of the changes responsible for relapse involves learning and memory processes that eventually triger relapse. In the current proposal we aim to charecterize a target for such intervention that previously was shown to erase drug-induced memories. We will examined when can one treatment that earsed cocaine-memories can be given after withdrawal and what is the exact target that is affectd in the brain. |
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8 .
Dr. Sagiv Shifman & Dr. Yoav Kohn
Dept. of Genetics & Jerusalem Mental Health Center, Eitanim Psychiatric Hospital & Hadassah School of Medicine, Dept. of Psychiatry., Hebrew University
Identification of genes potentially involved in childhood onset Schizophrenia.
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| Childhood onset schizophrenia (COS) is a rare and severe disorder. Response to treatment and prognosis are poor. Very little research has been conducted world-wide on this disorder. We propose to use the advantage of centralized treatment centers and databases which exist in Israel to recruit as many COS patients as possible. We will search their DNA for disease causing variants. Clinical data will be collected and analyzed and further studies using this sample will be planned. The better understanding of COS will benefit these patients, and will also broaden our knowledge on more common related disorders. |
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Second Year
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1 .
Izhar Bar-Gad
Gonda Brain Research Center, Bar Ilan University
Neurophysiological mechansim underlying striatal bicuculline induced hyper-behavioral symptoms
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| Multiple neurological disorders are associated with excessive behaviors such as tics,
compulsions or hyperactivity. These disorders are associated with dysfunctions of the
cortico-basal ganglia system which consists of motor, associative and limbic
pathways. Symptoms of these disorders may be evoked in laboratory animals by local
basal ganglia disinhibition. In the current study we propose studying the effect of
disinhibition of the limbic (stereotypy) and associative (hyperactivity) pathways on
the underlying neuronal activity. This work has clinical implications of improving our
understanding of the aforementioned disorders and scientific implications of
characterizing the functions of these pathways during normal and abnormal behavior. |
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2 .
Michal Ben-Shachar
English Department (Linguistics Division) and The Gonda Brain Research Center, Bar Ilan University
How learning to read shapes structural connectivity and cortical responses in adult illiterates
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| Reading allows us to derive meaning from print. Reading skills are usually mastered during childhood, in a process that has been extensively studied in cognitive psychology as well as in neuroscience. But what happens when one faces the challenge of acquiring literacy skills during adulthood? Can learning to read shape the adult brain? In this study we examine how adult individuals who have never learned how to read differ from those who have, in perceptual and language skills, brain structure and function. We then examine if and how these cognitive and neural properties can be changed by adult literacy programs. |
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3 .
Dr. Yoram Ben-Shaul
Department of Medical Neurobiology, Faculty of Medicine , Hebrew University
State dependent processing of reproductive chemosignals
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4 .
Evan Elliott
Faculty of Medicine, Bar Ilan University
Epigenetic analysis of the prefrontal cortex and anterior cingulate cortex in humans with Autism Spectrum Disorders
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| Current research suggests that the major factors leading to Autism Spectrum Disorders (ASD) include genetics and prenatal environmental factors. A specific chemical modification of our genome, known as DNA methylation, is known to be caused by environmental factors. Therefore, we hypothesize that faulty DNA methylation of the genome in the brain may be a major factor leading to the development of ASD. The proposed research will determine genomic regions with significant differences in DNA methylation in the human brain between normal and autistic individuals. Subsequent animal studies will determine the behavioral and clinical significance of the observed changes. |
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5 .
David Mankuta
Departments of Obsterics and Gynecology, Hadassah Medical Center, Hebrew University
Immunologic biomarkers related to ASDs development during pregnancy in high risk population
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| Autism spectrum disorders (ASD) are neurodevelopmental disorders, currently estimated to affect 1% of children. ASD is diagnosed mostly around the age of two to three years old. Despite the high prevalence of autism, there are limited clues for its pathogenesis, early detection or treatment.
Previous studies have shown abnormal immunologic profile for ASD children. We wish to further examine this profile, using a prospective study during pregnancy in high risk population, in order to find biomarkers that correlate with the appearance of ASD. We will focus particulary in the activity, responsivness and functionality of mast cells, eosinophils and natural killers (NK) cells.
Our findings are likely to promote the understanding of ASD and eventually help precede diagnosis. |
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6 .
Avi Priel
Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University
Developing a Novel Tool to Study the Transition from Acute to Chronic Pain
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| Chronic pain is defined as a pain that persists beyond the usual healing period. Continuous or intermittent, it can consume all aspects of a person's life, making it a massive socio-economic burden for the community. Here we study how an acute pain, normally relieves over time, transforms into a chronic pain. To this end, we are using a unique natural pharmacological tool we recently identified to study the pain behavior in animals and the cellular changes underlying chronic pain development. This study will therefore enhance our understanding of how chronic pain is induced, and will facilitate the development of specific analgesics. |
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7 .
Alon Shamir
The Neuroscience Research Lab, Mazra Mental Health Center
Pharmacologic inhibition of the NRG-ErbB4 signaling pathway in adult brain; effect on complex behavior associated with schizophrenia
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| Finding in postmortem human brain, animal models, genetic and functional
studies support the involvement of neuregulin and its ErbB4 receptor in the
pathophysiology of schizophrenia. However, how, and at which developmental stage
alteration in the NRG-ErbB4 signaling contributes to the pathophysiology of
schizophrenias is unknown. In the proposed study we will used a pharmacological
approach to elucidate the molecular and the behavioral role of the pathway in
schizophrenia. Toward this end, we will explore the effect of blocking the ErbB4
signaling pathway on behavioral paradigms relevant to the core symptoms of
schizophrenia in young adult mice brain. Revealing the potential mechanism of the
involvement of the pathway may lead to a new therapeutic avenue for symptoms of
schizophrenia. |
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8 .
Michael Wagner
Psychology and Industrial Engineering Department, Ariel College
"Feeling by Seeing": Reconstructing Haptic Sensing by a Non-attentive Visual Method
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9 .
Ohad Ben-Shahar
Department of Computer Science and the Zlotowski Center for Neuroscience, Ben-Gurion University
Lazy neurons for good shape: Perceptual inquiry, computational modeling, and cortical implementation
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| Visual curve completion is a fundamental perceptual mechanism that completes the missing parts between observed contour fragments. Despite its long history, this mysterious perceptual capacity is understood mostly phenomenologically, but less so psychophysically or computationally. This research program is designed to significantly advance our knowledge of the problem in all these fronts by proposing and exploring a new theory in which perceptual completion is a result of very basic physical/biological principles that might govern the operation of the cortical tissue. We plan to study several such principles, derive perceptual predictions, explore them
psychophysically, and develop neural circuits that implement them.
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2010 - 2011
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First Year
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1 .
Yaffa Yeshurun
, Haifa University
Attention as an attraction field (AAF): The development and evaluation of a novel model of spatial attention
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| The term spatial attention refers to the selective processing of information at a given location in space. Numerous studies, conducted both at the neuronal and behavioral levels, explored the effects of attention. We propose a model that can unify the outcomes of many such studies under a single attentional mechanism. Specifically, we suggest that the allocation of attention to a location attracts the centers of receptive fields towards this location. This shift of receptive fields towards the center of attention may be viewed as the physiological instantiation of the concentration of resources at the focus of attention. |
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2 .
Sagiv Shifman
, Hebrew University Jerusalem
The role of the X chromosome in autism
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| Autism is much more frequent in boys, but the reasons are unknown. We assume that boys are more vulnerable to develop autism because they have only one copy of the X chromosome and so if there is a mutation it will disrupt the gene with no extra functional copy to compensate. We propose to use a new method that will enable us to identify mutations across all genes on the X chromosome. The findings will lead to a better understanding of the biological causes of autism as well as the potential to develop new diagnostic tools for this disorder. |
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3 .
Rami Yaka
, Hebrew University Jerusalem
The role of oxidative stress in cocain addiction.
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| Part of the action of the highly addictive drug cocaine, is an increase in neurotoxicity by elevation of oxidative stress in areas of the brain that are responsible for reward and addiction. Recently we have shown that cocaine induces oxidative damage in cells and in animals that were exposed to cocaine. Moreover, we showed that application of antioxidants can attenuate the damage induced by cocaine in specific areas within the reward system. Here we will investigate the hypothesis that preventing drug-induced oxidative damage by antioxidants or antioxidants-like molecules will result in reversing the drug-induced alterations which will ultimately lead to prevention of the development and expression of cocaine addiction. |
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4 .
Amir Goldbourt
, Tel Aviv University
A molecular view on the role of lithium in the treatment Of bipolar disorder.
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| Lithium salts have been known as mood stabilizing drugs for bipolar disorder patients for over 50 years. Treatment of bipolar patients with lithium is succesful yet not without risk and adverse effect. In order to develop new drugs for the treatment of such patients, and to better understand the mechanism of the disease, the mode of action of lithium has to be known. Since the function of a protein, and a drug, are closely related to their combined structure, we proposed to study the exact structure of a lithium-enzyme complex using magic-angle spinning nuclear magnetic resonance. |
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5 .
Dalit Sela-Donenfeld
, Hebrew University Jerusalem
Molecular mechanisms underlying assembly of embryonic Brainstem interneuron circuits.
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| The brainstem is located in-between the spinal cord and upper brain. It possesses sensory/motor information and relays it to/from the brain and spinal-cord through interneurons. Interneurons are involved in functions like heart rate, breathing, sleeping, eating, consciousness, pain and coordination. They are formed during embryogenesis and acquire unique identities and wiring.
Defects in their formation are linked to sudden infant death, sleep apnea, hypoventilation, eating disorders as well as to problems in facial expression and movement. Brainstem nerve malfunctions are also associated with neurodegenerative diseases.
Despite their importance, our understanding of brainstem interneuron properties is sketchy. We aim to decipher how and where they form circuits. Ultimately, this study will discover fundamental aspects of brainstem formation and function, which will help to elucidate unknown mechanisms of brainstem diseases. |
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6 .
Sebastian Kadener
, Hebrew University Jerusalem
Use of behavioral marker for following neurodegeneration in a Drosophila model of Friedreich's ataxia.
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| Neurodegenerative diseases are characterized by loss of specific neuronal populations.
Although in many cases mutations have been identified, the mechanisms by which
these mutations lead to the disease are not clear. Fruitflies have been used with great
success to model neurodegenerative diseases. Fruitflies are easy to manipulate
genetically (expression levels of any gene can be easily up or down-regulated) and
have low maintenance cost facilitating the development of drug screenings for
thousands of compounds. The present plan is focused on the study of Friederich‟s
ataxia using the fruitfly model to further understand the disease and evelop drugs to treat it. |
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7 .
Oren Schuldiner
, Weizmann Institute of Science
The role of the un Kinase (JNK) pathway in developmental Axon pruning.
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| Neuronal remodeling involves the elimination of existing neuronal connections and
establishment of new connections and is essential for sculpting the mature nervous
systems of vertebrates and invertebrates during development. We study the process
of neuronal remodeling of specific neurons in the fruit-fly brain because it allows for a detailed analysis of the process at the molecular level. In a screen we performed, we
found that a key signaling kinase, called JNK, is required for axon elimination during
development. Here we propose to study the mechanisms by which JNK is activated
and how it regulates developmental axon elimination. |
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8 .
Eran Meshorer
, Hebrew University Jerusalem
tress-induced chromatin-related transcriptional memory In the mammalian brain.
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| DNA is wrapped around specialized histone proteins. The histone-DNA complex,
(with additional structural proteins) is termed chromatin. Chromatin regulation is
fundamental for gene expression of all cells. We previously found that
acetylcholinestaerse (AChE), displays adverse long-lasting transcriptional changes
following stress in the brain. Building on our preliminary data, we strongly believe
that chromatin regulation controls AChE’s long-lasting expression changes. We will
therefore analyze changes in AChE chromatin structure following stress. We will
further reverse the transcriptional changes of AChE with chromatin-targeted drugs.
These studies will therefore have profound implications for understanding the biology
of stress responses and for potential therapy. |
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9 .
Rony Panarsky
Department of Pharmacology, Hebrew University Jerusalem
Anti-inflammatory properties of ladostigil and its metabolites in primary microglia
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| Alzheimer’s disease (AD) is a devastating neurodegenerative disease that causes progressive memory loss and behavioral aberrations in about 5 percent of population over the age of 65 years. Increasing evidence points to oxidative-nitrative stress and microglial activation with release of inflammatory cytokines (Il1α/β, TNFα, IFNγ) as possible initiators of apoptosis in the aging brain leading to plaque disposition and neurodegeneration.
Microglia are a major source of oxidative (ROS) and nitrative (RNS) stress in the brain. These macrophage-like cells are present in the healthy brain in a dormant state and can be rapidly activated by damage as the result of stroke, trauma or pathogenic invasion. Activation of microglia is characterized by changes in their morphology and function that causes them to release a wide range of inflammatory cytokines (Il1α/β, IL-6, TNFα) as well as nitric oxide (NO) and superoxide. It may therefore be possible to slow the neurodegenerative process by reducing oxidative-nitrative stress and the prolonged activation of microglia in the brain.
Ladostigil (R-CPAI) [(N-propargyl)-(3R)-aminoindan-5-yl]-ethyl methyl carbamate is a novel compound which inhibits cholinesterase (ChE) and is also a brain selective inhibitor of monoamine oxidase (MAO).
In our study the potential protective ability of R-CPAI to reduce nitric oxide and inflammatory cytokines was evaluated in primary cultures of mouse microglia. The effect of R-CPAI was compared with three of its active metabolites, R-MCPAI, R-CAI and R-HPAI. R-CAI lacks the propargyl group, while R-MCPAI lacks the ethyl group on the carbamate N. R-HPAI is formed from R-CPAI by ChE and the carbamate moiety is replaced by a hydroxyl group.
We showed that in concentrations of 1nM-1uM, R-CPAI decreased the release of NO induced by LPS into the medium after 24 hrs. Metabolites R-MCPAI, R-CAI and R-HPAI all showed this anti-inflammatory activity. Since R-HPAI does not possess a carbamate moiety, it suggests that this group is not necessary for their protective activity against LPS in microglia and that it does not result from ChE inhibition. This was confirmed by a lack of effect of a more potent ChE inhibitor, rivastigmine. Neither does the presence of a propargyl moiety in the structure appear to be necessary for this activity since R-CAI was also active. RT-PCR analysis showed that all the metabolites reduced significantly the amounts of mRNA of iNOS, IL-1β and TNF-α in response to LPS at similar or lower concentrations than ladostigil. The protective effect of the compounds against LPS-induced microglial activation does not seem to result from their ability to activate nicotinic AchR, although such activation has been shown to reduce inflammatory processes in macrophages. The drugs may produce their action in microglia by altering the MAPK signaling cascade.
These results show that ladostigil has anti-inflammatory effects on microglia that may explain its neuroprotective effect in vivo. |
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10 .
Limor Regev
Department of Neurobiology, Weizmann Institute of Science
Amygdalar CRF: adaptive or maladaptive stress neuropeptide
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| The corticotropin-releasing factor (CRF) neuropeptide is an essential regulator of the neuro-endocrine stress response and is implicated in the control and maintenance of homeostasis. Flaws in the regulation of the stress-response can have severe psychological and physiological consequences and it has been suggested that dysregulation of the CRF system is involved in the development of anxiety disorders and depression. To further study the relative contribution of CRF, endogenously expressed by anxiety-linked brain structures, to anxiety and depression-like behaviors in mice, we designed and generated several lentiviral-based models aimed to manipulate the expression levels of CRF at specific brain regions. We have developed lentiviruses that over-expressing CRF, either continuously or at inducible manner, using CMV or tetracycline-induced promoters, respectively. In addition, we generated lentiviruses expressing shRNA aimed to knockdown CRF expression levels. All lentiviral constructs also contain a fluorescent reporter to allow verification of site of infection. In vitro and in vivo validation of these lentiviruses using biochemical and immunohistochemical techniques demonstrated their functionality. Stereotaxic injection of these viruses into the central nucleus of the amygdala of male mice created transgenic mice models that express lower or higher levels of CRF specifically at site of injection. A panel of anxiety and depression-like behavior tests were performed to elucidate the effect of each manipulation on basal and stress-induced anxiety and depression-like behaviors. These studies were followed by locomotion, learning and memory tests and histological and morphological analysis. Results obtained from this study, which will be presented at this conference, demonstrated the importance of amygdalar CRF in mediating the central stress response and its ambiguous role in stress-induced coping behaviors. |
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Second Year
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1 .
Galia Avidan
Psychology, Ben-Gurion University
Organizational principles of human cortical eye fields and their role in visual Perception
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2 .
Irit Lichter-Levin
Sourasky Medical Center, Sourasky Medical Center
Brain mechanisms underlying free recall versus recognition retrieval processes
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3 .
Danny Offen
elsenstein Medical Research Center, Tel Aviv University
Mesenchymal stem cells as a tool for delivery of neurotrophic factors to improve behavioral parameters in a transgenic model of Huntington's disease
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4 .
Kobi Rosenblum
Departments of Neurobiology & Ethology, Haifa University
Identifying, analyzing and manipulating cortical neuronal networks underlying sensory memory formation and recall
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| Sensory memories (for example, the memory for a new taste) are thought to be stored in the cortex. While we have, in recent years, learned a considerable amount about molecular events that take place in the gustatory cortex following novel taste learning, we know very little about the population of neurons that participate in acquiring and storing such sensory information. Several basic questions remain unanswered — among them, what types of neuron participate in acquiring and/or consolidating sensory memories? What are the relationships between these neurons? How long are these neuronal populations active? In this study, we are aiming to use taste learning and advanced molecular tools to understand better the ‘circuit or the type, localization and number of neurons underlying the formation and maintenance of sensory memories. |
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5 .
Son Preminger
Brain Research, Weizmann Institute of Science
Human self-initiated motivated behavior: functional neuroanatomy, plasticity and potential for rehabilitation
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6 .
Simone Shamay-Tsoory
Department of Psychology, Haifa University
The involvement of prefrontal asymmetry in processing of negative and positive emotions in patients with major depression: a Transcranial Magnetic Stimulation (TMS )study
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| It has been suggested that the brain’s left and the right hemispheres process differently positive vs. negative emotions. Indeed functional brain asymmetry substantially contributes to the psycho-physiological mechanisms of depression. Transcranial magnetic stimulation (TMS) is a new technique, reported to have an antidepressant effect when applied differently in the right vs. left hemispheres. In the proposed study, we will investigate the differential function of the two hemispheres in emotion processing in depression using TMS. We will examine whether negative biases to sad expressions in depression may be alleviated with right but not left TMS. We hope our findings will offer new insights into the mediating role of brain asymmetry that underlie the profound negative bias processing observed in depression. |
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7 .
Maoz Shamir
Department of Physiology, Ben-Gurion University
Centralized versus collective decision mechanisms in the brain
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| How does the brain perform computation? There are two opposing approaches to this question. One hypothesis claims that computations are done in a collective manner, distributed across a large neural population. The second sees computations executed in a centralized fashion, with decisions shaped by the responses of single cells. This study proposes the development of theoretical tools to investigate the extent of centralization. The extent of centralization in the central nervous system will be tested by applying my resulting theory to the framework of information coding in the visual system. |
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8 .
Anna Sterkin
Goldschleger Eye Research Institute, Tel Aviv University
Establishing electrophysiological markers to probe abnormal levels of neural interactions underlying learning and memory deficits
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| The adult brain retains significant potential for changes, termed plasticity. Plasticity is regulated by the ratio between inhibition and excitation (I/E) that specifically affects lateral interactions between neurons (LI). I/E is also affected by antidepressants, which may constitute a tool to explore plasticity. We found that perceptual learning improved abnormal LI in adults with a developmental visual deficit (amblyopia). We also observed disrupted LI in elderly subjects and in patients with depression, in concert with perceptual and memory deficits. Although we have recently reported specific neurophysiological markers of LI, the exact localization to a specific brain region in humans remains unclear. We propose to investigate the role of I/E in plasticity, short-term memory and learning, using neurophysiology, antidepressants and functional neuroimaging (fMRI), and so develop a tool for exploring depression, amblyopia and aging. |
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9 .
Yifat Prut
Department of Physiology, Hadassah Medical School & ICNC, Hebrew University Jerusalem
Motor correlates of entrainment to rhythmic auditory cues in humans
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| Sensory motor transformation is a fundamental process of the nervous system through which a sensory cue is translated into a motor action. An example of such interactions is motor entrainment to rhythmic auditory cues. The neural substrate which mediates the emergence of motor entrainment is still unclear. The aim of our study is to determine the contribution of different brain centers to the process of motor entrainment, and to assess whether motor information can be used by the auditory system to enhance sensory perception. We expect our results to clarify further the reciprocal impact between motor actions and auditory processing. |
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10 .
Rony Paz
Neurobiology, Weizmann Institute of Science
he effect of partial reinforcement on memory extinction: psychobiology, Neuronal correlates and possible implications
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| Memory extinction is the process by which older memories are modified and inhibited. Subtle changes in the way the memory was acquired can lead to differences in its strength and the ease of extinguishing it. Specifically, reinforcing a behavior or stimulus in a partial manner (not every time it occurs) leads to a ‘stronger’ memory (harder/takes longer to erase). In our study, we are trying to identify the underlying mechanisms in the brain, as this may lead to efficient learning paradigms, and explain why some emotional memories are harder to erase, as in post-traumatic stress disorder. |
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11 .
Anat Maril
Psychology, Hebrew University Jerusalem
Subsequent memory effects & the process of internal generation in prefrontal cortex
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12 .
Orna Almog
Department of Clinical Biochemistry, Health Sciences Faculty, Hebrew University Jerusalem
Adenylyl cyclase-5 is a potential target for mood stablization; unraveling the structure- function basis of carbamazepine's inhibition
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| The mood stabilizers lithium, valproate and carbamazepine, which are used to treat bipolar disorder, decrease brain cAMP. Adenylyl-cyclase (AC) is the enzyme which synthesizes and controls cAMP levels. There are nine membrane-bound AC isoforms (AC1 to AC9). We found that lithium and carbamazepine preferentially inhibit AC5. Carbamazepine apparently exerts the inhibition by interacting with the regulatory binding-site region of the enzyme. We will investigate this possibility using molecular-biology and biochemistry techniques. Unraveling the molecular basis of the interaction between carbamazepine and AC5 may serve as a basis for rational design of potential new mood-stabilizers which specifically inhibit AC5 and reduce brain cAMP. |
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13 .
Avi Avital
Department of Psychology and The Center for Psychobiological Research, The Yezreel Valley College
Stress cascade and schizophrenia-like symptoms: modeling in rat the etiology and onset
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| A valid animal model is needed to understand the etiology of schizophrenia and to test medications. Some of those most widely used involve injecting hallucinogenic substances such as ketamine, or applying stress to cause social isolation and other emotional impairments that are not always specific or sufficient for the disease occurrence. None of the existing model grasp the full spectrum of the disease. Our research goal is to create a comprehensive schizophrenia-like animal model by injecting ketamine, along with inducing prebubertal (acute or chronic) stress. |
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14 .
Nurit Gronau
Department of Psychology, Open University
The role of global contextual factors in visual object perception: an fMRI study
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15 .
Nitsan Kozlovsky
Anxiety and Stress Research Unit, Mental Health Center, Ben-Gurion University
Gene-environment interaction in an animal model of PTSD: What factors make the C57BL/6J mouse susceptible to stress, while the DBA/2J strain remains resilient?
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| Why do some individuals who are exposed to stress develop PTSD, while others do not? Stress-diathesis theories propose that the individual’s sensitivity to stressful events depends, at least in part, on their genetic makeup. Although fairly extensive research has been performed on the genetic basis of PTSD, the precise genes that exacerbate or buffer the effect of traumatic events on PTSD is still unknown. Interaction between different genes and between genes and the environment probably render some individuals vulnerable to developing PTSD and others resilient. Gene-environment studies that focus more specifically on distinct genes and endophenotypes and on influences of controlled environmental factors are thus needed. |
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16 .
Hilla Jakoby
Department of Psychology, Hebrew University Jerusalem
Stimulus-specific adaptation mechanisms and perceptual anchoring abilities as predictors of second language learning aptitude in neurotypical population
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17 .
Einat Shneor Labensohn
, Hadassah College, Jerusalem
Cortical reorganization following damage to the optic chiasm: Neuroimaging studies
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Third Year
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1 .
Edi Barkai, David Golomb and Israel Sekler
, Haifa University & Ben Gurion University
Learning-induced modifications in inhibitory synaptic transmission: Mechanism and functional significance
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2 .
Aviv Weinstein
Hadassah University Hospital, Hebrew University Jerusalem
A pharmaco-genetic and brain imaging study into nicotine induced Dopamine release in cigarette smokers measured with (I-123) IBZM in single photon emission tomography (SPECT)
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2009 - 2010
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First Year
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1 .
Talia Brandman
Tel Aviv University, Department of Psychology
The neural basis of the body inversion effect
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| Recent studies of human visual perception show that we recognize human bodies better when they are presented in an upright position rather than upside down. The drop in recognition for upside down rather than upright images is termed ‘inversion effect,’ and is unique to certain image categories, namely faces and bodies. Functional MRI studies have revealed several object selective areas in the visual cortex whose response to faces is significantly higher. Similar areas have also been found for human bodies. Whereas the neural basis of the face inversion effect has been recently investigated, little is known about the neural mechanisms underlying the body inversion effect. Here we used fMRI to study the processing of upright versus inverted bodies in the human brain and asked whether it is originated from body selective regions. The brain regions examined were the face-specific, body-specific and object-specific visual brain areas. The brain response to inverted body images was higher than to upright body images in the body-specific and object-specific regions, while the face-specific region showed the opposite effect of a higher response to upright than inverted body images. Furthermore, only body-specific regions showed discrimination abilities of different images of bodies, wace-specific and object-specific regions failing to show this effect. These discrimination abilities were found for both upright and inverted bodies. Although each of the object-category specific regions showed a different pattern of response to upright and inverted bodies, none showed a pattern that corresponds to the behavioral effect of better recognition for upright than inverted bodies. Further research with headless bodies will determine whether the higher response of the face-specific region to upright than inverted bodies was induced by the head or by the bodies. |
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2 .
Michael Cardon
Weizmann Institute of Science, Department of Neurobiology
Congenital immune deficits can explain late onset of prepulse inhibition abnormalities through regulation of neurogenesis and Kisspeptin expression
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| A number of neuropsychological syndromes, schizophrenia being a prime example, typically manifest in late adolescence and early adulthood. Cardon and her group propose that the late onset of these diseases is related to immune-dependent brain functions that normally develop at this period. In the well-known animal model for schizophrenia (maternal poly I:C injection) that causes delayed appearance of abnormal prepulse inhibition (PPI), they have shown there is a reduced immune response to brain-antigen both in vitro and in vivo. To demonstrate further that systemic immune deficits may explain delayed onset of abnormal PPI, they showed that in congenitally immune-deficient mice (SCID) abnormal PPI is apparent only at adulthood, and can be reversed by immune reconstitution.
They identified manifestation of immune-dependent regulation of hippocampal neurogenesis and Kisspeptin expression at the critical period of adolescence and early adulthood, and believe this could explain the gap between the inborn immune deficit and the timing of the onset of behavioral symptoms. Moreover, exogenous administration of a Kisspeptin-derived peptide improved the abnormal PPI in SCID mice. Taken together, Cardon’s findings link inborn immune malfunction with late manifestation of abnormal PPI. |
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3 .
Michal Eisenberg
Hebrew University of Jerusalem, Departments of Physiology and Neurobiology
The effects of movement repetition and expectation in monkey and human primary motor cortex
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| This study combines functional imaging techniques from human subjects with neuronal recordings from monkeys in primary motor cortex (M1) to see if repetition of the same movement twice in succession leads to a reduction of the functional MRI signal in the motor system.
Both humans and monkeys made ‘center-out’ reaching movements toward targets in the periphery in different directions separated by 45 degrees. In the monkey experiments, target location was random in the first block of trials, and in a fixed order in a second block. In this block, targets were presented in the same position on three successive occasions, and then in a second position in a counterclockwise direction a further three times. Interestingly, the average firing rate of the neurons increased when movement was toward their preferred direction (PD), and decreased when it was far from the PD. This effect was not due to target repetition. Rather, it suggests that neurons in M1 become more sensitive to direction of movement when the target position (and movement direction) is anticipated.
The results from the parallel experiment in humans are counter to what may be predicted from the neuronal responses in monkeys. Unexpectedly, repeating the same trial (within a ‘random’ sequence), leads to a clear suppression of fMRI activation in M1 compared with non-repeated trials. This suggests that an inference from fMRI adaptation about neuronal properties must be taken with caution. |
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4 .
Alexander Etlin
Hebrew University Jerusalem , School of Medicine
Proprioneurons with multifunicular projections are activated by sacrocaudal afferents to turn on the pattern generating circuitry in the absence of supraspinal control.
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| Sacrocaudal afferent (SCA) stimulation in isolated spinal cords of neonatal rats is used to study the neural pathways involved in sensory-activation of the thoracolumbar central pattern generators (CPGs). Surgical manipulations of the white matter revealed that the SCA-induced rhythm involves activation of segmental and non-segmental sacral relay neurons projecting through the ventral, ventrolateral, and dorsolateral funiculi (VF, VLF, and DLF), that the contribution of VF projections is prominent, and that activation of proprioneurons with short range projections is sufficient to turn on the CPGs on SCA stimulation. Confocal imaging following fluorescent backfilling of funicular axon bundles revealed that the sacral relay neurons projecting via the VF and VLF were distributed within laminae V, and VII-X; but those projecting through the DLF were located in the ipsilateral laminae II-V, VII, and the DLF itself. The VF projections were mainly crossed, while those of the VLF were predominantly uncrossed. Most of the crossed VLF axons ascended through the VF before joining the VLF. Therefore, these axons are interrupted following VF cuts, but are spared after VLF lesions. This complex organization forms a potent and durable means for activation of the CPGs in the absence of descending control of the brain and thereby providing a possible basis of alternative therapeutic approaches for the rescue of lost motor functions after spinal cord injury. |
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5 .
Tal Fishman
Technion Institute of Technology, Department of Pharmacology
Silencing/over-expressing selected genes as a novel model of sporadic Parkinson’s disease
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| We propose a new model of sporadic PD, based on silencing of the SKP1A gene, a component of the SCF complex (ubiquitin-proteasome/E3-ligase), found decreased in substantia nigra (SN) of sporadic PD.
SN-derived cell-line (SN4741 cells) were initially infected with short hairpin RNA lentiviruses (shRNA-LVs) encoding the murine transcript of the SKP1A gene or with non-target shRNA control (scrambled). We found that silencing of SKP1A resulted in increased susceptibility to cell damage induced by the parkinsonism-inducing neurotoxin, MPP+ and serum starvation, in parallel with a decline in the expression of the dopaminergic markers VMAT2 and DAT. SKP1A-deficient cells presented a delay in completion of the cell cycle, and inability to arrest at G0/G1 when induced to differentiate, progressing through S phase, and gradually culminating in a lethal phenotype. Stably enforced expression of wild type SKP1A duplicated the survival index of naïve SN4741 under proteasomal inhibition injury, suggesting a new structural role of SKP1 in dopaminergic neuronal function, besides its E3-ligase activity. The success of thIS in vitro study constituteS the basis for the development of an in vivo model of sporadic PD and will provide a valuable tool for the evaluation of drugs with potential disease-modifying activity. |
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6 .
Yael Mandelblat-Cerf
Hebrew University Jerusalem, Hadassah Faculty of Medicine
Long term adaptation to force field shows long term evolvement of neuronal changes
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| Yael Mandelblat-Cerf and her group are investigating gradual and long-term adaptation to a new environment. The experiment they designed distributed eight targets evenly in a circle around a center. Monkeys, trained in executing center-to-target reaching movements, were directed to reach one of the eight targets (‘learned direction’) under a force-field (FF), applied perpendicular to the hand-movement direction. The monkeys also executed reaches to other directions without the force-field. The neuronal activity of single cells in primary motor cortex was recorded, using chronically implanted arrays while two monkeys adapted to the new FF. Their performance showed gradual improvement through the five days of training. Movements under the FF to the learned direction became straighter, although they curved in the opposite direction when the FF was turned off (after effect), suggesting that monkey learned to push against the FF.
Neuronal activity modulations were examined along the five days of adaptation by tracing changes in the cells in three areas:
firing rate (FR) — neuronal activity
preferred directions (PD) — the movement direction in which the cell is most active
population vectors (PV) — a vector that indicates the direction in which the population of cells points
Their findings were:
Two distinct subpopulations of cells showed a change in FR — one an increase in FR, and the second a decrease.
While earlier studies have shown that FF caused PD to shift with the direction of FF (Li 2001), these researchers observed only two subpopulations of cells showing a shift in PD, since FF was applied only to a single direction.
PV to LD shifted from the target direction contrary to the FF direction.
These results present a neuronal signature for FF adaptation across days and explain why the observed changes in FR cause the shifts in PD and PV. Performance improved from day to day, yielding straighter movements in the LD under FF. The neuronal activity aims the hand in the direction against that of the FF, in order to achieve these straighter hand movements. |
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7 .
Limor Regev
Department of Neurobiology, Weizmann Institute of Science
Amygdalar CRF: adaptive or maladaptive stress neuropeptide
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| The corticotropin-releasing factor (CRF) neuropeptide is an essential regulator of the neuro-endocrine stress response and is implicated in the control and maintenance of homeostasis. Flaws in the regulation of the stress-response can have severe psychological and physiological consequences and it has been suggested that dysregulation of the CRF system is involved in the development of anxiety disorders and depression. To further study the relative contribution of CRF, endogenously expressed by anxiety-linked brain structures, to anxiety and depression-like behaviors in mice, we designed and generated several lentiviral-based models aimed to manipulate the expression levels of CRF at specific brain regions. We have developed lentiviruses that over-expressing CRF, either continuously or at inducible manner, using CMV or tetracycline-induced promoters, respectively. In addition, we generated lentiviruses expressing shRNA aimed to knockdown CRF expression levels. All lentiviral constructs also contain a fluorescent reporter to allow verification of site of infection. In vitro and in vivo validation of these lentiviruses using biochemical and immunohistochemical techniques demonstrated their functionality. Stereotaxic injection of these viruses into the central nucleus of the amygdala of male mice created transgenic mice models that express lower or higher levels of CRF specifically at site of injection. A panel of anxiety and depression-like behavior tests were performed to elucidate the effect of each manipulation on basal and stress-induced anxiety and depression-like behaviors. These studies were followed by locomotion, learning and memory tests and histological and morphological analysis. Results obtained from this study, which will be presented at this conference, demonstrated the importance of amygdalar CRF in mediating the central stress response and its ambiguous role in stress-induced coping behaviors. |
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8 .
Rony Panarsky
Department of Pharmacology, School of Pharmacy, Hebrew University Jerusalem
Anti-inflammatory properties of ladostigil and its metabolites in primary microglia
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| Alzheimer’s disease (AD) is a devastating neurodegenerative disease that causes progressive memory loss and behavioral aberrations in about 5 percent of population over the age of 65 years. Increasing evidence points to oxidative-nitrative stress and microglial activation with release of inflammatory cytokines (Il1α/β, TNFα, IFNγ) as possible initiators of apoptosis in the aging brain leading to plaque disposition and neurodegeneration.
Microglia are a major source of oxidative (ROS) and nitrative (RNS) stress in the brain. These macrophage-like cells are present in the healthy brain in a dormant state and can be rapidly activated by damage as the result of stroke, trauma or pathogenic invasion. Activation of microglia is characterized by changes in their morphology and function that causes them to release a wide range of inflammatory cytokines (Il1α/β, IL-6, TNFα) as well as nitric oxide (NO) and superoxide. It may therefore be possible to slow the neurodegenerative process by reducing oxidative-nitrative stress and the prolonged activation of microglia in the brain.
Ladostigil (R-CPAI) [(N-propargyl)-(3R)-aminoindan-5-yl]-ethyl methyl carbamate is a novel compound which inhibits cholinesterase (ChE) and is also a brain selective inhibitor of monoamine oxidase (MAO).
In our study the potential protective ability of R-CPAI to reduce nitric oxide and inflammatory cytokines was evaluated in primary cultures of mouse microglia. The effect of R-CPAI was compared with three of its active metabolites, R-MCPAI, R-CAI and R-HPAI. R-CAI lacks the propargyl group, while R-MCPAI lacks the ethyl group on the carbamate N. R-HPAI is formed from R-CPAI by ChE and the carbamate moiety is replaced by a hydroxyl group.
We showed that in concentrations of 1nM-1uM, R-CPAI decreased the release of NO induced by LPS into the medium after 24 hrs. Metabolites R-MCPAI, R-CAI and R-HPAI all showed this anti-inflammatory activity. Since R-HPAI does not possess a carbamate moiety, it suggests that this group is not necessary for their protective activity against LPS in microglia and that it does not result from ChE inhibition. This was confirmed by a lack of effect of a more potent ChE inhibitor, rivastigmine. Neither does the presence of a propargyl moiety in the structure appear to be necessary for this activity since R-CAI was also active. RT-PCR analysis showed that all the metabolites reduced significantly the amounts of mRNA of iNOS, IL-1β and TNF-α in response to LPS at similar or lower concentrations than ladostigil. The protective effect of the compounds against LPS-induced microglial activation does not seem to result from their ability to activate nicotinic AchR, although such activation has been shown to reduce inflammatory processes in macrophages. The drugs may produce their action in microglia by altering the MAPK signaling cascade.
These results show that ladostigil has anti-inflammatory effects on microglia that may explain its neuroprotective effect in vivo. |
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9 .
Boaz Sadeh
Department of Psychology, Tel Aviv University
Do upright and inverted faces recruit the same or different neural mechanisms? An N170 competition experiment
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| My research focuses on the way the brain processes and recognizes human faces. A basic premise in the field is the existence of a specialized mechanism in our cerebral visual system dedicated to face-processing. We have been investigating the nature of this specialized mechanism by using, among other techniques, measures of electrical potentials (ERPs) recorded from the scalp.
When we see pictures of various objects, the ERP which appears about 170 milliseconds after appearance of the picture is larger when the picture is of a face than of another object. This well known ERP is labeled N170. Surprisingly, when the face is presented upside down, the ERP becomes even larger, a phenomenon not observed with any other inverted objects.
There are two possible explanations for the N170 inversion effect exist. First, our specialized mechanism for face processing works harder when the face is presented upside down. Second, inverted faces may recruit another, more generalized, object-processing mechanism, in addition to the face-related mechanism.
In the present study, we record ERPs while the participant looks at a face, upright or inverted, that appears on the screen next to another pre-existing picture (which can be an upright or inverted face or another object). When a picture belongs to the same functional category as the pre-existing one (for example, face + face), its N170 is lower than in other cases (for example, object + face). Thus, by comparing different combinations — object + face, object + inverted face, face + inverted face, and so on — we can identify the extent to which common mechanisms are used to process these items. Our results are in line with the view that inverted faces recruit the upright face processing mechanism, but are also processed by an additional non-face mechanism. |
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10 .
Alit Stark
Department of Neurobiology, Hebrew University Jerusalem
Representation of dynamic and kinematic parameters of wrist flexion in the human brain
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| Even very simple movements that require little though or overt attention — scratching the head, reaching out an arm for a coffee cup — require very complex motor interactions. These interactions occur both on a functional level (among neurons, for example) and between levels (brain neurons, spinal cord neurons and muscles). Debate exists as to the motor brain codes or the commands given when the brain plans and executes movements. The central dogma of motor control is a top-down hierarchy of motor system processing: from abstract goals to specific instructions to muscles (muscle dynamics).
It is still unclear, however, which level (or combination of levels) in this hierarchy is processed by the primary motor cortex. Does the primary motor cortex code the identity of muscles and the amount of force each muscle should produce to contract and execute a desired movement (dynamic coding)? Or, does it code higher-level parameters related to the direction and velocity of the whole limb (kinematic coding)? In addition, which brain regions are involved in each type of coding? These remain open questions.
To dissociate the relative contribution of dynamic and kinematic movement parameters to human brain activity, we measured BOLD responses using fMRI, as subjects performed well-defined wrist flexion movements. In our first experiment, our aim was to characterize the representation of movement dynamics while controlling kinematic parameters. Thirteen right-handed subjects were trained to make repetitive isolated movements of their right or left wrists against different loads. We found that the strength of activation within the sensorimotor cortical network (areas M1, PM, SMA and S1) increased monotonically with the load. Consistent with some single-unit studies in primates, this shows that the BOLD signal throughout the sensorimotor cortical network increases monotonically with the force exerted.
To characterize the complementary representation of kinematics while controlling for movement dynamics, we carried out a second experiment. Nine right-handed subjects repeatedly moved their wrists against a constant load. Movement distance, duration and velocity varied systematically between conditions. We found that movement extent and duration both contributed similarly to the M1 BOLD response, while peak movement speed was largely irrelevant. Thus, large-amplitude actions (in time or space) lead to an increased BOLD response.
Taken together, our results show that both kinematic and dynamic parameters of single-joint movements influence BOLD activity in the human sensorimotor cortex. |
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11 .
Dekel Taliaz
Department of Neurobiology, Weizmann Institute of Science
The role of brain-derived neurotrophic factor in the antidepressant effect of desipramine and electroconvulsive treatment
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| This study builds on earlier research performed by Taliaz, in which he found that depressive-like behavior and a reduction in neurogenesis in rats resulted from reduced BDNF (a growth factor expressed mainly within the brain), using RNA interference and lentiviral vectors injected exclusively into the dentate gyrus.
In this study, he has gone on to test whether elevation in hippocampal BDNF expression is essential for the behavioral effects of antidepressant treatments and whether it correlated with neurogenesis. He found that BDNF knockdown within the dentate gyrus blocked the effect of chronic treatment with desipramine (DES) in the forced swim tests. The effect of electroconvulsive therapy (ECT), however, was not blocked by BDNF knockdown within the same sub-region. While the mechanism of DES action seems to depend on elevation of hippocampal BDNF, ECT may exert its behavioral effects through different or additional mechanisms. |
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12 .
Daniel Offen
Felsenstein Medical Research Center, Tel Aviv University
Mesenchymal stem cells as a tool for delivery of neurotrophic factors to improve behavioral parameters in a transgenic model of Huntington’s disease
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| Huntington’s disease (HD) results from the genetically programmed degeneration of neurons in certain areas of the brain. This degeneration causes uncontrolled movements, loss of intellectual faculties and emotional disturbance. At this time, there is no way either to stop or reverse the course of HD and the medications administered cause severe side effects. Discovery of the HD gene has led the way for an efficient animal model. In the current proposal we aim to test the stem cells generated by our novel protocol as an effective treatment for transgenic HD mice. We hope this will develop into new strategies for using the stem cells of HD patients as their own therapeutic modality. |
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13 .
Kobi Rosenblum
Department of Neurobiology and Ethology, University of Haifa
Identifying, analyzing and manipulating cortical neuronal networks underlying sensory memory formation and recall
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| Sensory memories (for example, the memory for a new taste) are thought to be stored in the cortex. While we have, in recent years, learned a considerable amount about molecular events that take place in the gustatory cortex following novel taste learning, we know very little about the population of neurons that participate in acquiring and storing such sensory information. Several basic questions remain unanswered — among them, what types of neuron participate in acquiring and/or consolidating sensory memories? What are the relationships between these neurons? How long are these neuronal populations active? In this study, we are aiming to use taste learning and advanced molecular tools to understand better the ‘circuit or the type, localization and number of neurons underlying the formation and maintenance of sensory memories. |
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14 .
Dr. Leon Deouell
Department of Psychology, Hebrew University
In the eyes of the beholder: Correlation between induced gamma-band responses and eye movements
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| The scalp-recorded EEG is a convenient and non-invasive method for measuring brain activity with millisecond resolution. One type of EEG activity, known as the induced gamma band response (iGBR), was thought to reflect the synchronous firing of neurons, which represent different aspects of a perceived object (e.g., its color and shape, or its different parts). However, we have recently found conclusive evidence showing that the iGBR in fact reflects involuntary eye movements. Our project will examine details of how different stimuli affect these eye movements and the conditions under which eye movements affect the iGBR. |
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15 .
Edi Barkai, David Golomb and Israel Sekler
Biology & Neurobiology, University of Haifa
Learning-induced modifications in inhibitory synaptic transmission: mechanisms and functional significance
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| Most modern research on biological mechanisms underlying learning and memory in the mammalian brain has concentrated on learning–relevant enhancement of excitatory synaptic transmission and intrinsic neuron excitability. Finding such post-training enhancement of neuronal excitability raises a new fundamental question: What prevents the cortical network from exploding into very high activity levels due to this increased excitability? The “natural” candidate for a learning-dependent compensatory mechanism is inhibitory synaptic transmission. Activity-dependent enhancement of fast, GABAA mediated inhibitory synaptic transmission, either by increasing Chloride ion conductance or by hyperpolarizing their reversal potential, was recently demonstrated in learning conditions, including development and Long Term Potentiation. However, it is
yet to be determined whether and how such modifications are relevant to learning and memory. The aim of our project is to describe quantitatively mechanisms by which learning-induced modifications in inhibitory synaptic transmission modulate induction and preservation of long-term memories in the cortex, while efficiently preventing the appearance of epileptic-like activity. To bridge the gap between the molecular level and long-lasting behavioral modifications, our study will combine olfactory discrimination learning with single cell neurophysiology of olfactory cortex pyramidal neurons, molecular biology of the GABAA receptor and the Potassium-Chloride co-transporter, and modeling of large neuronal networks. |
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16 .
Prof. Hagit Cohen
Anxiety and Stress Research Unit. Faculty of Health Sciences, Ben-Gurion University
Assessment of differential effects of stress hormones and noradrenergic manipulation on traumatic memory consolidation and reconsolidation as reflected in behavioral stress responses
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| Post-traumatic stress disorder (PTSD) is an incapacitating chronic anxiety disorder induced by extreme experiences such as combat, terror attacks, rape and other violent crimes, child and marital abuse, accidents and natural disasters. It is estimated that about one in twelve people in the US suffer from PTSD at some point in their lives, with women affected about twice as often as men. The high prevalence rates of PTSD incur significant individual, institutional and governmental health costs, resulting in an estimated $3 billion annual productivity loss in the US in 2003. The cost of PTSD exceeds that of all other anxiety disorders, and much of this expenditure is accounted for by direct costs of treatment-seeking and medical evaluation.
To date there are almost no empirical data on which to base recommendations for immediate post-exposure pharmacological intervention to effectively forestall development of PTSD.
This study will examine the effects of immediate post-exposure pharmacological intervention, using the adrenocortical stress hormone corticosterone and agents that act at adrenergic receptors, in an animal model of PTSD. The model focuses on the degree of individual behavioral response to the stress paradigm, enabling quantification of behavioral effects of the different interventions. |
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17 .
Dr. Reuven Stein
Life Sciences Faculty, el-Aviv University
Molecular characterization of the neuropathology and cognitive deficits in a model of neurofibromatosis and evaluation of potential treatments
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| Neurofibromatosis type 1 (NF1) is a common, complex, incurable genetic disease that is characterized by a high incidence of tumors in the nervous system. In addition, approximately 50% of children with NF1 suffer from learning disabilities. The gene responsible for the disease, neurofibromin, shuts down the active form of a protein called Ras. A model for NF1 (Nf1+/− ) has been established and shown to exhibit similar cognitive deficits as NF1 itself.
Our overall objective is to unravel molecular details underlying cognitive deficits in Nf1+/− brains and develop a treatment that will alleviate these cognitive deficits. Our studies will include two complementary tasks. First, we will determine neuropathological, signaling and cognitive-associated impairments of Nf1+/−. Secondly, we will examine whether and how environmental stimulation or pharmacological treatment with a specific Ras inhibitor alleviates Nf1+/− cognitive deficits. |
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18 .
Dr. Anat Barnea
Natural and Life Sciences, The Open University of Israel
Neurobiological aspects of migratory behavior: a neuroethological study, comparing migrant and resident species in Israel
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| This behavioral neurobiology study combines field and laboratory work to explore neurobiological mechanisms underlying migration. We hypothesize that the species’ biology (migrant or resident) correlates seasonally with processing of spatial information and with neurobiological parameters. Pairs of closely related species (migratory and resident) will be seasonally treated with a cell birth date marker, and their brains processed 5 weeks later for histology and immunohistochemistry. We will measure new neuronal recruitment, hippocampal volumes and other relevant brain regions, to make two comparisons: inter-specific (migrants vs. residents), and intra-specific (juveniles vs. adults; seasonal changes). Analysis of stable isotopes will identify origin and we will search for correlations between length of migration route and neurobiological parameters. We will also measure hormones known to influence neuronal recruitment.
We hope our study will: 1) broaden knowledge on neuronal mechanisms underlying behavior, and on the poorly understood functional significance of adult
Neurogenesis; 2) clarify the potential role of specific brain regions in obtaining navigational information; 3) help us understand the limits of long-term memory acquisition and the control and function of adult brain plasticity. This may help in clinical applications, by suggesting new approaches to prevention of neuronal death and promoting neuronal replacement. |
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19 .
Prof. Ehud Zohary
Department of Neurobiology, The Hebrew University
Cortical plasticity in the adult human visual system following retinal damage caused by Macular Degeneration
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| Contrary to long held beliefs, there is evidence that sensory maps are not immutable in the adult cerebral cortex. However, the degree to which massive changes in the cortical representation of the sensory and motor maps indeed take place after an injury to the peripheral organ (such as damage to the eye or amputation of a limb) is still hotly disputed. We will assess this issue in human patients suffering from chronic retinal damage (caused by macular degeneration)
or limb loss. We will also track the dynamics of the putative cortical changes in the visual cortex by generating reversible virtual lesions in healthy humans wearing appropriately designed contact lenses for a week. Analogously, we will track changes in the motor cortex by studying people with a limb immobilized in a cast for a month (due to a fracture). This research project will provide us with a better understanding of human cortical plasticity and its relationship to behavior. |
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20 .
Shlomo Wagner
Department of Neurobiology and Ethology, University of Haifa
Information processing in the vomeronasal system and the genetic expression of the channel-rhodopsin-2 gene in specific vomeronasal organ neurons
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| Most mammals rely on a specialized sensory system, the vomeronasal system, for sensing pheromones, which mediate social and reproductive interactions between individuals of the same species. However, the physiological mechanisms mediating information processing in the vomeronasal system are virtually unexplored, because of certain technical obstacles. We will bypass these obstacles by combining genetic engineering and a cutting-edge technique for light-induced stimulation of neurons. The proposed genetically modified line enables us to monitor, for the first time, the brain’s neuronal responses to stimulation of the vomeronasal system under anesthesia. Results of this study may be a breakthrough in the exploration of information processing in the vomeronasal system. |
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21 .
Gabi Aisenberg Romano
Faculty of Medicine, Tel Aviv University
Effect of SSRI treatment on affective symptoms and fertility treatment outcome in women undergoing in vitro fertilization for unexplained infertility – a prospective placebo-controlled study.
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| Women undergoing IVF show a high prevalence of depressive and anxiety symptoms, with stress having harmful consequences on IVF and pregnancy outcomes. The involvement of an immunological cascade in the process has been suggested. Treatment in this setting is usually psychotherapeutic rather than pharmacotherapeutic. There is, however, reasonable biological evidence for the beneficial influence of antidepressant therapy on pregnancy and wellbeing, and pharmacotherapy is more available and affordable than psychotherapy in the public health system. We are therefore studying the efficacy of antidepressant treatment in women undergoing IVF treatment, presenting with mild mood symptoms. We hypothesize that treatment will result not only in a greater attenuation of affective symptoms, but also in higher pregnancy success rates. We also anticipate certain immunological stress-reactive factors proving to be the biological mechanism that underlie these effects. |
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22 .
Orna Almog
Health Sciences Faculty, Ben-Gurion University
Adenylyl cyclase-5 as a potential target for mood stabilization; unraveling the structure-function basis of carbamazepine inhibition
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| The mood stabilizers lithium, valproate and carbamazepine, which are used to treat bipolar disorder, decrease brain cAMP. Adenylyl-cyclase (AC) is the enzyme which synthesizes and controls cAMP levels. There are nine membrane-bound AC isoforms (AC1 to AC9). We found that lithium and carbamazepine preferentially inhibit AC5. Carbamazepine apparently exerts the inhibition by interacting with the regulatory binding-site region of the enzyme. We will investigate this possibility using molecular-biology and biochemistry techniques. Unraveling the molecular basis of the interaction between carbamazepine and AC5 may serve as a basis for rational design of potential new mood-stabilizers which specifically inhibit AC5 and reduce brain cAMP. |
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23 .
Avi Avital
Department of Psychology, Jezreel Valley College
Stress cascade and schizophrenia-like symptoms: modeling in rat the etiology and onset
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| A valid animal model is needed to understand the etiology of schizophrenia and to test medications. Some of those most widely used involve injecting hallucinogenic substances such as ketamine, or applying stress to cause social isolation and other emotional impairments that are not always specific or sufficient for the disease occurrence. None of the existing model grasp the full spectrum of the disease. Our research goal is to create a comprehensive schizophrenia-like animal model by injecting ketamine, along with inducing prebubertal (acute or chronic) stress. |
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24 .
Ofer Golan
Department of Psychology, Bar Ilan University
The effect of auditory perception and theory of mind on receptive prosodic skills in autism spectrum disorders and typically developed adults
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| The term prosody refers to the acoustic attributes of speech, defining the semantic or emotional meaning of an utterance. Individuals with autism spectrum disorders (ASD) lack intact abilities to comprehend the prosodic language cues that are vital for social communication. Using a battery of auditory tasks that increase in complexity, we are aiming to track down auditory abilities responsible for the capacity to comprehend the prosodic attributes of speech, and to examine the interrelations between those abilities and higher cognitive abilities involved in the perception of prosody. These associations will be examined in ASD in comparison with typically developed adults to reveal the mechanisms underlying prosodic difficulties in ASD. |
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25 .
Nurit Gronau
Department of Psychology, The Open University of Israel
The role of global contextual factors in visual object perception: an fMRI study
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| The present research is investigating how the immediate contextual environment of an object — that is, a functionally associated stimulus for example, a desk-lamp associated with a desk) — affects object recognition and neural object representation. Three questions will be explored:
1) Are functionally-related object pairs perceived better than functionally unrelated objects, due to reduced competition between contextually-grouped stimuli?
2) Does the presence of a functionally-related stimulus affect explicit and implicit memory (for example, repetition-priming) measures for visual object transformations (for example, object location change)?
3) can the spatial properties of an object, such as its orientation or its direction of action, reflexively guide spatial attention to a contextually-relevant location in the visual field? |
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26 .
Nitsan Kozlovsky
Anxiety & Stress Research Unit, Ben-Gurion University
Gene-environment interaction in an animal model of PTSD: what factors make the C57BL/6J mouse susceptible to stress, while the DBA/2J strain remains resilient?
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| Why do some individuals who are exposed to stress develop PTSD, while others do not? Stress-diathesis theories propose that the individual’s sensitivity to stressful events depends, at least in part, on their genetic makeup. Although fairly extensive research has been performed on the genetic basis of PTSD, the precise genes that exacerbate or buffer the effect of traumatic events on PTSD is still unknown. Interaction between different genes and between genes and the environment probably render some individuals vulnerable to developing PTSD and others resilient. Gene-environment studies that focus more specifically on distinct genes and endophenotypes and on influences of controlled environmental factors are thus needed. |
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27 .
Rony Paz
Department of Neurobiology, Weizmann Institute of Science
Effect of partial reinforcement on memory extinction: psychobiology, neuronal correlates and possible implications
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| Memory extinction is the process by which older memories are modified and inhibited. Subtle changes in the way the memory was acquired can lead to differences in its strength and the ease of extinguishing it. Specifically, reinforcing a behavior or stimulus in a partial manner (not every time it occurs) leads to a ‘stronger’ memory (harder/takes longer to erase). In our study, we are trying to identify the underlying mechanisms in the brain, as this may lead to efficient learning paradigms, and explain why some emotional memories are harder to erase, as in post-traumatic stress disorder. |
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28 .
Yifat Prut
Department of Physiology, The Hebrew University
Motor correlates of entrainment to rhythmic auditory cues in humans
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| Sensory motor transformation is a fundamental process of the nervous system through which a sensory cue is translated into a motor action. An example of such interactions is motor entrainment to rhythmic auditory cues. The neural substrate which mediates the emergence of motor entrainment is still unclear. The aim of our study is to determine the contribution of different brain centers to the process of motor entrainment, and to assess whether motor information can be used by the auditory system to enhance sensory perception. We expect our results to clarify further the reciprocal impact between motor actions and auditory processing. |
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29 .
Simone Shamay-Tsoory
Department of Psychology, University of Haifa
Involvement of prefrontal asymmetry in processing of negative and positive emotions in patients with major depression: a transcranial magnetic stimulation (TMS) study
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| It has been suggested that the brain’s left and the right hemispheres process differently positive vs. negative emotions. Indeed functional brain asymmetry substantially contributes to the psycho-physiological mechanisms of depression. Transcranial magnetic stimulation (TMS) is a new technique, reported to have an antidepressant effect when applied differently in the right vs. left hemispheres. In the proposed study, we will investigate the differential function of the two hemispheres in emotion processing in depression using TMS. We will examine whether negative biases to sad expressions in depression may be alleviated with right but not left TMS. We hope our findings will offer new insights into the mediating role of brain asymmetry that underlie the profound negative bias processing observed in depression. |
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30 .
Maoz Shamir
Department of Psychology, Ben-Gurion University
Centralized versus collective decision mechanisms in the brain
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| How does the brain perform computation? There are two opposing approaches to this question. One hypothesis claims that computations are done in a collective manner, distributed across a large neural population. The second sees computations executed in a centralized fashion, with decisions shaped by the responses of single cells. This study proposes the development of theoretical tools to investigate the extent of centralization. The extent of centralization in the central nervous system will be tested by applying my resulting theory to the framework of information coding in the visual system. |
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31 .
Anna Sterkin
Goldschleger Eye Research Institute, Tel Aviv University
Establishing electrophysiological markers to probe abnormal levels of neural interactions underlying learning and memory deficits
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| The adult brain retains significant potential for changes, termed plasticity. Plasticity is regulated by the ratio between inhibition and excitation (I/E) that specifically affects lateral interactions between neurons (LI). I/E is also affected by antidepressants, which may constitute a tool to explore plasticity. We found that perceptual learning improved abnormal LI in adults with a developmental visual deficit (amblyopia). We also observed disrupted LI in elderly subjects and in patients with depression, in concert with perceptual and memory deficits. Although we have recently reported specific neurophysiological markers of LI, the exact localization to a specific brain region in humans remains unclear. We propose to investigate the role of I/E in plasticity, short-term memory and learning, using neurophysiology, antidepressants and functional neuroimaging (fMRI), and so develop a tool for exploring depression, amblyopia and aging. |
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32 .
Rakefet Ackerman
Department of Psychology, Ben-Gurion University
The heuristic basis for the sense of understanding of younger and older adults
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| Learners of all ages must monitor their understanding to regulate their learning, and know when to rely on a subjective sense of understanding. This sense is not, however, necessarily accurate. We will examine the cues that generate a sense of understanding in healthy younger and older adults and assess whether this sense is biased by superficial characteristics of the material learned. With executive function deteriorating during adulthood, we will investigate differences between younger and older adults in the underlying processes involved in understanding texts of various kinds. We expect to find that, under certain conditions, biases in the sense of understanding in older adults will be greater than that in younger adults. Where their judgment is equally accurate, we expect selection of strategies for improving knowledge will be less efficient in older adults. We believe our findings will help define goals for cognitive training that will foster true and reliable understanding |
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33 .
Liat Gantz
Department of Neurology, Weizmann Institute of Science
Dynamics of learning in cooperative sensory networks of the adult human brain
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34 .
Yaakov Hoffman
Brain Research Center, Bar Ilan University
Processing of incongruent stimuli: ocular motor evidence for attentional, memory, and hemispheric components
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35 .
Hilla Jakoby
Department of Psychology, The Hebrew University
Stimulus-specific adaptation mechanisms and perceptual anchoring abilities as predictors of second language learning aptitude in neurotypical population
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36 .
Zehavit Kariv-Inbal
Department of Neurobiology, Tel Aviv University
Amelioration of the pathological synergism between amyloid beta and ApoE4 in vivo by distinct lipid diets
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37 .
Hagit Magen
School of Occupational Therapy, The Hebrew University
Perceptual and attentional processes in individuals with sensory modulation disorder: An EEG study
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| Individuals with sensory modulation disorder (SMD) exhibit inappropriate (diminished or exaggerated) responses to typical sensory input. The sensory disorder in these individuals may lead to disorders in emotional stability and cognitive performance. While SMD is a feature of other conditions such as ADHD and autism, it has recently been recognized that it may occur without any other diagnostic condition. Our research will examine the perceptual and attentional functions of these individuals solely with SMD, using behavioral and brain activity measures (EEG) to validate it as a distinct syndrome and establish valid diagnostic tools. |
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38 .
Johanna Schumann
Department of Neurobiology & Ethology, University of Haifa
The role of the NMDA receptor complex in cocaine psychomotor sensitization
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39 .
Einat Shneor Labensohn
Department of Neurology, The Hebrew University
Cortical reorganization following damage to the optic chiasm: Neuroimaging studies
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40 .
Eteri Tsitsiashvili
Chaim Sheba Medical Center,, Tel Aviv University
Development of a treatment based on perceptual learning for strabismic amblyopia in children
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Second Year
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1 .
Miki Bloch
Sourasky Medical Center, Tel Aviv University
The effect of gonadal steroids on emotional processing and regulation abnormalities in women with a predisposition to postpartum depression.
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| Studies of the underlying causes of depression have shown common cognitive biases in attending to and recall of negative emotional stimuli in depressed or depression-prone women. It has been hypothesized that such abnormalities play a role in the development of depression. It has also been shown that the unique hormonal conditions of the postpartum period are etiologically related to the onset of postpartum depression (PPD). We hypothesize that specific hormonal conditions can trigger depressogenic cognitive schemas in women with a specific vulnerability to PPD, while not doing so in normal controls or in those with past major depression. We propose studying this by examining performance in cognitive tasks in two hormonal conditions - the early (estrogen) and late (progesterone) phases of the menstrual cycle. |
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2 .
Ruth Defrin and Karni Ginzburg
, Tel Aviv University
Chronic pain and reactivity to painful stimuli among combat-related PTSD patients
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3 .
Yoav Gothilf
, Tel Aviv University
Light entrainment of the circadian clock
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| Abnormalities in the daily biological clock contribute to the development of mood disorders. The daily clock is mainly synchronized by light, with bright-light therapy having a positive effect on those with seasonal and other mood disorders. To better understand the molecular mechanism by which light synchronizes the daily clock, we will use the unique zebra-fish model to investigate the regulation of the period2 gene, which is activated by light and is important for the synchronization of the clock. We believe this investigation will lead to the development of drug-based therapies for seasonal and other mood disorders. |
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4 .
Tzuri Lifschytz
Hadassah Medical Center, Hebrew University Jerusalem
RGS2 gene activity levels and the propensity to develop anxiety and/or depression following chronic mild stress
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| Among the causes of depression and anxiety, a substantial degree of susceptibility is known to be contributed by genetic factors. In the past decade, the RGS2 gene, a member of a protein family that regulates neural transmission, was found to be associated with anxiety and depression in both humans and animal models. The goal of our research is to create a comprehensive animal model in which to assess the contribution of different levels of gene activity to the development of anxiety and depression following exposure to environmental stress. This will provide a model for studying a potentially similar relationship in humans. |
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5 .
Yehuda Pollack
, Sha’are Zedek Medical Center
Risk-taking and decision-making under uncertainty in adolescents with attention-deficit and hyperactivity disorder
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6 .
Rami Yaka
, The Hebrew University
Identification of new drug targets for cocaine addiction using a proteomic approach
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| New understanding of drug abuse and addiction has shown that both depend on drug-effects on brain function. Drug addiction can be defined as inability to regulate the drive to obtain the drug, while reducing the drive for natural rewards. These behavioral changes are manifested by neuropharmacological actions on a common brain-reward circuit, known as the reward system. We propose a proteomics approach to studying these neuroadaptations at molecular level during different stages of cocaine administration, using a common behavioral paradigm for cocaine addiction. |
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2008 - 2009
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First Year
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1 .
Amir Amedi
Hebrew University of Jerusalem, Faculty of Medicine and Program of Cognitive Science
Cognitive neuroscience of mental imagery versus perception in the three topographical senses
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| Mental imagery is an important cognitive ability, used in memory, and cross-modal integration. Most studies of visual mental imagery have suggested a substantial overlap in the neural substrates that support perception and imagery. Why, however, are our subjective experiences so different if the neural substrate that subserves imagery and perception is so similar? We suggest here an alternative theory of the neural basis of mental imagery. We propose studying it with advanced brain imaging and electrophysiological techniques, which will tell us how imagery arises from neural processes in all three topographical sensory modalities: sight, hearing and touch. |
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2 .
Sharon Anavi-Goffer
Ariel University Center of Samaria, Behavioral Sciences and Molecular Biology
A role for cannabinoid CB2 receptor in schizophrenia
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| Schizophrenia is one of the most prominent forms of psychiatric illness in young people. It is associated with deficits in cognitive function, and with anxiety and depression - symptoms which are enhanced by the consumption of cannabis. This suggests the involvement of a signaling system in the brain which is sensitive to cannabis and cannabis-mimicking (cannabinoid) drugs. In some schizophrenic patients, alterations in some components of the endogenous cannabinoid system have been observed. The contribution of the 'non-psychoactive' cannabinoid CB2 receptor to disease etiology has not, however, been investigated. We propose to explore the effect of the CB2 receptor in the development and course of schizophrenia, along with the effectiveness of CB2 receptor-mediated treatment. We believe that identifying a role for the CB2 receptor in the disease's etiology may generate a new class of non-psychoactive therapeutic drugs, free of side-effects on the brain. |
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3 .
Galia Avidan
Ben Gurion Univesrity of the Negev, Psychology Department
Investigating the organization principles of human cortical eye-fields and their role in visual perception
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| Saccadic eye movements bring segments of the visual field onto the high acuity portion of the retina, thus enabling detailed analysis of the foveated object during the subsequent fixation period. While saccades are visually controlled motor responses, their operation also controls the sampling of visual input. Their involvement with vision, therefore, takes the form of an interactive loop of saccades, which are simultaneously visually guided while affecting the sampling of the visual scene. We propose using brain imaging and eye-movement tracking techniques to map the neural representation of this visuo-motor loop. |
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4 .
Miki Bloch
Sourasky Medical Center, Ambulatory Psychiatric Department
The effect of gonadal steroids on emotional processing and regulation abnormalities in women with a predisposition to postpartum depression
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| Studies of the underlying causes of depression have shown common cognitive biases in attending to and recall of negative emotional stimuli in depressed or depression-prone women. It has been hypothesized that such abnormalities play a role in the development of depression. It has also been shown that the unique hormonal conditions of the postpartum period are etiologically related to the onset of postpartum depression (PPD). We hypothesize that specific hormonal conditions can trigger depressogenic cognitive schemas in women with a specific vulnerability to PPD, while not doing so in normal controls or in those with past major depression. We propose studying this by examining performance in cognitive tasks in two hormonal conditions - the early (estrogen) and late (progesterone) phases of the menstrual cycle. |
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5 .
Yoav Gothilf
Tel Aviv University, Neurobiology Department
Light entrainment of the circadian clock: regulation of period2 in the zebra-fish model
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| Abnormalities in the daily biological clock contribute to the development of mood disorders. The daily clock is mainly synchronized by light, with bright-light therapy having a positive effect on those with seasonal and other mood disorders. To better understand the molecular mechanism by which light synchronizes the daily clock, we will use the unique zebra-fish model to investigate the regulation of the period2 gene, which is activated by light and is important for the synchronization of the clock. We believe this investigation will lead to the development of drug-based therapies for seasonal and other mood disorders. |
| close |
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6 .
Tzuri Lifschytz
Hebrew University of Jerusalem, Psychiatry Department
Evaluation of the interaction between activity levels of the RGS2 gene and the propensity to develop anxiety and/ or depression following chronic mild stress
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| Among the causes of depression and anxiety, a substantial degree of susceptibility is known to be contributed by genetic factors. In the past decade, the RGS2 gene, a member of a protein family that regulates neural transmission, was found to be associated with anxiety and depression in both humans and animal models. The goal of our research is to create a comprehensive animal model in which to assess the contribution of different levels of gene activity to the development of anxiety and depression following exposure to environmental stress. This will provide a model for studying a potentially similar relationship in humans. |
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7 .
Anat Maril
Hebrew University of Jerusalem, Psychology and Cognitive Sciences
Subsequent memory effect and the process of internal generation in anterior prefrontal cortex
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| Although the anterior-most region of the prefrontal cortex (rPFC) has been linked to a variety of cognitive processes, little evidence exists as to its possible role in memory encoding. Based on the reasoning that encoding of a stimulus occurs when and where critical components of the initial processing of that stimulus are carried out, we hypothesize that encoding-related activation could be found in rPFC for stimuli whose processing engages rPFC. Our proposed task uses two such components - integration and internal generation, while also producing unique items for each trial - to enable subsequent memory testing. We seek to demonstrate that encoding-related activation in rPFC will distinguish between subsequently remembered and forgotten items. We then propose to isolate internal generation as the cognitive component of the encoding task which engages rPFC. |
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8 .
Yehuda Pollak
Shaare Zedek Medical Center , Psychology
Risk-taking and decision-making under uncertainty in adolescents with attention-deficit and hyperactivity disorder
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| Attention deficit/hyperactivity disorder (ADHD) is a common condition which affects the quality of life of the affected individuals and their families. Of concern is the tendency of individuals with ADHD toward impulsive decision-making under uncertainty. To study the processes that underlie impulsive decision-making, we will have adolescents with and without ADHD perform various tasks designed to make behavior-choices in conditions that are either risky (when chances of reward and loss are known) or ambiguous (when chances are unknown). They will also undertake tasks that tap their ability to learn which choices are associated with better outcomes. We expect to see adolescents with ADHD performing these tasks poorly. |
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9 .
Irit Shapira-Lichter
Sourasky Medical Center, Functional Brain Center
Brain mechanisms underlying free recall versus recognition retrieval processes: a multimodal approach
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| Brain retrieval operations can be characterized by the quantity of external cues that initiate them. Disproportionate impairment in free recall (no cues), as compared with recognition, has been demonstrated in many neurological and psychiatric disorders, but the understanding of free recall's distinctive neuronal mechanisms remains a challenge. Using a unique fMRI paradigm that we developed, we have shown that free recall, unlike recognition, is mediated by distinct neural substrates. In our study, we will complement the picture with human intracranial electroencephalographic recording, which will better characterize temporal aspects of the mechanisms that selectively support free recall. |
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10 .
Rami Yaka
Hebrew University of Jerusalem, Pharmacology
Identification of new drug targets for cocaine addiction using a proteomics approach
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| New understanding of drug abuse and addiction has shown that both depend on drug-effects on brain function. Drug addiction can be defined as inability to regulate the drive to obtain the drug, while reducing the drive for natural rewards. These behavioral changes are manifested by neuropharmacological actions on a common brain-reward circuit, known as the reward system. We propose a proteomics approach to studying these neuroadaptations at molecular level during different stages of cocaine administration, using a common behavioral paradigm for cocaine addiction. |
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11 .
Leon Deouell
Hebrew University of Jerusalem, Psychology
In the eyes of the beholder: the correlation between induced gamma band responses and eye movements
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| EEG recorded from the scalp is a convenient way of non-invasively measuring electrical brain activity at millisecond resolution. One activity recorded with EEG, known as induced gamma band response (iGBR), was thought to reflect the synchronous firing of neurons which represent different aspects of a perceived object (for example, its color, shape or different parts). We, however, have conclusive results that the iGBR, in fact. reflects involuntary eye movements. Our project will examine the details of how different stimuli affect these movements, and the conditions under which they affect the iGBR. |
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12 .
Rakefet Ackerman
Ben Gurion Univesrity of the Negev, Psychology
The heuristic basis for the sense of understanding in younger and older adults
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| Learners of all ages must monitor their understanding to regulate their learning, and know when to rely on a subjective sense of understanding. This sense is not, however, necessarily accurate. We will examine the cues that generate a sense of understanding in healthy younger and older adults and assess whether this sense is biased by superficial characteristics of the material learned. With executive function deteriorating during adulthood, we will investigate differences between younger and older adults in the underlying processes involved in understanding texts of various kinds. We expect to find that, under certain conditions, biases in the sense of understanding in older adults will be greater than that in younger adults. Where their judgment is equally accurate, we expect selection of strategies for improving knowledge will be less efficient in older adults. We believe our findings will help define goals for cognitive training that will foster true and reliable understanding |
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13 .
Zehavit Kariv-Inbal
Tel Aviv University, Department of Neurobiology
Prevention and reversal of the pathological effects of apoE4 by diet
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| Alzheimer's disease, the most common dementia in the elderly, is characterized by declining cognitive performance and scar tissue in distinct brain areas. Growing evidence suggests that the protein apoE4 and the peptide A? play important roles in the initiation and development of the disease, and that dietary constituents such as lipid and cholesterol are also involved. The mechanisms underlying these effects and the extent to which they cross-interact are not, however, known. The overall objective of our project is to develop lipid-related diets that can prevent and or delay onset and progression of the neuronal impairment and cognitive dysfunctions induced by apoE4 and A? in Alzheimer's disease. We will use a transgenic mouse model recently developed by the Michaelson group at Tel Aviv University to investigate the extent to which the neurotoxicity of A? and apoE4 can be prevented and/or reversed by distinct lipid-related diets. |
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14 .
Hagit Magen
Hebrew University of Jerusalem, Department of Psychology
Perceptual and attentional processes in individuals with sensory modulation disorder: an EEG study
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| Individuals with sensory modulation disorder (SMD) exhibit inappropriate (diminished or exaggerated) responses to typical sensory input. The sensory disorder in these individuals may lead to disorders in emotional stability and cognitive performance. While SMD is a feature of other conditions such as ADHD and autism, it has recently been recognized that it may occur without any other diagnostic condition. Our research will examine the perceptual and attentional functions of these individuals solely with SMD, using behavioral and brain activity measures (EEG) to validate it as a distinct syndrome and establish valid diagnostic tools. |
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15 .
Eteri Tsitsiashvili
Tel Aviv University, Sheba Medical Center
Development of a perceptual-learning treatment for childhood strabismic amblyopia
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| Amblyopia is a developmental disorder in spatial vision that affects approximately 2-3% of children, characterized by lowered visual acuity in one eye which can not be corrected by glasses or contact lenses. The result is often a loss of stereoscopic vision (3D) and depth perception. Under amblyopia, vision is reduced with no changes in the fundus of the eye and without any organic affections of the visual pathways and centers1,2,3. At the present time, the pathophysiological mechanisms of amblyopia remain unclear. Numerous anatomical and physiological investigations on the visual pathways in animals and humans indicate that neuronal interactions at all levels of the visual system are affected4,5. Diagnostics and adequate treatment of amblyopia remains so far a topical
problem in clinical ophthalmology.
There are several types of amblyopia; the two most common types are strabismic and
anisometropic. In strabismic amblyopia, the eyes are not aligned properly and, as a result, the nonpreferred eye is not adequately stimulated and the visual neurons do not develop normally. In anisometropic amblyopia, the eyes have different refractive powers, thus the brain cannot balance the difference and favors the stronger eye. |
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Second Year
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1 .
Irit Akirav
University of Haifa, Psychology Department
Stress effects on extinction and reacquisition of inhibitory avoidance: possible involvement of cannabinoid CB1 receptors in the amygdala-hippocampal-accumbens pathway.
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| Extinction is a behavioral paradigm for the suppression of a fear response and it is the basis for the treatment of mental disorders associated with learned fear. Extinction-like treatments are vulnerable to reversal by a number of environmental factors, particularly stress. The cannabinoids, which are found in the cannabis plant, regulate stress and fear extinction. Our aim is to examine whether cannabinoids in the amygdala-hippocampus-accumbens circuit, which is important for memory, emotion and addiction, could represent a therapeutic target for stressed-induced disorders (such as anxiety and affective disorders), that are associated with inappropriate retention of aversive memories. |
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2 .
Ron Amir
Hebrew University of Jerusalem, Cell and Animal Biology
The role of the sodium channel Nav 1.3 in the mechanism of chronic neuropathic pain.
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| Neuropathic pain', pain associated with injury or disease of neural tissue, is an unsolved health problem of major proportions worldwide. Abnormal electrical activity,generated in sensory neurons, is strongly suggested to mediate neuropathic pain. This activity is the outcome of changes in the expression of certain molecules following nerve injury. Over-expression of sodium channel molecules, known to be critical for neuronal excitability, and especially of the Nav1.3 subtype, has been proposed to play a key role. Using a newly available mouse strain in which Nav1.3 was ablated, I will challenge this hypothesis. Confirming that Nav1.3 knockout reduces the levels of the abnormal electrical activity and neuropathic symptoms would advance the understanding of these devastating conditions and might be a significant contribution to efforts of developing better therapeutics for chronic neuropathic pain patients. |
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3 .
Yaniv Assaf
Tel Aviv University, Neurobiochemistry
Can imaging be used as a biomarker of cognitive decline?
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| Cognitive decline accompanies many brain diseases and processes either as primary symptom (as in aging) or as secondary effect (as frequently happens following stroke.). Cognitive decline is multi-factorial meaning it can affect many functions (memory & learning, processing speed, etc.). In this work we will use magnetic resonance imaging (MRI) to extract function-specific brain changes in aged subjects. We wish to show that regional MRI brain changes can be used as a bio-marker for function specific cognitive decline. Implications of this study might range from better understanding of cognitive related brain changes to early diagnosis of cognitive decline. |
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4 .
Ohad Ben-Shahar
Ben Gurion Univesrity of the Negev, Neuroscience
Perceptual singularities without feature contrast implications to covert and over attention.
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| The analysis of texture patterns and their segregation is at the heart of visual information processing. More than two decades of research into orientation-based texture segregation has focused, however, on a rather constrained set of stimuli that led to straightforward models of segregation based on abrupt changes in the texture's dominant feature (i.e., orientation). Recently, we showed that general (orientation-defined) textures that go beyond the constrained set used so far trigger strong perceptual singularities that require a new segregation theory based on multiple curvatures. Here we explore this new theory in the context of visual attention to gather additional support for its applicability to various aspects of visual perception. |
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5 .
Claude Brodski
Ben Gurion Univesrity of the Negev, Health Sciences
Methylphenidate (Ritalin) treatment: Pharmacological mode of action and consequences for brain development.
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| Attention-deficit hyperactivity disorder (ADHD), characterized by hyperactivity, inattention and impulsivity is the most common psychiatric disorder in school age children and is highly heritable. Ritalin (methylphenidate) is the first-line pharmacological treatment for this disorder. However, despite its widespread use, the precise pharmacological mode of action and long-term consequences for brain development remain poorly understood, in part, due to a lack of appropriate animal models. We have previously characterized a mouse mutant recapitulating aspects of ADHD.The aim of our study is to characterize molecular changes in mouse adult mutants resulting from pre-adolescent Ritalin exposure. In addition, we will use this mouse model to study the short term pharmacological effects of this drug. Our results will contribute to a better assessment of long term effects of juvenile Ritalin exposure and provide insights into the pharmacological mode of action of this drug. |
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6 .
Rena Cooper-Kazaz
Hadassah Hebrew University Medical Center, Psychiatry Department
Augmentation of the antidepressant action of sertraline with triiodothyronine (T3) and reboxetine:Clinical efficacy, adverse effects and predictors of response.
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| Major depression is very common and its successful treatment is not an easy task. A significant proportion of patients need additional treatment in order to achieve full remission of their illness. The thyroid hormone, triiodothyronine (T3), is a potentially useful but under-utilized treatment strategy in such cases. We previously demonstrated that T3 augmentation is safe and effective. In this project we aim to further refine indications for the use of T3 by identifying a sub-group of patients who are more likely to respond to it and also by establishing the time in the treatment course when T3 should be added. The results of this project could have significant, direct clinical implications. |
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7 .
Ruth Defrin & Karni Ginzburg
Tel Aviv University, Faculty of Medicine & School for Social Work
Chronic pain and reactivity to painful stimuli among combat-related PTSD patients
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| While previous studies recognized that many PTSD casualties endure chronic pain, the underlying mechanisms for this co-existence are not well established. One reason for this is the dearth in quantitative studies that examine the nature of the pain system among PTSD patients. In this study we aim to examine the prevalence and intensity of chronic pain, as well as the reactions of PTSD subjects to experimentally induced pain, and to explain these factors by the specific characteristics of PTSD, namely anxiety sensitivity, pain catastrophizing, fear of pain, and dissociation. |
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8 .
Daniel Gitler
Ben Gurion Univesrity of the Negev, Health Sciences
Determination of the molecular and cellular basis of eipleptogenesis induced by synapsin loss of function.
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| Epilepsy is a central nervous system disease which afflicts 0.5-2% percent of the population. The hallmark of epilepsy is the recurrence of seizures during which brain activity becomes overly synchronized, precipitating a devastating loss of function and/or consciousness. Although studied for decades, the root causes of epilepsy remain ill-defined. Recently, a case of inherited familial epilepsy involving the synapsin I gene was reported. Based on our observation that mice lacking all synapsin genes suffer from epilepsy, we plan to investigate epileptogenesis, i.e. the underlying mechanisms of epilepsy, taking advantage of our knowledge concerning the role of synapsins in neurotransmission. These studies used central visual field presentation. More recently, we introduced eccentric search arrays and found hemispheric differences in feature search. Moreover, we exploited recently this new paradigm for testing transfer of learning effects between hemispheres and across visual dimensions, to see if there is a learning specificity and dynamics for the peripheral presentation. We found transfer for easy tasks and not for hard tasks. However, the method used left an ambiguity as to what type of transfer was taking place in the easy task case: The ambiguity that arises is that the transfer that we found for the easy tasks, could be interpreted as transfer across tasks, and not between hemispheres.We aim now to extend the preliminary study and to test the possibility of cross-hemifield and cross-task transfer by involving more tasks and subjects. These findings would extend the notion that feature search with easy conditions is performed at high cortical levels. It would suggest that these high levels are those where mechanisms of representation include much of the visual field on both sides of the vertical meridian as well as representations based on a number of dimensions |
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9 .
David Gurwitz
Sackler Faculty of Medicine Tel Aviv University, Health Sciences
Transcriptional and functional regulation of the serotonin transporter in human lymphoblasts by estradiol and SSRI drugs.
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| Depression is twice more common among women than men (20% and 10% during life, respectively), and hormones may be implicated in this bias. The study would examine the effects of the hormone estradiol on the expression and function of the serotonin transporter (5-HTT) in human lymphoblastoid cells (immortalized cells prepared from while blood cells). This protein is the drug target for many antidepressant drugs including Prozac, Seroxat and Cipralex. We shall also study the combined effect of estradiol and anti-depressant drugs on 5-HTT expression. These studies would improve our understanding about and the two-fold female gender bias in depression. |
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10 .
Raphael Lamprecht
University of Haifa, Neurobiology Department
Molecular chaperone in memory formation
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| We are interested to study the molecular and cellular mechanisms of fear memory formation of rats using the fear conditioning assay where an animal associates a neutral stimulus (tone) with an aversive event. After very few pairings long lasting fear memories are established. Fear conditioning memory formation is subserved in brain by the lateral amygdala (LA). We propose to study the role of a protein chaperone Hsp90 in fear conditioning. This protein regulates the structure, function and cellular distribution of key neuronal proteins and is involved in central neuronal functions such as gene expression and neuronal transmission. Understanding how Hsp90 function in fear memory formation could facilitate the development of drugs that inhibit Hsp90 activity in patients prone to excessive fear and might help to prevent some of the debilitating consequences of fear learning. |
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11 .
Yonatan Loewenstein
Hebrew University of Jerusalem, Neurobiology Department
The computational principles and neural mechanism underlying contraction bias.
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| Humans and animals tend to overestimate the physical magnitude of small objects and underestimate the magnitude of large ones. We hypothesize that this illusion, known as 'contraction bias,' results from uncertainty in the neural representation of the estimated objects. When in doubt, subjects shift their magnitude estimation in the direction of the expected magnitude.
We will challenge our hypothesis by conducting psychophysical experiments and will study the possible neural mechanism by constructing a neural network model. Through this work, we expect to advance our knowledge of the algorithms and neural mechanisms that underlie the memory and the estimation of magnitudes. |
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12 .
Mouna Maroun
University of Haifa, Neurobiology Department
Effects of stress on plasticity in the hippocampus, amygdala and prefrontal cortex circuit.
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| Traumatic events are engraved in our memory; yet, some aspects of the traumatic event are forgotten and impossible to be remembered. There are three brain structures that have been implicated in emotional memory, the amygdala, the hippocampus and the prefrontal cortex. The amygdala gives the emotional valence to the event, the hippocampus contributes to the contextual information and cues of the event and the prefrontal cortex exert an inhibition over the amygdala if the situation does not predict danger. These three structures are anatomically interconnected.The aim of this study is to understand the mechanism of the triadic interaction and the relative involvement and role of each of these structures. |
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13 .
Marina Pavlovskaya
Loewenstein Rehabilitation Hospital, Neurophysiology Department
Hemispheric and cross-dimensional transfer of perceptual learning effects under easy and hard conditions.
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| The adult visual system retains a surprising degree of plasticity evident in the ability of subjects to improve substantially and rapidly on a wide range of visual tasks. Most studies of visual perception learning have used simple visual stimuli in discrimination tasks and, correspondingly, the learning observed has been specific to the stimuli used for training. It has been shown that the degree of specificity depended on the difficulty of the training conditions: learning effects transfer for easy tasks and are considerably specific with harder conditions. These differences are presumably related to cerebral modification site: hard tasks are seen as requiring low-level (specific) representations while easy tasks are performed using high cortical level mechanism alone. Essentially, learning could be seen as a top-down guided process, which begins at high-level areas of the visual system, and progresses backwards to the input levels. |
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14 .
Ronit Pinkas-Kramarski
Tel Aviv University, Neurobiochemistry
Autophagy inducing drug, as a novel treatment for brain injury.
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| Autophagy controls the number of surviving cells and only recently has become a focus in neurodegenerative disorders. Recently it was demonstrated that autophagy is involved in neurodegeneration. In our most recent studies we have unraveled a possible involvement of Beclin 1, a protein that regulate autophagy, in neurodegeneration. We observed an increased expression of Beclin 1 following closed head injury (CHI) in neurons and astrocytes in mice. Our hypothesis is that Beclin 1 and autophagy are part of the repair mechanism following injury. This hypothesis of autophagy serving as a homeostatic and rescue mechanism led us to examine the possibility that enhanced autophagy may improve the recovery from CHI. To test this hypothesis we used rapamycin as an inducer of autophagy and tested rapamycin effect on the recovery. We found that rapamycin treatment improves the recovery from head trauma indicating that enhanced autophagy may serve as neuroprotective mechanism. This proposed study is aimed at further study the involvement of autophagy in recovery from head trauma and substantiate our finding of rapamycin treatment as a useful neuroprotective drug. |
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15 .
Uri Polat
Tel Aviv University, Faculty of Medicine
Probing levels of deficient visual information processing
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| The visual system integrates information across time and space. The time-window in which the first percept is formed is short, while longer time-constant is found for complete integration, presumably to enable higher cognitive and/or top-down processing to further process the first percept. Thus, information processing may be sub-divided into two steps: 1) fast and transient and 2) slower sustained stages. We recently developed a psychophysical paradigm which now is advanced further by visual evoked potentials technique to explore spatial-temporal information processing. Our results suggest that grouping is involved with fast-transient inhibition and slow-sustained excitation and that the grouping reflects a combination of early and late sources.We aim to probe the levels of information processing by exploring how the two steps affect each other. We will study 3 groups of participants, each demonstrating impairment at different levels: depression showing high level deficiencies, amblyopia resulting from low level impairment and older age that experience both. The excitation and inhibition are suggested to be impaired in these groups as well. The results will improve our understanding about the information processing in general and may provide an objective and supportive tool in clinical assessment. |
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16 .
Hamutal Slovin
Bar Ilan University, Brain Research
Real-time imaging of saccadic suppression in the visual cortex.
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| Saccades are the rapid eye movements that are used to inspect the environment with high acuity. During and after these rapid shifts of gaze we are usually unaware of any image motion or image displacement. This phenomenon known as saccadic suppression has been extensively investigated; however, the neural mechanisms underlying saccadic suppression remained illusive. A central goal of the current research proposal is to determine the role of neuronal population activity within the visual cortex, using high spatial and temporal resolution, in mediating visual perception during saccadic eye movements |
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17 .
Michael Wagner
Ariel University Center of Samaria, Industiral Engineering & Psychology
Virtual depth instatic and dynamic displays: Physiological versus cognitive factors of depth perception and vergence control.
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| Virtual depth (i.e. 3D space information based on 2D display) relies on binocular and monocular mechanisms. Binocular cues result from vergence (to fixate objects in different depths, the eyes change their angle of convergence) and disparity (the different vantage-points from which the eyes view cause different retinal projections). Monocular cues are based on linear perspective provided by gradients of size, distance and optic flow. Based on preliminary data we will distinguish between "strong" and "weak" depth perceivers and focus on peculiar phenomena by which monocular - static or dynamic - depth cues also elicit vergence eye movements, "converging" to fixate on a virtual rather than real object distance. |
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18 .
Edi Barkai, David Golomb and Israel Sekler
Ben-Gurion University of the Negev, University of Haifa, Biology & Neurobiology
Learning-induced modification in inhibitory synaptic transmission: mechanisms and functional significance
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| Most of the current research on biological mechanisms underlying learning
and memory in the mammalian brain has been concentrating on learning-relevant
enhancement of excitatory synaptic transmission and enhancement of intrinsic
neuronal excitability. Such enhancement of both excitatory and intrinsic neuronal
excitability after training give rises to a new fundamental question: What prevents the
cortical network from exploding despite the increased excitability?
The "natural" candidate for learning-dependent compensatory mechanism is
inhibitory synaptic transmission. Activity-dependent enhancement of fast, GABAAmediated inhibitory synaptic transmission, either by increasing the conductance for Cl- ions or by hyperpolarizing their reversal potential, was recently demonstrated in developmental and LTP-like processes. However, whether and how such modifications are relevant to learning and memory is yet to be determined.
The aim of our proposed project is to describe quantitatively the mechanisms
by which learning-induced modifications in inhibitory synaptic transmission modulate
the induction and preservation of long-term memories in the cortex, while efficiently
preventing the appearance of epileptic-like activity. To bridge the gap between the
molecular level and long-lasting behavioral modifications, our study will combine
olfactory discrimination learning with single cell neurophysiology of piriform
(olfactory) cortex pyramidal neurons, molecular biology of the GABAA receptor and
the K+/Cl- co-transporter, and modeling of large neuronal networks. |
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19 .
Hagit Cohen
Ben Gurion Univesrity of the Negev, Anxiety and Stress Research Unit. Faculty of Health Sciences
Assessment of differential effects of stress hormones and noradrenergic manipulation on traumatic memory (re)consolidation as reflected in behavioral stress responses
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| Post-traumatic stress disorder (PTSD) is an incapacitating chronic syndrome reflecting a disorder of cognitive, emotional and physiological processing and/or recovery from the initial reaction to exposure to a potentially traumatic experience (PTE). Most individuals affected by the PTE will adapt within a period of 1-4 weeks following the trauma, and only a small proportion will develop long-term psychopathology. The development of PTSD is often an evolving process and extends over time through a series of stages ranging from relatively contained distress to severe disability. Exposure to traumatic stress engenders a significant degree of vulnerability to subsequent stress exposure on two levels: Firstly, one of the core-symptoms of PTSD is a cue-elicited psychophysiological response.
Secondly, prior trauma stress responses a key risk-factor for subsequent PTSD. An effective immediate postexposure intervention could critically affect the restoration of stability, to encouraging resilience and the ability to cope and thrive in the face of adversity.
PTSD involves processes linked to memory at two key stages - the primary consolidation of the initial traumatic memory and the recurrent reawakening and reconsolidation of these memories in response to cues. Each of these stages involves the activation of the stress-response cascade on the physiological level. Two pivotal systems involved in this cascade, either or both of which may be directly or indirectly involved in the processes of traumatic memory, are the HPA-axis and the ANS.
This study intends to examine the effects of pharmacological interventions aimed at each of these systems at each of these stages, using the adrenocortical stress hormone corticosterone and agents which act at adrenergic receptors, in an animal model of PTSD. The model focus on degree of individual behavioral response to the stress paradigm, enabling quantification of the behavioral effects of interventions as reflected in prevalence rates of severely, partially and minimally affected individuals.
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20 .
Reuven Stein
Tel Aviv University, Life Sciences Faculty
Molecular characterization of neuropathology and cognitive deficits in a model of neurofibromatosis and an evaluation of potential treatments
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| Approximately 50% of children with NF1 suffer from cognitive disabilities which are associated with some forms of anatomical abnormalities, suggesting that neurofibromin mutation plays a role in the manifestation of the NF1 cognitive deficits. However, the nature of these abnormalities, the mechanism whereby neurofibromin deficiency or mutation causes them and the relationship between the mutations to the cognitive deficits are not known. The major obstacle in studying the mechanism whereby neurofibromin mutations lead to cognitive disabilities in humans is the
enormous variability between different NF1 patients and the obvious difficulty in working with human materials. To overcome these problems we proposed to utilize the mouse model (Nf1+/? mice) for NF1 behavioral deficits. The Nf1+/? mice display a range of behavioral abnormalities that parallel the cognitive profile associated with NF1 patients. The advantage offered by the mouse model is the uniformity of the genetic background, the availability of the experimental material and the ability to
manipulate the experimental system. This animal model of NF1 is therefore likely to provide us with an understanding of the pathogenesis of cognitive deficits in NF1.
The overall objective of the present study is to unravel the molecular details which underlie the behavioral deficits in the Nf1+/? mice and to develop a treatment that will alleviate these cognitive deficits.
We began our studies by examining the brain architecture of Nf1+/? mice using the T2 MRI analysis. We confirmed our preliminary results and showed that some brain regions exhibit statistically significant enhancement in the T2 values as compared to the values obtained in the brains of age and gender matched control WT mice. The regions that show the most significant changes are the M1/S1 cortex, hippocampus caudate-putamen, pyramidal tract and internal capsule. Interestingly in addition to the regions which are involved in cognition (e.g., the hippocampus) the enhancement was observed also in regions which control motor behavior such as the internal capsule. The latter result is of particular importance since it has been previously
reported that children with NF1 suffer also from motor impairments but the cause of these impairments are not known. Since the MRI studies suggested that the Nf1+/? mice may also exhibit motor impairments similar to those reported for humans suffer from NF1, we examined the motor performance of WT and Nf1+/? mice. Our results show that indeed Nf1+/? mice suffer from motor impairments.
The results obtained at this stage of the research have already yielded important findings.
1. They show that the cognitive deficits observed in these mice are associated with
anatomical impairments.
2. They identified for the first time anatomical impairments in Nf1+/? mice brain areas which are associated with motor performance.
3. They showed that the Nf1+/? mice suffer from motor deficits.
4. They substantiate our hypothesis that the Nf1+/? mice are suitable model system for studying the molecular basis of the cognitive and motor deficits in human subjects.
5. They set the ground for the next set of experiments which will examine the ability of the Ras inhibitor, FTS, to alleviate these cognitive and motor deficits. |
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21 .
Talma Hendler
Sourasky Medical Center, Functional Brain Imaging Unit
Spatio-Temporal Features of in-vivo Human Brain Mapping: Complementary measures from EEG, fMRI, and DTI
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| As the neural correlates of cognitive phenomena of ever growing complexity are being investigated, an urgent need for multimodal imaging emerges. To this effect, robust novel analytical and practical tools are required for handling large amounts of data that capture spatio-temporal characteristics of the human brain.
A stable access to a multimodal imaging facility is imperative if diagnostic as well as cognitive neuroscience laboratories are to remain competitive. We propose a center for exploring multimodal functional brain activity for diagnostic and research. The facility already applies two functional brain measurments-functional MRI reflecting cellular activation, and Diffusion Weighted Imaging (DWI) of white matter tractography and myelin integrity. In addition, an MR compatible electro-encephalography (EEG) will provide a simultaneous acquisition of temporally accurate measures of local and long-range synchronized neuronal activity. A range of analytical tools will also be developed in situ to extract combined brain features. The availability of multi-modal imaging technologies and analytic expertise in one center provides a focused effort to unveil healthy and distributed dynamics of the human brain. Its location within a clinical-setup lays the ground for developing novel approaches in diagnosis and treatment of diffused brain pathologies such as attention deficit, epilepsy, schizophreni and dementia. |
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22 .
Shlomo Wagner
University of Haifa, Neurobiology and Ethology
Information processing in the vomeronasal system: a genetic study
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| Most mammals rely on a specialized sensory system, the vomeronasal system (VNS), for pheromonal communication that mediates social and reproductive interactions. However, recent studies directly implicated involvement of the main olfactory system (MOS) in pheromonal communication. Thus, the division of labor between the two systems with regards to sensing pheromones remains unclear. We hypothesize that each of these systems processes pheromonal stimuli in a fundamentally different way and thus extracts distinct aspects of the pheromonal information.
Whereas the physiological mechanisms of information processing in the MOS have been very well studied, those of the VNS remain almost unexplored. The main reasons for this neglect are our ignorance regarding the vomeronasal ligands themselves and the requirement for active pumping of ligands to activate of the vomeronasal sensory organ (VNO). These problems prevent recording of the brain neuronal responses to sensory stimuli applied to the VNO of anesthetized animals. I propose to bypass these obstacles by using genetic engineering to express a photo-activated cationic channel - the channelrhodopsin-2 - in one population of VNO neurons. By photo-stimulation of the VNO in genetically modified mice we expect to be able to mimic VNO activation by a single ligand and to record the brain's neuronal responses to this stimulation.
We expect this study to be a breakthrough in the exploration of information processing in the vomeronasal system. |
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23 .
Hadas Okon-Singer
Tel Aviv University, Physiology
Finding the basis for reduced functional brain asymmetry in focal epilepsy
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| This study uses a combined approach of functional magnetic resonance
imaging (fMRI) and event related potentials (ERPs), in order to assess cortical reorganization in epilepsy. Two main projects are currently in progress: 1. Measurement of signal conduction between and within hemispheres using simultaneous recording of ERP and fMRI. This project is currently in progress with healthy participants. The next stage will be to run the same experiment with epilepsy patients. 2. Recordings from intracranial electrodes implanted in patients with epilepsy that are evaluated for surgery. This project is based on several paradigms assessing language functions, signal conduction and emotional processing.
The obtained knowledge regarding cortical re-organization in patients with
epilepsy may assist in the planning of surgical intervention in these patients. A further
aim of this study is to explore within versus between hemisphere mechanisms in focal
epilepsy, in order to understand the characteristics and causes of cortical
abnormalities in epilepsy. Cortical plasticity and reorganization of cognitive functions
in epilepsy can serve as a unique and high-quality manner to examine cognitive
functionality in abnormal as well as the healthy brain.
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24 .
Amir Perelberg
Hebrew University of Jerusalem, Evolution, Systematics and Ecology
Cooperative behavior: evolutionary biology and behavioral psychology
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| My research integrates explanations of evolutionary biology mechanisms with behavioral psychology processes to address a fundamental puzzle in science: why humans and other animals cooperate? Current theory in both biology and psychology usually emphasizes individual material gains. By treating immediate outcomes as surrogates for fitness, motivation is also assumed to parallel the evolution of cooperation by natural selection. Supporting evidence was based mainly on
models that reduce cooperation to an individual experience by means of anonymous and physically isolated subjects. But when social dimensions are restored, there is evidence for a bias to cooperate, expressed as more cooperation than expected from immediate material gains. Moreover, cooperation in nature is usually complex and requires long time to learn. During this learning stage, individuals receive few rewards (if any) for substantial periods, but continue to cooperate, in contrast to the tendency of both humans and other animals to strongly discount the value of delayed
outcomes. The current study experimentally simulates more realistic scenario of cooperative behavior, where individuals are familiar with each-other, can choose with whom to cooperate, devise a strategy and share the outcomes. Non-invasive behavioral experiments are conducted on a captive group of chimpanzees at the Biblical Zoo, Jerusalem. With the assistance of physiological measurements and observations of social behaviors, research examines the seemingly paradox that
psychological processes generating a seemingly 'irrational' cooperation bias are nonetheless biologically adaptive by increasing long-term individual fitness. |
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Third Year
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1 .
Anat Barnea
The Open University, Natural and Life Science
Neurobiological aspects of migratory behavior in birds: a neuroethological study, comparing migrant and resident species in Israel
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| This behavioral neurobiology study combines field and laboratory work, to explore neurobiological mechanisms underlying birds' migration. The hypothesis: the species' biology (migrant or resident) correlates seasonally with processing of spatial information and with neurobiological parameters. Pairs of closely related wild species
(migratory and resident) will be seasonally trapped, treated with a cell birthdate
marker, and their brains processed 5 weeks later for histology and immunohistochemistry. We will measure new neuronal recruitment, hippocampal
volumes and other relevant brain regions, to make two comparisons: interspecific
(migrants vs. residents), and intraspecific (juveniles vs. adults; seasonal changes).
Analysis of stable isotopes in the birds' feathers will identify origin of the birds and
will search for correlations between length of migration route and neurobiological
parameters. We will also measure hormones, known to influence neuronal
recruitment.
We hope that the work will: 1) Broaden knowledge on neuronal mechanisms
underlying behavior, and on the poorly understood functional significance of adult
neurogenesis. 2) Clarify the potential role of some brain regions, and how
navigational information is obtained. 3) Contribute to understanding of the limits of
acquisition of new long-term memories and of the control and functions of the
plasticity of the adult brain. This might help in clinical application, by suggesting new
approaches for the prevention of neuronal death and for promoting neuronal
replacement. |
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2 .
Ehud Zohary
Hebrew University of Jerusalem, Neurobiology
Cortical plasticity in the adult human visual system following retinal damage caused by Macular Degeneration
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| Sensory maps are not immutable in the adult cerebral cortex. For example, there is strong evidence that neurons in the somatosensory cortex, which are initially unresponsive due to a peripheral injury affecting their original receptive field (such as digit amputation), map a neighboring unaffected digit after some time (Merzenich et al., 1984). The global result is often a massive change in the cortical topography, up to centimeters of cortical tissue (Pons et al., 1991). However, the degree to which drastic changes in cortical maps take place after an analogous retinal injury is still hotly disputed (Smirnakis et al., 2005). The objective of the proposed research is to test if cortical reorganization can be observed in humans suffering from peripheral organ damage (such as retinal degeneration, or limb amputation) in adulthood, and assess the dynamics of these changes. To that end we plan to study patients suffering from macular degeneration (MD), a disease that typically obliterates foveal vision. We will also try to assess the time course of the putative cortical changes by generating reversible central 'virtual' scotomata in healthy humans wearing appropriately designed contact lenses for a week. The prediction of the remapping hypothesis is that trans-cranial magnetic stimulation to the occipital pole (which normally elicits sensation of faint light in the central visual field) should lead to phosphene sensation in the periphery. Similarly, using fMRI we will study the degree of cortical remapping in the motor system following chronic or reversible limb damage (caused by limb amputation or limb casting). The prediction is that neighboring regions in the motor map extend at the expanse of the area normally devoted to missing or immobilized limb. By mapping motor cortical output maps immediately after the cast removal, and in fixed intervals (1 week, 1 month, 6 months) we will be able to assess the dynamics of the changes in the motor cortical maps. This research project is bound to provide us with a better understanding of human cortical plasticity and its relationship to behavior. |
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3 .
Inna Slutsky
Tel Aviv University, Physiology and Pharmacology
Reversal of Age-Dependent Memory Decline by Magnesium Ion
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| Memory traces are believed to be represented by the pattern and strength of synaptic connections. However, the endogenous mechanisms needed to retain memory capacity remain elusive. Our previous study indicates that the spatio-temporal pattern of Ca2+ flux controls the intrinsic plasticity of synapses. A selective reduction of Ca2+ flux associated with uncorrelated activity could be achieved by adjusting the voltage-dependent magnesium (Mg) block of the NMDA receptors (NMDARs). Increasing Mg block induces up-regulation of NR2B-containing NMDARs, contributing to the enhancement of synaptic plasticity in vitro1. Moreover, our recent results show that increase in [Mg]CSF modifies the expression of plasticity-associated proteins and reverses age-associated memory decline2. In the current research proposal we attempt to determine whether [Mg]CSF affects memory function of young rats. The proposed research will determine whether increase in endogenous Mg concentration generally improves memory function in young and ageing rats. |
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2007 - 2008
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4 .
Anna Sterkin
Sheba Medical Center, Eye Research
Functional neural network involved in decision making in patients with depression using fMRI.
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| Major depression disorder (MDD) is characterized by periods of depressed mood or loss of interest and/or pleasure in nearly all previously enjoyed activities. Patients suffering from MDD perform poorly on memory and many other cognitive tasks, compared to healthy individuals. However, there are indications from a preceding study in our laboratory that MDD patients perform differently than healthy individuals also in a perceptual, i.e. non-cognitive, task. We measured visual perception of illusory contours (not physically existing in the image), including standard decision making parameters. With the sensitivity to real visual patterns preserved, MDD patients gave significantly fewer positive responses for illusory ones. Based on these results, we are trying to resolve whether MDD patients have a sensory deficit in the mechanism that supports perception of illusory contours, or, alternatively, a network malfunction, resulting in their inability to integrate contextual information and/or impaired memory. The latter possibility is consistent with the recent suggestion that some symptoms of MDD may reflect an impairment of the Brain Reward System, mediating reward and motivation. The study involves neuroimaging (functional magnetic resonance imaging, fMRI) and visual evoked potentials (VEP) with simultaneous behavioral measurements. These experiments will reveal the neuronal substrate for the observed behavioral deficits. Preliminary results indicate that neuronal correlates of illusory contour perception are found as early as in the primary visual cortex. Finding the exact functional location of the deficit, whether early in the visual processing stream or in the complex network involved in cognitive levels of processing, may be implemented in MDD diagnosis. |
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First Year
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1 .
Irit Akirav
University of Haifa, Psychology Department
Stress effects on extinction and reacquisition of inhibitory avoidance: possible involvement of cannabinoid CB1 receptors in the amygdala-hippocampal-accumbens pathway.
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| Extinction is a behavioral paradigm for the suppression of a fear response and it is the basis for the treatment of mental disorders associated with learned fear. Extinction-like treatments are vulnerable to reversal by a number of environmental factors, particularly stress. The cannabinoids, which are found in the cannabis plant, regulate stress and fear extinction. Our aim is to examine whether cannabinoids in the amygdala-hippocampus-accumbens circuit, which is important for memory, emotion and addiction, could represent a therapeutic target for stressed-induced disorders (such as anxiety and affective disorders), that are associated with inappropriate retention of aversive memories. |
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2 .
Ron Amir
Hebrew University of Jerusalem, Cell and Animal Biology
The role of the sodium channel Nav 1.3 in the mechanism of chronic neuropathic pain.
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| Neuropathic pain', pain associated with injury or disease of neural tissue, is an unsolved health problem of major proportions worldwide. Abnormal electrical activity,generated in sensory neurons, is strongly suggested to mediate neuropathic pain. This activity is the outcome of changes in the expression of certain molecules following nerve injury. Over-expression of sodium channel molecules, known to be critical for neuronal excitability, and especially of the Nav1.3 subtype, has been proposed to play a key role. Using a newly available mouse strain in which Nav1.3 was ablated, I will challenge this hypothesis. Confirming that Nav1.3 knockout reduces the levels of the abnormal electrical activity and neuropathic symptoms would advance the understanding of these devastating conditions and might be a significant contribution to efforts of developing better therapeutics for chronic neuropathic pain patients. |
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3 .
Yaniv Assaf
Tel Aviv University, Neurobiochemistry
Can imaging be used as a biomarker of cognitive decline?
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| Cognitive decline accompanies many brain diseases and processes either as primary symptom (as in aging) or as secondary effect (as frequently happens following stroke.). Cognitive decline is multi-factorial meaning it can affect many functions (memory & learning, processing speed, etc.). In this work we will use magnetic resonance imaging (MRI) to extract function-specific brain changes in aged subjects. We wish to show that regional MRI brain changes can be used as a bio-marker for function specific cognitive decline. Implications of this study might range from better understanding of cognitive related brain changes to early diagnosis of cognitive decline. |
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4 .
Ohad Ben-Shahar
Ben Gurion Univesrity of the Negev, Neuroscience
Perceptual singularities without feature contrast implications to covert and over attention.
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| The analysis of texture patterns and their segregation is at the heart of visual information processing. More than two decades of research into orientation-based texture segregation has focused, however, on a rather constrained set of stimuli that led to straightforward models of segregation based on abrupt changes in the texture's dominant feature (i.e., orientation). Recently, we showed that general (orientation-defined) textures that go beyond the constrained set used so far trigger strong perceptual singularities that require a new segregation theory based on multiple curvatures. Here we explore this new theory in the context of visual attention to gather additional support for its applicability to various aspects of visual perception. |
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5 .
Claude Brodski
Ben Gurion Univesrity of the Negev, Health Sciences
Methylphenidate (Ritalin) treatment: Pharmacological mode of action and consequences for brain development.
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| Attention-deficit hyperactivity disorder (ADHD), characterized by hyperactivity, inattention and impulsivity is the most common psychiatric disorder in school age children and is highly heritable. Ritalin (methylphenidate) is the first-line pharmacological treatment for this disorder. However, despite its widespread use, the precise pharmacological mode of action and long-term consequences for brain development remain poorly understood, in part, due to a lack of appropriate animal models. We have previously characterized a mouse mutant recapitulating aspects of ADHD.The aim of our study is to characterize molecular changes in mouse adult mutants resulting from pre-adolescent Ritalin exposure. In addition, we will use this mouse model to study the short term pharmacological effects of this drug. Our results will contribute to a better assessment of long term effects of juvenile Ritalin exposure and provide insights into the pharmacological mode of action of this drug. |
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6 .
Rena Cooper-Kazaz
Hadassah Hebrew University Medical Center, Psychiatry Department
Augmentation of the antidepressant action of sertraline with triiodothyronine (T3) and reboxetine:Clinical efficacy, adverse effects and predictors of response.
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| Major depression is very common and its successful treatment is not an easy task. A significant proportion of patients need additional treatment in order to achieve full remission of their illness. The thyroid hormone, triiodothyronine (T3), is a potentially useful but under-utilized treatment strategy in such cases. We previously demonstrated that T3 augmentation is safe and effective. In this project we aim to further refine indications for the use of T3 by identifying a sub-group of patients who are more likely to respond to it and also by establishing the time in the treatment course when T3 should be added. The results of this project could have significant, direct clinical implications. |
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7 .
Ruth Defrin & Karni Ginzburg
Tel Aviv University, Faculty of Medicine & School for Social Work
Chronic pain and reactivity to painful stimuli among combat-related PTSD patients
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| While previous studies recognized that many PTSD casualties endure chronic pain, the underlying mechanisms for this co-existence are not well established. One reason for this is the dearth in quantitative studies that examine the nature of the pain system among PTSD patients. In this study we aim to examine the prevalence and intensity of chronic pain, as well as the reactions of PTSD subjects to experimentally induced pain, and to explain these factors by the specific characteristics of PTSD, namely anxiety sensitivity, pain catastrophizing, fear of pain, and dissociation. |
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8 .
Daniel Gitler
Ben Gurion Univesrity of the Negev, Health Sciences
Determination of the molecular and cellular basis of eipleptogenesis induced by synapsin loss of function.
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| Epilepsy is a central nervous system disease which afflicts 0.5-2% percent of the population. The hallmark of epilepsy is the recurrence of seizures during which brain activity becomes overly synchronized, precipitating a devastating loss of function and/or consciousness. Although studied for decades, the root causes of epilepsy remain ill-defined. Recently, a case of inherited familial epilepsy involving the synapsin I gene was reported. Based on our observation that mice lacking all synapsin genes suffer from epilepsy, we plan to investigate epileptogenesis, i.e. the underlying mechanisms of epilepsy, taking advantage of our knowledge concerning the role of synapsins in neurotransmission. These studies used central visual field presentation. More recently, we introduced eccentric search arrays and found hemispheric differences in feature search. Moreover, we exploited recently this new paradigm for testing transfer of learning effects between hemispheres and across visual dimensions, to see if there is a learning specificity and dynamics for the peripheral presentation. We found transfer for easy tasks and not for hard tasks. However, the method used left an ambiguity as to what type of transfer was taking place in the easy task case: The ambiguity that arises is that the transfer that we found for the easy tasks, could be interpreted as transfer across tasks, and not between hemispheres.We aim now to extend the preliminary study and to test the possibility of cross-hemifield and cross-task transfer by involving more tasks and subjects. These findings would extend the notion that feature search with easy conditions is performed at high cortical levels. It would suggest that these high levels are those where mechanisms of representation include much of the visual field on both sides of the vertical meridian as well as representations based on a number of dimensions |
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9 .
David Gurwitz
Sackler Faculty of Medicine Tel Aviv University, Health Sciences
Transcriptional and functional regulation of the serotonin transporter in human lymphoblasts by estradiol and SSRI drugs.
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| Depression is twice more common among women than men (20% and 10% during life, respectively), and hormones may be implicated in this bias. The study would examine the effects of the hormone estradiol on the expression and function of the serotonin transporter (5-HTT) in human lymphoblastoid cells (immortalized cells prepared from while blood cells). This protein is the drug target for many antidepressant drugs including Prozac, Seroxat and Cipralex. We shall also study the combined effect of estradiol and anti-depressant drugs on 5-HTT expression. These studies would improve our understanding about and the two-fold female gender bias in depression. |
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10 .
Raphael Lamprecht
University of Haifa, Neurobiology Department
Molecular chaperone in memory formation
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| We are interested to study the molecular and cellular mechanisms of fear memory formation of rats using the fear conditioning assay where an animal associates a neutral stimulus (tone) with an aversive event. After very few pairings long lasting fear memories are established. Fear conditioning memory formation is subserved in brain by the lateral amygdala (LA). We propose to study the role of a protein chaperone Hsp90 in fear conditioning. This protein regulates the structure, function and cellular distribution of key neuronal proteins and is involved in central neuronal functions such as gene expression and neuronal transmission. Understanding how Hsp90 function in fear memory formation could facilitate the development of drugs that inhibit Hsp90 activity in patients prone to excessive fear and might help to prevent some of the debilitating consequences of fear learning. |
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11 .
Yonatan Loewenstein
Hebrew University of Jerusalem, Neurobiology Department
The computational principles and neural mechanism underlying contraction bias.
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| Humans and animals tend to overestimate the physical magnitude of small objects and underestimate the magnitude of large ones. We hypothesize that this illusion, known as 'contraction bias,' results from uncertainty in the neural representation of the estimated objects. When in doubt, subjects shift their magnitude estimation in the direction of the expected magnitude.
We will challenge our hypothesis by conducting psychophysical experiments and will study the possible neural mechanism by constructing a neural network model. Through this work, we expect to advance our knowledge of the algorithms and neural mechanisms that underlie the memory and the estimation of magnitudes. |
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12 .
Mouna Maroun
University of Haifa, Neurobiology Department
Effects of stress on plasticity in the hippocampus, amygdala and prefrontal cortex circuit.
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| Traumatic events are engraved in our memory; yet, some aspects of the traumatic event are forgotten and impossible to be remembered. There are three brain structures that have been implicated in emotional memory, the amygdala, the hippocampus and the prefrontal cortex. The amygdala gives the emotional valence to the event, the hippocampus contributes to the contextual information and cues of the event and the prefrontal cortex exert an inhibition over the amygdala if the situation does not predict danger. These three structures are anatomically interconnected.The aim of this study is to understand the mechanism of the triadic interaction and the relative involvement and role of each of these structures. |
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13 .
Marina Pavlovskaya
Loewenstein Rehabilitation Hospital, Neurophysiology Department
Hemispheric and cross-dimensional transfer of perceptual learning effects under easy and hard conditions.
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| The adult visual system retains a surprising degree of plasticity evident in the ability of subjects to improve substantially and rapidly on a wide range of visual tasks. Most studies of visual perception learning have used simple visual stimuli in discrimination tasks and, correspondingly, the learning observed has been specific to the stimuli used for training. It has been shown that the degree of specificity depended on the difficulty of the training conditions: learning effects transfer for easy tasks and are considerably specific with harder conditions. These differences are presumably related to cerebral modification site: hard tasks are seen as requiring low-level (specific) representations while easy tasks are performed using high cortical level mechanism alone. Essentially, learning could be seen as a top-down guided process, which begins at high-level areas of the visual system, and progresses backwards to the input levels. |
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14 .
Ronit Pinkas-Kramarski
Tel Aviv University, Neurobiochemistry
Autophagy inducing drug, as a novel treatment for brain injury.
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| Autophagy controls the number of surviving cells and only recently has become a focus in neurodegenerative disorders. Recently it was demonstrated that autophagy is involved in neurodegeneration. In our most recent studies we have unraveled a possible involvement of Beclin 1, a protein that regulate autophagy, in neurodegeneration. We observed an increased expression of Beclin 1 following closed head injury (CHI) in neurons and astrocytes in mice. Our hypothesis is that Beclin 1 and autophagy are part of the repair mechanism following injury. This hypothesis of autophagy serving as a homeostatic and rescue mechanism led us to examine the possibility that enhanced autophagy may improve the recovery from CHI. To test this hypothesis we used rapamycin as an inducer of autophagy and tested rapamycin effect on the recovery. We found that rapamycin treatment improves the recovery from head trauma indicating that enhanced autophagy may serve as neuroprotective mechanism. This proposed study is aimed at further study the involvement of autophagy in recovery from head trauma and substantiate our finding of rapamycin treatment as a useful neuroprotective drug. |
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15 .
Uri Polat
Tel Aviv University, Faculty of Medicine
Probing levels of deficient visual information processing
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| The visual system integrates information across time and space. The time-window in which the first percept is formed is short, while longer time-constant is found for complete integration, presumably to enable higher cognitive and/or top-down processing to further process the first percept. Thus, information processing may be sub-divided into two steps: 1) fast and transient and 2) slower sustained stages. We recently developed a psychophysical paradigm which now is advanced further by visual evoked potentials technique to explore spatial-temporal information processing. Our results suggest that grouping is involved with fast-transient inhibition and slow-sustained excitation and that the grouping reflects a combination of early and late sources.We aim to probe the levels of information processing by exploring how the two steps affect each other. We will study 3 groups of participants, each demonstrating impairment at different levels: depression showing high level deficiencies, amblyopia resulting from low level impairment and older age that experience both. The excitation and inhibition are suggested to be impaired in these groups as well. The results will improve our understanding about the information processing in general and may provide an objective and supportive tool in clinical assessment. |
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16 .
Hamutal Slovin
Bar Ilan University, Brain Research
Real-time imaging of saccadic suppression in the visual cortex.
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| Saccades are the rapid eye movements that are used to inspect the environment with high acuity. During and after these rapid shifts of gaze we are usually unaware of any image motion or image displacement. This phenomenon known as saccadic suppression has been extensively investigated; however, the neural mechanisms underlying saccadic suppression remained illusive. A central goal of the current research proposal is to determine the role of neuronal population activity within the visual cortex, using high spatial and temporal resolution, in mediating visual perception during saccadic eye movements |
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17 .
Michael Wagner
Ariel University Center of Samaria, Industiral Engineering & Psychology
Virtual depth instatic and dynamic displays: Physiological versus cognitive factors of depth perception and vergence control.
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| Virtual depth (i.e. 3D space information based on 2D display) relies on binocular and monocular mechanisms. Binocular cues result from vergence (to fixate objects in different depths, the eyes change their angle of convergence) and disparity (the different vantage-points from which the eyes view cause different retinal projections). Monocular cues are based on linear perspective provided by gradients of size, distance and optic flow. Based on preliminary data we will distinguish between "strong" and "weak" depth perceivers and focus on peculiar phenomena by which monocular - static or dynamic - depth cues also elicit vergence eye movements, "converging" to fixate on a virtual rather than real object distance. |
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18 .
Edi Barkai, David Golomb and Israel Sekler
University of Haifa and Ben Gurion University, Depts. of Biology & Neurobiology
Learning-induced modifications in inhibitory synaptic transmission:
Mechanisms and functional significance.
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| Most of the current research on biological mechanisms underlying learning and memory in the mammalian brain has been concentrating on learning-relevant enhancement of excitatory synaptic transmission and enhancement of intrinsic neuronal excitability. Such enhancement of both excitatory and intrinsic neuronal excitability after training give rises to a new fundamental question: What prevents the cortical network from exploding despite the increased excitability? The "natural" candidate for learning-dependent compensatory mechanism is inhibitory synaptic transmission. Activity-dependent enhancement of fast, GABAA mediated inhibitory synaptic transmission, either by increasing the conductance for Cl- ions or by hyperpolarizing their reversal potential, was recently demonstrated in developmental and LTP-like processes. However, whether and how such modifications are relevant to learning and memory is yet to be determined. The aim of our proposed project is to describe quantitatively the mechanisms by which learning-induced modifications in inhibitory synaptic transmission modulate the induction and preservation of long-term memories in the cortex, while efficiently preventing the appearance of epileptic-like activity. To bridge the gap between the molecular level and long-lasting behavioral modifications, our study will combine olfactory discrimination learning with single cell neurophysiology of piriform (olfactory) cortex pyramidal neurons, molecular biology of the GABAA receptor and the K+/Cl- co-transporter, and modeling of large neuronal networks. |
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19 .
Hagit Cohen
Ben Gurion Univesrity of the Negev, Anxiety & Stress Research Unit
An assessment of the differential effects of stress hormones and noradrenergic manipulation on traumatic memory consolidation and reconsolidation as reflected in behavioral stress responses.
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| Post-traumatic stress disorder (PTSD) is an incapacitating chronic anxiety disorder induced by extreme experiences such as combat, terror attacks, rape and other violent crimes, child and marital abuse, accidents and natural disasters. It is estimated that in the US population, lifetime prevalence rates for PTSD are in the range of 8%, with women reportedly affected about twice as often as men. The high prevalence rates of PTSD incur significant individual, institutional and governmental health costs, resulting in an estimated $3 billion annual productivity loss in the US in 2003. The cost of PTSD exceeds that of all other anxiety disorders, and much of this expenditure is accounted for by direct costs of treatment-seeking and medical evaluation.To date there are almost no empirical data on which to base recommendations for immediate post-exposure pharmacological interventions to effectively forestall the development of PTSD. This study intends to examine the effects of pharmacological interventions immediate post-exposure, using the adrenocortical stress hormone corticosterone and agents which act at adrenergic receptors, in an animal model of PTSD. The model focuses on the degree of individual behavioral response to the stress paradigm, enabling quantification of the behavioral effects of interventions, as reflected in prevalence rates of severely, partially and minimally affected individuals. |
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20 .
Reuven Stein
Tel Aviv University, Neurobiology Department
Molecular characterization of the neuropathology and cognitive deficits in the model of neurofibromatosis type 1 and evaluation of potential treatments.
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| Neurofibromatosis type 1 (NF1) is a common, complex, incurable genetic disease that is characterized by a high incidence of tumors in the nervous system. In addition, approximately 50% of children with NF1 suffer from learning disabilities. The gene responsible for the disease, neurofibromin, shuts down the active form of a protein called Ras. A mouse model for NF1 (Nf1+/? ) has been established and shown to exhibit similar cognitive deficits as humans with NF1.The overall objective of the present study is to unravel the molecular details which underlie the cognitive deficits in Nf1+/? mice brains and to develop a treatment that will alleviate these cognitive deficits. The proposed studies will be carried out by two complementary tasks. First, we will determine the neuropathological, signaling and cognitive-associated impairments of the Nf1+/? mice. Secondly, we will examine whether and how an environmental stimulation or a pharmacological treatment with a specific Ras inhibitor alleviates the Nf1+/? cognitive deficits. |
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21 .
David Anaki
Hebrew University of Jerusalem, Department of Psychology
Electrophysiological correlates associated with face and object perception
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| In my current work I am investigating the memory systems that enable this process, the characteristics of the integration process, and the features of the visual representations that are formed. These issues are examined by combining electrophysiological (ERP) and behavioral techniques, and by examining healthy individuals as well as individuals with specific neuropsychological deficits affecting various aspects of visual perception, such as agnosia, prosopagnosia, and simultanagnosia. |
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22 .
Tzuri Lifschytz
Hebrew University of Jerusalem, Department of Psychiatry
Behavioral and biochemical effects of specific thyroid hormone receptor modulators (STRM's) in animal models of antidepressant activity.
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| The essence of this program is to explore, using appropriatebehavioral and biochemical research paradigms, the antidepressant potential of synthetic thyroid receptor modulators (STRMs). This is an important new direction in research on antidepressant agents. The efficacy of the medications currently available is limited and there is a great need for novel approaches. |
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23 .
Guy Horev
Weizmann Institute, Department of Neurobiology
Head and whiskers movement strategies of rats during object localization
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| Studying the motor-sensory loop of the vibrissal system in freely-moving rats by adapting a movement notation method to an object localization task's existing database. Preliminary results from this notation method suggest that rats can control their whiskers movements by executing specific movements with their head, and as a result to improve their performance. In the coming two years, Guy plans to build a model for object localization's neural encoding schemes and to verify it by comparing the model predictions with empirical data from manipulated sensory system, behavior, or task. |
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24 .
Amir Perelberg
Hebrew University of Jerusalem, Department of Evolution
Cooperative behavior in chimpanzees: bridging the gap between evolutionary biology and behavioral psychology processes.
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25 .
Michael Tsoory
Weizmann Institute, Department of Neurobiology
Evaluating the consequences of exposure to stressors during the mouse's 'juvenility' on coping with stressors in adulthood and the involvement of CRF receptors: Developing a mouse model for the predisposition for mood and anxiety disorders in adulthood following 'childhood trauma'.
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| Childhood trauma is associated with higher rates of both mood and anxiety disorders in adulthood. The exposure of rats to stressors during juvenility has comparable effects, and was suggested as a model of induced predisposition for these disorders. The neural cell adhesion molecule (NCAM) and its polysialylated form PSA-NCAM are critically involved in neural development, activity-dependent synaptic plasticity, and learning processes. We examined the effects of exposure to stressors during juvenility on coping with stressors in adulthood and on NCAM and PSA-NCAM expression within the rat limbic system both soon after the exposure and in adulthood. Exposure to stressors during juvenility reduced novel-setting exploration and impaired two-way shuttle avoidance learning in adulthood. Among naive rats, a development-related decrease of about 50% was evident in the PSA-NCAM to NCAM expression ratio in the basolateral amygdala, in the CA1 and dentate gyrus regions of the hippocampus, and in the entorhinal cortex. In juvenile-stressed rats, we found no such decrease, but rather an increase in the polysialylation of NCAM (approx50%), evident soon after the exposure to juvenile stress and also in adulthood. Our results suggest that exposure to stressors during juvenility alters the maturation of the limbic system, and potentially underlies the predisposition to exhibit stress-related symptoms in adulthood. |
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26 .
Shlomo Wagner
University of Haifa, Neurobiology Department
Exploring information processing in the vomeronasal system, using genetically modified mice expressing the channel rhodopsin-2 gene in a specific population of vomeronasal organ neurons.
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| Most mammals rely on a specialized sensory system, the vomeronasal system, for sensing pheromones, which mediate social and reproductive interactions between individuals of the same species. However, the physiological mechanisms mediating information processing in the vomeronasal system are virtually unexplored, because of some technical obstacles. In the proposed research we plan to bypass these obstacles by combining genetic engineering in mice and a cutting-edge technique for light-induced stimulation of neurons. The proposed genetically modified mouse line will enable us to monitor, for the first time, brain neuronal responses to stimulation of the vomeronasal system in anesthetized mice. We expect this study to be a breakthrough in the exploration of information processing in the vomeronasal system. |
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Second Year
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1 .
Orna Almog
Ben Gurion Univesrity of the Negev, Clinical Biopharmacology
A structural study of the interaction of calbindin D28k with the lithium inhibited enzyme IMPase
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| Inositol monophosphatase (IMPase) is a key enzyme in regulating the phosphatidylinositol (PI) signaling system. It catalyzes the dephosphorylation of myo-inositol monophosphates to free myo-inositol. Lithium (Li), the drug of choice in the treatment of bipolar disorder (manic-depressive illness), inhibits IMPase activity at therapeutically-relevant concentrations but has well-recognized limitations. Reduced IMPase activity may lead to depletion of intracellular myo-inositol. Since myo-inositol is used in the re-synthesis of the signal precursor phosphatidylinositol (PI), its depletion may attenuate hyperactive signaling.
Recently, it was shown that calbindin D28k (calbindin) is an activator of IMPase. It has been suggested that calbindin attaches to residues 55-66 of IMPase, enhancing its activity. Calbindin could thus be a key endogenous regulator of the PI signaling cycle.
The aim of the proposed research is to characterize the interaction between the specific sequences of IMPase and calbindin, and to understand the mechanism by which calbindin activates IMPase. To address this goal, we will over-express human calbindin and will co-crystallize it with the specific synthetic peptides.
The structural analysis of the interaction between IMPase and calbindin may serve as a basis for future drug design for treating bipolar disorder patients. A rationally designed inhibitor of IMPase could replace lithium compounds which are highly charged and polar. |
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2 .
Yair Bar Haim
Tel Aviv University, Psychology Department
Neural Correlates of Threat Processing in Anxiety
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| A normative function of the mechanisms underlying fear is to facilitate detection of danger in the environment and to help people respond effectively to threatening situations. Malfunction in processing threat-related information have been assigned a prominent role in the etiology of anxiety disorders. However, little is known about the neural substrates of the differences between anxious and non-anxious individuals in threat-related processing. In a set of three studies, assessing normative and clinically anxious participants, we intend to shed light on the neural correlates of these individual differences. |
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3 .
Dorit Ben-Shalom
Ben Gurion University of the Negev, Visual Perception
Superior and not so superior visual search in autism
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| Several studies suggest that subjects with autism conduct visual searches better than controls. At the same time, adults with autism report difficulties in finding objects in everyday life. We tested one such adult and found, that his visual search is indeed better under some conditions, but not others. In addition, he shows other abnormalities in visual attention. We would like to explore the superior and not so superior aspects of search in high-functioning autism, to get a better understanding of visual strengths and difficulties, as well as get inspiration for potential future intervention to partially alleviate some of these difficulties. |
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4 .
Alon Chen
Weizmann Institute, Neurobiology Department
The roles of central corticotropin releasing factor receptors in mediating stress-related neuroendocrine and behavioral responses.
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| When physiological or psychological stimuli is perceived as stressful, the brain activates many neuronal circuits to adapt to the demand. The CRF family of neuropeptides and receptors is essential for coordinating the behavioral and endocrine responses to stress and implicated in the control of arousal, anxiety, cognitive functions and appetite. Dysregulation of the stress response can have severe psychological and physiological consequences and chronic hyperactivation of the CRF system has been linked to many affective disorders such as anxiety, anorexia nervosa and melancholic depression. Specifying the contributions of the CRF family of ligands and receptors to the maintenance of homeostasis and to stress-linked emotional disorders may improve our ability to design therapeutic interventions and thus manage affective and other disorders. |
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5 .
Yael Chertkow-Deutsher
The Technion, Psychobiology-psychiatry
Epigenetic factors in the vulnerability to PTSD; The role of DNA methylation
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| Posttraumatic Stress Disorder (PTSD) is a psychiatric disorder that may occur following exposure to a stressful environmental event (20% of exposed population). Currently no specific gene has been associated with PTSD. Epigenetic processes, such as DNA methylation, are means to affect genome plasticity and adaptation to environmental alternation. To investigate the potential role of DNA methylation in PTSD, we will examine the pattern of global methylation in the brains of PTSD-like rats. In addition, we will examine in this model the promoter of glucocorticoid receptor, whose methylation pattern has been shown to be affected by stress. |
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6 .
Doron Gothelf
Schneider Hospital for Children, Clinical Psychiatry
Genetic and cognitive endophenotypes and neuropsychiatric risk factors for the development of psychosis in velocardiofacial syndrome (22qll.2 deletion syndrome).
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| Although schizophrenia is highly hereditary, the cause of the disease is still unknown. Therefore, longitudinal studies of individuals with a well-defined risk factor for psychosis are important for identifying pathological mechanisms associated with schizophrenia. Velocardiofacial syndrome (VCFS) is the most common known genetic risk factor for schizophrenia. Up to one-third of individuals with VCFS develop a schizophrenia-like disorder. In the previous grant period of the National Institute for Psychobiology in Israel we recruited a large cohort of children and adolescents with VCFS and characterized their genetic, cognitive, and psychiatric profile. We now plan to conduct a longitudinal follow-up of this cohort using integrative multidisciplinary scientific approach to identify genetic, cognitive executive functioning and psychiatric risk factors for the development of schizophrenia in this high-risk population. |
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7 .
Amir Karniel
Ben Gurion University of the Negev, Biomedical Engineering
Motor Memory - does it address the past or the future?
|
| It was recently suggested that memory is better equipped to handle the future than the
past. This is indeed a provocative statement about episodic memory which is thought
to describe a previously experienced event.
Motor memories, however, are expected to handle the future. They employ
experience from the past to represent the properties of our body and external
environment. These representations are used to plan our future movements.
We propose to experimentally test this fascinating dichotomy for motor tasks before
and after mental practice and strive to answer the question: Does the motor memories
represent the past or the future? |
| close |
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8 .
Noga Kronfeld-Schor
Tel Aviv University, Department of Zoology
Modulating affective responses by changing photoperiod in fat sand rats: Possible mechanisms and insights into Seasonal Affective Disorder (SAD)
|
| Our goal is studying effects of seasonal acclimation on mood and emotional state in an animal model of Seasonal Affective Disorder (SAD), a malady of recurring cycles of seasonal depression and remission. From a biological perspective, SAD may represent a form of seasonal acclimation, once biologically (and evolutionary) advantageous. Preliminary results indicate that the fat sand rat, a diurnal rodent with behavior and physiology typical to other diurnal mammals, is sensitive to short daylight period, with a response which is indicative of depression. We propose to continue this study by using a set of physiological and behavioral paradigms to gain insights on SAD mechanisms and on potential therapies. |
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9 .
Gil Levkowitz
Weizmann Institute, Molecular Biology
Zebrafish as a vertebrate model to investigate developmental dysfunctions of dopaminergic pathways
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| Dopaminergic brain cells (neurons) have been associated with drug addiction, mood disorders and Parkinson's disease. Our team has recently shown that zebrafish is a valid vertebrate model to study developmental alterations in the dopaminergic system and that genetic manipulation of zebrafish causes marked phenotypic changes in dopaminergic neurons. In the proposed study, we aim to employ zebrafish in order to study genetic pathways underlying dopaminergic development and function. By studying how dopaminergic neurons operate during normal brain development we may also begin to understand the genetic basis for neuro-psychiatric disorders and find new ways to alleviate these neurological impairments. |
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10 .
Jeannette Schaeffer
Ben Gurion Univesrity of the Negev, Linguistics
Grammatical and pragmatic properties of DPs in the language of Hebrew speaking children with Grammatical Specific Language Impairment
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| This project investigates noun phrases in Hebrew acquiring children with Grammatical Specific Language Impairment (H-GSLI). We hypothesize that a) linguistic sub-abilities (e.g. grammar and pragmatics (=language use)) are autonomous, and b) that children with GSLI are impaired in their grammar only, but not in their pragmatics. We will test these hypotheses by conducting experiments on grammatical and pragmatic properties of noun phrases with children with H-GSLI. With the results we hope to contribute to a) a better understanding of the organization of language; b) a more refined characterization of Hebrew GSLI; c) the development of new methods to help children with GSLI. |
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11 .
Anat Barnea
The Open University, Dept. of Natural and Life Sciences
Neurobiological aspects of migratory behavior in birds:A neuroethological study, comparing migrant and resident species in Israel.
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| This study includes both field and laboratory work, in an effort to understand how the brain enables birds to migrate over long distances. We assume that migrants process more spatial information than resident birds. To test this hypothesis, we are seasonally comparing wild migratory and resident birds. Various methodologies are used to measure the number of new neurons that are recruited in the brains of the tested species, their blood hormonal levels, and (for migratory birds) the length of migration routes. The results will enable a comparison between migrant and resident birds, and a search for correlations between behavior and neurobiological mechanisms underlying it. We hope that the work will contribute to our basic understanding of the acquisition of new long-term memories, as well as to suggestions for new approaches in clinical applications for brain repair. |
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12 .
Ehud Zohary
Hebrew University of Jerusalem, Neurobiology Department
Cortical plasticity in the adult human (visual/motor) cortex following damage to the eripheral organ (retina/ limb)
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| Contrary to long held belief, there is evidence that sensory maps are not immutable in the adult cerebral cortex. However, the degree to which massive changes in the cortical representation of the sensory and motor maps indeed take place after an injury to the peripheral organ (such as damage to the eye or amputation of a limb) is still hotly disputed. We plan to assess this issue in human patients suffering from chronic retinal damage (caused by macular degeneration) or limb loss. We will also attempt to track the dynamics of the putative cortical changes in the visual cortex by generating reversible virtual lesions in healthy humans wearing appropriately designed contact lenses for a week. Analogously, we will track changes in the motor cortex by studying people having their limb immobilized in a cast for a month (due to a fracture). The goal of this research project is to attain a better understanding of human cortical plasticity and its relationship to behavior. |
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13 .
Alexandra Kavushansky
The Technion, Psychiatry Department
The plasticity-related genes CAM-L1, laminin and CREB in physical vs. .psychological stress: implication to stress-related psychiatric disorders
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| Stress has been initially defined as a universal, non-specific response of an organism to various environmental demands ("stressors"). However, acute and chronic stressors differ in their physiological and behavioral outcomes. Physical and psychological stressors also activate different brain areas and may lead to different stress-related disorders, such as post-traumatic stress disorder (PTSD - following physical stress) vs. major depression - following psychological stress. Neuronal plasticity-related genes have been demonstrated to be oppositely expressed in the brain following stress and anti-depressant treatment, suggesting a role of these genes in both stress and treatment of depression. However, specific patterns of activation of these plasticity markers by different stressors have not been established. I am investigating behavioral, endocrine and molecular outcomes of acute vs. chronic exposure tophysical stressors (such as shock) vs. psychological stressors (such as social defeat). Following the stress procedures, subjects will be tested for anxiety- and depression-like behaviors, plasma levels of stress hormones, and expression of specific plasticity-related genes in stress-related areas of the brain. Understanding how different stressors affect plastic processes in the brain will assist in developing more cause-specific treatment of stress-related illness. |
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14 .
Inna Slutsky
Tel Aviv University, Physiology Department
Reversal of age-dependent memory decline by magnesium ion
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| Memory is profoundly affected by aging. However, the endogenous mechanisms needed to retain memory capacity remain elusive. Our recent work suggests that the concentration of magnesium in cerebrospinal fluid ([Mg]CSF) is a key regulator of synaptic plasticity and memory. In intact animals, increasing Mg2+ consumption elevates [Mg]CSF, reversing age-associated decline of memory. This is achieved mechanistically by retaining the synaptic network in a "juvenile" configuration. As a significant portion of the human population, particularly the aging, suffers from a Mg deficiency, this work suggests that increasing Mg consumption might be beneficial for improving learning and memory in humans. |
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Third Year
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1 .
Opher Donchin
Ben Gurion University of the Negev, Biomedical Engineering
The deep cerebellar nuclei and their role in learning to make reaching movements.
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| Motor learning is one of our most important functions as human beings, but it takes place in the background where we can barely notice it. A part of the brain called the cerebellum is supposed to be involved in this process. In this project, I test that theory by examining whether chemicals that 'turn off' parts of the cerebellum temporarily affects the ability of a cat to learn a simple motor task where the cat learns to reaches out and grab a feeding tube despite a force that pushes the paw aside during the reach. |
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2 .
Yoram Gutfreund
The Technion, Physiology and Biophysics
Investigation of the neural signals that guide experience-dependent plasticity in the auditory localization system of the barn owl.
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| The main goal of the proposed research is to understand how information about the location of a sound source is represented in the brain and how this representation is shaped by sensory experience and by sensory context. We will study the central auditory system of the barn owl. Barn owls are chosen for this study because of their superb auditory and visual localization capabilities a. The acoustic basis for the owl's sound localization is similar to many other species including humans, but, perhaps because they rely on sound localization for survival, the neural representation of auditory space is sharper than in any other species studied. This enables us to identify biological effects with high sensitivity and confidence. |
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3 .
Dana Cohen
Bar Ilan University, Brain Research Center
Neural mechanisms of learning, reversal learning and generalizing in rats.
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| One of the main goals of neuroscience is to unravel the basic neuronal mechanisms that underlie functions such as learning, memory, perception and motor control. To that end, one needs to understand the nature of the activity and interactions between large populations of individual neurons. Our lab pioneered the technique of chronic and simultaneous extracellular recording from multiple neurons distributed across different brain areas in awake behaving primates and rats1,2. This method provides a powerful tool for studying brain areas essential for performing various behavioral tasks. During my post doctoral training, I have used this method to record activity in rat primary motor cortex (MI) during motor skill learning task which I have developed3. The main findings of my study were: (1) Unlike associative learning where the neuronal changes lag behavioral improvement, during skill learning neuronal activity changes in MI correlate with the improvement in performance. The neural activity changes also precede structural changes. (2) MI actively balances the learning-induced firing rate changes of individual neurons such that the average firing rate of the population remains constant throughout learning. (3) Faster movement onset requires more neurons to change their firing probability instantaneously, and most importantly (4) the uncertainty in movement direction, introduced by the variability in single neuron firing, does not decrease with learning but is reduced by the neuronal population allowing generation of accurate movements. These findings are likely to strongly affect neuronal models of motor learning because they provide novel information essential for accurate design of these models. Most recently we were able to improve and miniaturize the recording electrode-arrays to allow recording in mice4. Using the optimized electrode arrays, I am now able to record activity in striatum and motor cortex of wild type mice as they learn to walk on a rota-rod5. In the future, I plan to use this powerful technique to investigate neural coding of brain functions such as motor learning, motor control and perception as detailed below. |
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2006 - 2007
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First Year
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1 .
Anat Barnea
The Open University, Neurobiology Department
Neurobiological aspects of migratory eriphera in birds: a neuroethological study, comparing migrant and resident species in Israel
|
| This study includes both field and laboratory work, in an effort to understand how the brain enables birds to migrate over long distances. We assume that migrants process more spatial information than resident birds. To test this hypothesis, we are seasonally comparing wild migratory and resident birds. Various methodologies are used to measure the number of new neurons that are recruited in the brains of the tested species, their blood hormonal levels, and (for migratory birds) the length of migration routes. The results will enable a comparison between migrant and resident birds, and a search for correlations between behavior and neurobiological mechanisms underlying it. We hope that the work will contribute to our basic understanding of the acquisition of new long-term memories, as well as to suggestions for new approaches in clinical applications for brain repair. |
| close |
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2 .
Ehud Zohary
Hebrew University of Jerusalem, Neurobiology Department
Cortical plasticity in the adult human (visual/motor) cortex following damage to the eripheral organ (retina/ limb)
|
| Contrary to long held belief, there is evidence that sensory maps are not immutable in the adult cerebral cortex. However, the degree to which massive changes in the cortical representation of the sensory and motor maps indeed take place after an injury to the peripheral organ (such as damage to the eye or amputation of a limb) is still hotly disputed. We plan to assess this issue in human patients suffering from chronic retinal damage (caused by macular degeneration) or limb loss. We will also attempt to track the dynamics of the putative cortical changes in the visual cortex by generating reversible virtual lesions in healthy humans wearing appropriately designed contact lenses for a week. Analogously, we will track changes in the motor cortex by studying people having their limb immobilized in a cast for a month (due to a fracture). The goal of this research project is to attain a better understanding of human cortical plasticity and its relationship to behavior. |
| close |
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3 .
Amir Karniel
Ben Gurion University of the Negev, Biomedical Engineering
Motor Memory - does it address the past or the future?
|
| It was recently suggested that memory is better equipped to handle the future than the
past. This is indeed a provocative statement about episodic memory which is thought
to describe a previously experienced event.
Motor memories, however, are expected to handle the future. They employ
experience from the past to represent the properties of our body and external
environment. These representations are used to plan our future movements.
We propose to experimentally test this fascinating dichotomy for motor tasks before
and after mental practice and strive to answer the question: Does the motor memories
represent the past or the future? |
| close |
|
|
|
4 .
Doron Gothelf
Schneider Hospital for Children, Clinical Psychiatry
Genetic and cognitive endophenotypes and neuropsychiatric risk factors for the development of psychosis in velocardiofacial syndrome (22qll.2 deletion syndrome).
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| Although schizophrenia is highly hereditary, the cause of the disease is still unknown. Therefore, longitudinal studies of individuals with a well-defined risk factor for psychosis are important for identifying pathological mechanisms associated with schizophrenia. Velocardiofacial syndrome (VCFS) is the most common known genetic risk factor for schizophrenia. Up to one-third of individuals with VCFS develop a schizophrenia-like disorder. In the previous grant period of the National Institute for Psychobiology in Israel we recruited a large cohort of children and adolescents with VCFS and characterized their genetic, cognitive, and psychiatric profile. We now plan to conduct a longitudinal follow-up of this cohort using integrative multidisciplinary scientific approach to identify genetic, cognitive executive functioning and psychiatric risk factors for the development of schizophrenia in this high-risk population. |
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5 .
Gil Levkowitz
Weizmann Institute, Molecular Biology
Zebrafish as a vertebrate model to investigate developmental dysfunctions of dopaminergic pathways
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| Dopaminergic brain cells (neurons) have been associated with drug addiction, mood disorders and Parkinson's disease. Our team has recently shown that zebrafish is a valid vertebrate model to study developmental alterations in the dopaminergic system and that genetic manipulation of zebrafish causes marked phenotypic changes in dopaminergic neurons. In the proposed study, we aim to employ zebrafish in order to study genetic pathways underlying dopaminergic development and function. By studying how dopaminergic neurons operate during normal brain development we may also begin to understand the genetic basis for neuro-psychiatric disorders and find new ways to alleviate these neurological impairments. |
| close |
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6 .
Jeannette Schaeffer
Ben Gurion Univesrity of the Negev, Linguistics
Grammatical and pragmatic properties of DPs in the language of Hebrew speaking children with Grammatical Specific Language Impairment
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| This project investigates noun phrases in Hebrew acquiring children with Grammatical Specific Language Impairment (H-GSLI). We hypothesize that a) linguistic sub-abilities (e.g. grammar and pragmatics (=language use)) are autonomous, and b) that children with GSLI are impaired in their grammar only, but not in their pragmatics. We will test these hypotheses by conducting experiments on grammatical and pragmatic properties of noun phrases with children with H-GSLI. With the results we hope to contribute to a) a better understanding of the organization of language; b) a more refined characterization of Hebrew GSLI; c) the development of new methods to help children with GSLI. |
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7 .
Yael Chertkow-Deutsher
The Technion, Psychobiology-psychiatry
Epigenetic factors in the vulnerability to PTSD; The role of DNA methylation
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| Posttraumatic Stress Disorder (PTSD) is a psychiatric disorder that may occur following exposure to a stressful environmental event (20% of exposed population). Currently no specific gene has been associated with PTSD. Epigenetic processes, such as DNA methylation, are means to affect genome plasticity and adaptation to environmental alternation. To investigate the potential role of DNA methylation in PTSD, we will examine the pattern of global methylation in the brains of PTSD-like rats. In addition, we will examine in this model the promoter of glucocorticoid receptor, whose methylation pattern has been shown to be affected by stress. |
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8 .
Leon Deouell
Hebrew University of Jerusalem, Psychology Department
Is the frontal lobe involved in non-intentional change detection? An ERP and fMRI investigation
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| To achieve our goals, we frequently need to focus attention on certain regions of space or class of stimuli, and ignore the rest. This can be perilous if a critical change happens outside the focus of attention that requires action. Recording of brain electrical activity with EEG has revealed a mechanism that responds automatically to changes in the auditory environment outside the focus of attention, as soon as 100-200 milliseconds after the change. In this project, we will determine the contribution of the frontal lobes to this process, using a combination of EEG and functional MRI. |
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9 .
Noga Kronfeld-Schor
Tel Aviv University, Department of Zoology
Modulating affective responses by changing photoperiod in fat sand rats: Possible mechanisms and insights into Seasonal Affective Disorder (SAD)
|
| Our goal is studying effects of seasonal acclimation on mood and emotional state in an animal model of Seasonal Affective Disorder (SAD), a malady of recurring cycles of seasonal depression and remission. From a biological perspective, SAD may represent a form of seasonal acclimation, once biologically (and evolutionary) advantageous. Preliminary results indicate that the fat sand rat, a diurnal rodent with behavior and physiology typical to other diurnal mammals, is sensitive to short daylight period, with a response which is indicative of depression. We propose to continue this study by using a set of physiological and behavioral paradigms to gain insights on SAD mechanisms and on potential therapies. |
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10 .
Alon Chen
Weizmann Institute, Neurobiology Department
The roles of central corticotropin releasing factor receptors in mediating stress-related neuroendocrine and behavioral responses.
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| When physiological or psychological stimuli is perceived as stressful, the brain activates many neuronal circuits to adapt to the demand. The CRF family of neuropeptides and receptors is essential for coordinating the behavioral and endocrine responses to stress and implicated in the control of arousal, anxiety, cognitive functions and appetite. Dysregulation of the stress response can have severe psychological and physiological consequences and chronic hyperactivation of the CRF system has been linked to many affective disorders such as anxiety, anorexia nervosa and melancholic depression. Specifying the contributions of the CRF family of ligands and receptors to the maintenance of homeostasis and to stress-linked emotional disorders may improve our ability to design therapeutic interventions and thus manage affective and other disorders. |
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11 .
Orna Almog
Ben Gurion Univesrity of the Negev, Clinical Biopharmacology
A structural study of the interaction of calbindin D28k with the lithium inhibited enzyme IMPase
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| Inositol monophosphatase (IMPase) is a key enzyme in regulating the phosphatidylinositol (PI) signaling system. It catalyzes the dephosphorylation of myo-inositol monophosphates to free myo-inositol. Lithium (Li), the drug of choice in the treatment of bipolar disorder (manic-depressive illness), inhibits IMPase activity at therapeutically-relevant concentrations but has well-recognized limitations. Reduced IMPase activity may lead to depletion of intracellular myo-inositol. Since myo-inositol is used in the re-synthesis of the signal precursor phosphatidylinositol (PI), its depletion may attenuate hyperactive signaling.
Recently, it was shown that calbindin D28k (calbindin) is an activator of IMPase. It has been suggested that calbindin attaches to residues 55-66 of IMPase, enhancing its activity. Calbindin could thus be a key endogenous regulator of the PI signaling cycle.
The aim of the proposed research is to characterize the interaction between the specific sequences of IMPase and calbindin, and to understand the mechanism by which calbindin activates IMPase. To address this goal, we will over-express human calbindin and will co-crystallize it with the specific synthetic peptides.
The structural analysis of the interaction between IMPase and calbindin may serve as a basis for future drug design for treating bipolar disorder patients. A rationally designed inhibitor of IMPase could replace lithium compounds which are highly charged and polar. |
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12 .
Yair Bar Haim
Tel Aviv University, Psychology Department
Neural Correlates of Threat Processing in Anxiety
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| A normative function of the mechanisms underlying fear is to facilitate detection of danger in the environment and to help people respond effectively to threatening situations. Malfunction in processing threat-related information have been assigned a prominent role in the etiology of anxiety disorders. However, little is known about the neural substrates of the differences between anxious and non-anxious individuals in threat-related processing. In a set of three studies, assessing normative and clinically anxious participants, we intend to shed light on the neural correlates of these individual differences. |
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13 .
Dorit Ben-Shalom
Ben Gurion University of the Negev, Visual Perception
Superior and not so superior visual search in autism
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| Several studies suggest that subjects with autism conduct visual searches better than controls. At the same time, adults with autism report difficulties in finding objects in everyday life. We tested one such adult and found, that his visual search is indeed better under some conditions, but not others. In addition, he shows other abnormalities in visual attention. We would like to explore the superior and not so superior aspects of search in high-functioning autism, to get a better understanding of visual strengths and difficulties, as well as get inspiration for potential future intervention to partially alleviate some of these difficulties. |
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14 .
Anat Barnea
The Open University, Neurobiology Department
Neurobiological aspects of migratory eriphera in birds: a neuroethological study, comparing migrant and resident species in Israel
|
| This study includes both field and laboratory work, in an effort to understand how the brain enables birds to migrate over long distances. We assume that migrants process more spatial information than resident birds. To test this hypothesis, we are seasonally comparing wild migratory and resident birds. Various methodologies are used to measure the number of new neurons that are recruited in the brains of the tested species, their blood hormonal levels, and (for migratory birds) the length of migration routes. The results will enable a comparison between migrant and resident birds, and a search for correlations between behavior and neurobiological mechanisms underlying it. We hope that the work will contribute to our basic understanding of the acquisition of new long-term memories, as well as to suggestions for new approaches in clinical applications for brain repair. |
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15 .
Ariela Gordon-Shaag
Hebrew University of Jerusalem, Physiology Department
The molecular basis of TRPV1 modulation by Nerve Growth factor
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| Pain is a prevalent problem in our society, especially as our population ages and the common therapies (opiates and COX-2 inhibitors) are suboptimal in both safety and efficacy. Understanding the pain receptors responsible for inflammatory pain would be a big step toward developing more effective therapies. In my post-doctoral studies at Prof. Minke's laboratory I will be examining a human pain receptor called TRPV1. This receptor is activated by several stimuli: heat, acid and an extract from hot chili peppers called capsaicin. Capsaicin is what chili peppers use to "trick" us into thinking that they are hot: the peppers do not raise the temperature in our mouths - rather they activate the same receptor as heat. Capsaicin provides us with an excellent and specific tool for studying TRPV1, (heat and acid have other non-specific effects on the cell membrane). TRPV1 forms an ion channel - a tunnel in the cell membrane that opens up in the presence of one these stimuli. The passage of charged atoms through the tunnel transmits the message to our brains that something is hot or painful. TRPV1 is involved in the phenomena of hyperalgesia, the lowering of the pain threshold in the presence of multiple stimuli, a common problem for people with inflammatory pain. If we understand how this pain receptor works we can design new therapies for treating pain. I will be studying the role of a group of fatty lipids in the cell membrane in mediating TRPV1 activation. |
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16 .
Alexandra Kavushansky
The Technion, Psychiatry Department
The plasticity-related genes CAM-L1, laminin and CREB in physical vs. .psychological stress: implication to stress-related psychiatric disorders
|
| Stress has been initially defined as a universal, non-specific response of an organism to various environmental demands ("stressors"). However, acute and chronic stressors differ in their physiological and behavioral outcomes. Physical and psychological stressors also activate different brain areas and may lead to different stress-related disorders, such as post-traumatic stress disorder (PTSD - following physical stress) vs. major depression - following psychological stress. Neuronal plasticity-related genes have been demonstrated to be oppositely expressed in the brain following stress and anti-depressant treatment, suggesting a role of these genes in both stress and treatment of depression. However, specific patterns of activation of these plasticity markers by different stressors have not been established. I am investigating behavioral, endocrine and molecular outcomes of acute vs. chronic exposure tophysical stressors (such as shock) vs. psychological stressors (such as social defeat). Following the stress procedures, subjects will be tested for anxiety- and depression-like behaviors, plasma levels of stress hormones, and expression of specific plasticity-related genes in stress-related areas of the brain. Understanding how different stressors affect plastic processes in the brain will assist in developing more cause-specific treatment of stress-related illness. |
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17 .
Hadas Okon-Singer
Ben Gurion Univesrity of the Negev, Behavioral Sciences
Reduced Functional Brain Asymmetry in Focal Epilepsy: Modification in .Regional Activity or Neural Conduction?
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| Studies have demonstrated functional reorganization of language in patients with epilepsy. To assess cortical plasticity in epilepsy, I am using multi-scale imaging modalities: white matter organization and integration by the structural measure of diffusion tensor imaging (DTI), regional neural activity measured by functional magnetic resonance imaging (fMRI), and neural conductivity measured by event related potentials (ERPs). I will study patients with epilepsy and matched controls. In order to evaluate the relationship of epilepsy to various functional asymmetries, a battery of tests will be used examining language, motor, and auditory-related cortical changes. It is hoped that the knowledge obtained regarding cortical reorganization in patients with epilepsy may improve surgical intervention in these patients. A further aim of the study is to explore within- versus between-hemisphere mechanisms in focal epilepsy, in order to understand better the characteristics and causes of cortical abnormalities in epilepsy. In addition, cortical plasticity and reorganization of cognitive function in epilepsy may serve as a clue to cognitive functionality in the abnormal as in the healthy brain. |
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Second Year
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1 .
Yoram Bonneh & Misha Tsodyks
Weizmann Institute, Neurobiology Department
Investigation of the cause and consequence of sensory hyper-sensitivity in autism.
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| Despite many reports of severe sensory disturbances in people with autism spectrum disorder (ASD), such as hyper and hypo- sensitivity and sensory or perceptual overload, very little is known about the responsible brain mechanisms. Possible causes include over excitatory local sensory networks with high gain on the input, poor top-down attentional modulation of sensory processing and/or large fluctuations of arousal that modulate sensory processing. We propose to investigate the underlying cause and abnormal mechanisms associated with the sensory disturbances in ASD in a detailed study that combines a physiological measure of arousal or autonomic activity (galvanic skin response, GSR) with psychophysical evaluation of early visual, auditory and tactile mechanisms that underlie sensory gain, such as sensitivity, discrimination and adaptation. The GSR measure will allow testing of low-functioning children who do not cooperate but show startle response and even aversion to certain sensory stimuli in a way similar to "fear conditioning". We will also study multi-modal responses which reflect sensory load and their relation to fluctuations of arousal as cases of severe crossmodal interference have been reported. Understanding of the mechanisms that underlie the severe sensory disturbances in autism could lead to the development of early diagnosis tools, "sensory diets" as well as rehabilitation methods. |
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2 .
Ariel Knafo
Hebrew University of Jerusalem, Psychology Department
The molecular genetic architecture of prosocial behavior: Polymorphisms and individual differences, using a multimethod approach including laboratory games.
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| Prosocial behavior, beyond its obvious importance to societal functioning, has implications for individuals' relationships, behavioral adjustment, wellbeing, and mental health. We propose to investigate the genetic origins of individual differences in prosocial behavior. 270 sibling pairs who have participated in a former study and whose DNA has been obtained and analyzed together with a wide range of psychosocial indicators will participate.
We adopt a multi-method approach to assessing prosocial behavior. In addition to well-established personality self-report scales we will obtain sibling reports on prosocial behavior and individuals' self-report on the importance of prosocial and other values in their life. More importantly, two resource allocation tasks, with monetary rewards as the stimulus, will assess costly (therefore realistic) prosocial behaviors.
Several candidate genes, with established links to neuropsychological functioning, will be analyzed. Among these are MAOA and TPH2, formerly implicated in aggression, a behavior negatively related to prosocial behavior.
The association of different polymorphisms to the diverse measures of prosocial behavior will be examined, for the first time in conjunction with the motivations that underlie it, indexed by participants' value priorities. Through understanding the molecular genetic architecture of prosocial behavior, this interdisciplinary study will advance knowledge regarding this important behavior. |
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3 .
Ilan Lampl
Weizmann Institute, Neurobiology Department
Membrane potential up and down states: mechanisms of generation and their role in shaping neuronal response to sensory stimulation.
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| Intracellular recordings from anesthetized and awake animals show that the membrane potential of many cortical neurons is bi-stable, fluctuating rapidly between two potential states ("up and down states"). Since cortical firing mechanism is believed to be reliable, it was speculated that cortical states might be the primary source of trial-to-trial variability of response. Furthermore, it is suggested that cortical states underlie high cognitive behaviors such as persistent activity during working memory and modulation of attention. In the absence of stimulation, cortical states are highly correlated even between distant cells and are dependent on cortical synaptic activity. Upon sensory stimulation, the dynamics of the two state fluctuations change dramatically, with the potential spending more time in the up state. Moreover, the responses of a cortical neuron are strongly dependent upon the immediate state at the time of response. Nevertheless, the mechanisms underlying these complex interactions between cortical states and sensory inputs are still unknown. Through a series of intracellular recording experiments on neurons from the barrel cortex of anesthetized rats, we aim to reveal the cellular, synaptic and network mechanisms that generate cortical states and to study how these mechanisms govern responses to sensory stimulation. Revealing these mechanisms will have significant implications for our understanding of information processing in the primary sensory areas and high level of cognitive processes. |
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4 .
Shai Shoham
Herzog Hospital Jerusalem, Research Department
Dietary lithium supplementation for delaying brain aging processes.
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| The present project explores effects of dietary lithium (Li) supplementation on astrocytic and neuronal markers of aging and on cognitive decline in aging mice. In preliminary work we found that dietary Li supplementation of 0.25% (2.5gr/Kg diet) for one month attenuated astrocytic markers of aging in the hippocampus of adult C57BL mice without affecting body weight. In the present project, in experiment 1, senescence accelerated mice (SAMP8 strain) are allocated to receive 0.0%, 0.1%, or 0.2% lithium, from 2 to 8 months of age. Experiment 2 tests effects of Li in C57BL mice receiving high-fat diet. There are three lithium levels: 0.0%, 0.1%, and 0.2% and two fat levels 6% and 15%, 6 groups total, receiving dietary treatments from 7 to19 months of age. Experiment 3 tests effects of age at onset, and duration of treatment with Li added to high fat diet, from 7, 10, or 13 months of age. Potential Li-induced renal toxicity is tested by immunostaining of water channels in kidney sections. Li dose is adjusted to achieve non-toxic treatment. Attenuation of markers of aging in hippocampus and of cognitive deficits is expected to lay the foundation for Li supplementation to delay cognitive decline in aging. |
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5 .
Drorit Saar
University of Haifa, Brain and Behavior Department
Mechanisms underlying learning induced enhancement of synaptic transmission: quantal analysis study.
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| The purpose of the proposed research is to describe the mechanisms by which learning-induced synaptic enhancement is generated and maintained in the mammalian cortex.
Rats that are trained with odor-discrimination tasks demonstrate dramatic increase in their capability to acquire memory of new odors, once they have learned the task (rule learning). We have previously shown several training-related forms of long-term synaptic modifications in the intra-cortical connection in the rat piriform cortex, which are preserved in brain slices. These include reduced paired-pulse facilitation (PPF) (Saar et al., 1999), reduced rise time of EPSPs (Saar et al., 2002), decreased predisposition for long-term potentiation (LTP) and increased predisposition for long-term depression (LTD) (Lebel et al., 2001).
Here, we will examine possible pre- and post-synaptic mechanisms that may underlie the observed synaptic modifications. Whole-cell patch clamp recordings from visualized pyramidal neurons in layer II of the piriform cortex will be used to study learning-induced modifications in spontaneous and evoked quantal synaptic events. The study will include detailed analysis of excitatory and inhibitory synaptic transmission. Also, the role of PKA and PKC-dependent second messenger systems in generating and maintaining these long-term synaptic modifications will be studied.
The proposed experimental paradigm, in which learning-induced physiological modifications will be studied quantitatively at the cellular level, offers a unique framework for describing basic mechanisms that underlie learning in the mammalian brain. |
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6 .
Miki Bloch
Tel Aviv University, Psychiatry Department
Gonadal steroid manipulation and personality characteristics: association with mood fluctuations and in vitro fertilization outcomes
|
| Biological susceptibility related to interactions between the hypothalamic pituitary gonadal (HPG) axis and other neuromodulators, has been hypothesized to account for gender differences in the prevalence of mood disorders. The current study's primary aim is to investigate the association between neuroendocrine fluctuations and mood disorders by monitoring mood states over distinct hormonal phases during in-vitro-fertilization (IVF) treatment. The secondary goal of this study is to explore psychological profiles and coping mechanisms of women undergoing IVF, and to identify the ones that are associated with successful psychological adaptation to the process and a successful biological outcome. Participating women will be recruited among women who are being treated at the Tel-Aviv Sourasky Medical Center Fertility Unit. The sample size (n=210) was determined by power analysis computations. IVF protocols include controlled manipulation of ovarian steroids (progesterone and estrogen), resulting in uniquely well-specified hormonal phases (baseline, hypogonadal, follicular and luteal). Participants' mood and subjective well-being during these distinct phases will be monitored in 2 different IVF protocols. Data will include biological measurements (reproductive hormones, prolactin, androgens, cortisol, neurosteroids, follicle number, pregnancy tests and fetal pulse on week 10) and psychological measurements (SCID interview, MMPI, BSI, Speilberger state and trait anxiety inventories, CES-D, Fordyce subjective well-being visual analogue scale, Markstrom ego-strength scale and the COPE inventory). |
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7 .
Yossi Chalamish
Weizmann Institute, Neurobiology Department
The conrol of visual imagery and attention under hypnotic suggestion: an fMRI study of the human visual cortex.
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| A fundamental question in human visual system studies is the mapping of cortical areas directly associated with visual experience. Typical attempts to dissociate the response to outside visual stimulation from the perceptual state involved studying brain regions associated with binocular rivalry. (Tong and Kanwisher, Neuron, Logothetis) and visual imagery (Ishai, Kanwisher).
Here we propose a novel approach in which hypnotic suggestion will be used to dissociate external visual states from their perceptual manifestation through vivid imagery and its control.
During the present year we examined the hypnotizable traits of 87 volunteers (using the standard Stanford hypnotizable test), and have gathered a selected group of 7 volunteers with high hypnotizable traits.
In psychophysical tests this group are able to present, during hypnotic condition, a positive visual hallucinations (see images that do not exist), and negative visual hallucinations(ignore images that are placed in the center of their visual field).
Our next step is to use the hypnotic suggestions while scanning the high hypnotizability subject's brains in functional magnetic resonance imaging system. Three main lines of research will be pursued: a. producing vivid imagery in the absence of visual stimulation. b. Producing the sensation of blank field despite the presence of an external visual stimulation. c. Producing vivid imagery of one category of objects , (e.g. faces), when the external stimuli contain another category, (e.g. houses).
the use of hypnotic suggestion will provide a powerful new methodology that will allow a more effective control over visual imagery, and by that allow better identification of the cortical mechanisms involved in conscious visual awareness, and those which are "reflexively" activated by the external visual stimuli. It is also hoped to define the nature of the imagery, and try to reveal how it emerge in extreme pathologic cases of hallucinations in several psychiatric and organic disorders.
The power of our project is that it merges experts from two disciplines - that of hypnotic suggestions on the one hand, and that of functional mapping on the other. The expertise of Dr. Chalamish and Dr. Solomonovitch in hypnosis, and that of Prof. Malach in functional mapping of the human visual system, provides an exciting opportunity to develop a rigorous "neuroanatomy"of conscious awareness
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8 .
Michal Taler & Irit Gil-Ad
Felsenstein Medical Research Center,
Evaluation of the effect of various antidepressants on brain IGF-I and IGFII and their receptors expression in normal and stressed rats. Relevance to antidepressants-induced neurotrophic activity.
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| Insulin like growth factors ( IGFs) I and II are potent neurotrophic and survival factors in the brain, acting by activation of specific receptors. Previous studies have demonstrated that IGF-I possesses a potent neuroprotective effect, and plays a role in brain growth, neural plasticity and cognition. Recent evidence suggests that depression is associated with decreased neural plasticity and disrupted information processing. Antidepressants were found to facilitate synaptic connections and neuroplasticity, as also evidenced by their induced-stimulation of trophic elements such as BDNF and CREB. However, the information on the effect of antidepressants on the IGF system in the brain is scarce. The aims of the following study are to elucidate, in normal and stressed rats, the effect of subchronic administration of antidepressants derived from different classes: (serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin and norepinephrine reuptake inhibitors (SNRIs) and atypical antidepressants), on the expression of IGF I and II and on their receptors in the prefrontal cortex, hippocampus and hypothalamus. We also wish to determine the effect of these antidepressants on serum IGFI and II levels in controls and stressed rats. Finally we wish to shed light on the possible role of the central IGF system in depression, and to broaden our information on the antidepressants-induced neurotrophic activity. |
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9 .
Uri Polat
Tel Aviv University, Faculty of Medicine
Relationships between information processing, decisions and cognitive reward in major depression
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| Cardinal signs of Major Depressive Disorder (MMD) are impairment of cognitive tasks (CT) and unhedonic symptoms that have recently been suggested to be mediated by an impairment of the Brain Reward System (BRS). Our proposal is to psychophysically study the link between these symptoms, information processing, and the reward-demanding/gain-based decision making tasks that rely on CT. We will explore how patients and control subjects adapt their decision criteria to varying contextual and statistical conditions to operate different combinations of CT. The connection to the reward system will be explored by manipulating the probability of appearance of a certain stimuli configuration and/or by changing the type of explicit external rewards. The information processing will be explored using temporal masking. Our pilot results, using a basic contrast filling-in experiment, show that MDD seem to have conservative criteria regardless of the context of the input signals. The conservative criteria may suggest that the filling in process is absent, probably due to reduced excitation between neurons. Alternatively, it may suggest that they are unable to match their internal representation to the different stimuli information and rewards, in order to reach a more optimal decision - pointing to a possible connection to the impaired BRS. |
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10 .
Marina Pavlovskaya
: Loewenstein Hospital, Neurophysiology Department
Low level visual processing in unilateral neglect syndrome: contrast detection and contrast matching study
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| Uninilateral spatial neglect (USN) is characterized by a failure to perceive stimuli on the contralesional side. Extinction is another phenomenon, commonly associated with USN, where patients are able to detect the contralesional stimulus when presented unilaterally, but fail under bilateral stimulus stimulation. Accumulating evidence for an elaborated processing of "neglected" visual stimuli suggests that low-level visual processing remains intact and the failure of perception occurs due to a high-level "gating" mechanism. However, the nature of this gating mechanism that has a large impact on understanding USN as well as normal perception is currently unknown. Here we propose to explore the nature of this gating mechanism by studying low-level visual processing in USN patients such as involved in contrast sensitivity, perceived contrast and vernier acuity. If the failure of perception in USN is due to "gating", then stimuli that pass the gate should be perceived normally in terms of low-level visual properties, e.g. with the correct contrast, orientation and visual acuity. On the other hand, if USN is due to attenuated processing on the neglected side, then such visual properties should be affected. Preliminary results in contrast matching support the first hypothesis by showing that when they see, they see it right, i.e. with the correct perceived contrast. |
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11 .
Michal Hershfinkel
Ben Gurion University of the Negev, Department of Morphology
The molecular mechanism linking zinc deficiency to learning and memory disorders.
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| A hallmark of mild zinc deficiency, common in both developed and undeveloped
countries, is impairment of learning and memory and the appearance of eating disorders
most notably anorexia nervosa. This deficit, monitored in human and animal models, is
typically accompanied by neuronal loss. Despite the fact that zinc deficiency is
widespread, the signaling mechanisms linking zinc to neuronal survival during crucial
stages of development are unknown. We have identified a zinc sensing receptor (ZnR) in
epithelial cells which our preliminary results indicate is also active in the brain. The ZnR
is a Gq-coupled receptor that triggers intracellular signaling pathways such as MAP and
PI3-kinase, which are crucial for cell survival. Furthermore, ZnR plays a key role in
regulation of ion transport via the Na+/H+ exchanger (NHE1) which in epithelial cells is
also known to regulate cell survival. We hypothesize that zinc, acting through the ZnR,
has a signaling role in the brain, promoting the activation of cell signaling cascades and
ion transporters that promote neuronal survival. In this proposal, combining biochemical
methods and live imaging of brain slices, we will study the role of the brain-ZnR in the
regulation of two major transport systems: the Na+/K+/2Cl- (NKCC) co-transporter and
the Na+/H+ exchanger (NHE). These transporter proteins are important for ion and pH
homeostasis and, thereby, for neuronal survival. By functionally activating or silencing
ZnR, we will characterize the specific role of this receptor in regulating these transporters.
Subsequently, application of kinases and transporter inhibitors and an NHE1 knockout
model will allow us to determine of the precise role of this isoform, which is particularly
crucial for cell survival. The results of these experiments will provide novel insight into
the molecular mechanisms linking zinc deficiency to the impairment of learning and
memory and may provide important Insight towards the treatment of anorexia nervosa.
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12 .
Avraham Zangen
Weizmann Institute, Neurobiology Department
Neurochemical characterizations of a genetic and an environmental rat model for depressive behavior.
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| Depression is among the most prevalent forms of mental illness. Although the etiology of this disease is poorly understood, it has become clear that the risk for depression is partially genetic. Currently available antidepressants have some efficiency in the control of depressive symptoms, but improvement in terms of latency of onset, side effect profile and especially treatment of non-responders is needed. Moreover, we lack objective diagnostics tests identifying individuals with depression or determining which antidepressant treatment would be most effective for a given individual. Such improvements may come after better understanding of neurochemical and genetic factors underlying the disease. Such research requires controlled measurements of gene expression and neurochemical factors within specific relevant brain regions. Therefore, an animal model for depressive behavior is needed. Most of the models for depression are based on the assumption that depression is a response to acute or chronic stress and ignore the genetic component. We have therefore started to create a genetic animal model based on the core symptoms for depression. We plan to study the genetic contribution and to characterize neurochemical factors that may define depressive behaviors. Our main tools will be gene arrays (and using reward-related brain regions) and microdialysis for monitoring release of monoamines and beta-endorphin. We also intend to use an 'environmental-induced' (chronic mild stress, CMS) animal model for depression and compare the results obtained in the different models of the different components of depressive behavior. We anticipate that our rat model for depression will help the isolation and identification of genetic and neurochemical factors underlying the etiology of this disabling disorder and we hope that our studies will become a basis for future development of a treatment with better outcome and fewer side effects. |
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13 .
Rami Yaka
Hebrew University of Jerusalem, School of Pharmacy
Regulation of GABAa receptor function by ethanol
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| The goal of the proposed study is to explore the molecular mechanisms that regulate the function of the ionotropic ?-aminobutyric acid type A (GABAA) receptors under basal conditions and following exposure to ethanol. The majority of GABAA receptor subtypes in the adult brain are composed of heteropentameric assemblies of ?, ? and ? subunits. Individual GABAA receptor subtypes are associated with distinct neuronal structures and subcellular distributions, and their differential activation is correlated with distinct pharmacological and behavioral phenotypes. Previously we demonstarted a molecular mechanism for the regulation of the phosphorylation state and function of the NMDA receptor and how ethanol modulate its function (Yaka et al., 2002; Yaka et al., 2003a; Yaka et al., 2003c). Based on similarities between the molecular mechanisms that regulate NMDA and GABAA receptors, we will test the hypothesis that regulation of GABAA and NMDA receptors may share common molecular mechanisms.
We will use multiple approaches utilizing immunohistochemical, biochemical and electrophysiological techniques to determine first, the localization of GABAA receptor subunits in areas relevant to addiction, second the signaling pathways and specific kinases that regulate the phosphorylation state and function of the GABAA receptors and finally we will examine how ethanol alter these processes.
Understanding the molecular mechanisms that underlie the regulation of GABAA receptor function will enable us to identify targets for the design of new therapeutic agents that will alter the function of specific populations of GABAA receptors in specific brain areas, involved not only in the development of drug addiction but also in a wide range of neurological disorders associated with modified GABA receptor function such as epilepsy, anxiety and depression. |
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14 .
Simone G. Shamay-Tsoory
University of Haifa, Psychology Department
Characterization of theory of mind and empathy deficits in Schizophrenia: a neuropsychological examination of affective vs. cognitive aspects of social cognition.
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| Patients suffering from schizophrenia show impaired emotional and social behavior, such as misinterpretation of social situations and lack of Theory of Mind (ToM). However, the empathic abilities of these patients has never been examined before and there is conflicting evidence regarding their ability to perform basic ToM tasks. Based on previous findings, it is suggested that the behavioral deficit of schizophrenic patients may be due to impaired empathy and 'affective ToM' abilities, rather than to a general impairment in ToM. Furthermore, it is suggested that empathy and 'affective ToM' deficits are related to prefrontal cortical functioning and to the severity of negative symptoms.
To assess different facets of ToM and empathy, tasks that differ in the level of emotional processing will be administered to schizophrenic patients, age-matched patients with depression and healthy controls. The relation between empathy, 'affective ToM' and prefrontal cognitive functioning will be assessed using Cambridge Neuropsychological Test Automated Battery subtests sensitive to frontal circuits functioning.
The relationship between specific symptoms of schizophrenia, ToM and empathy will also be assessed.
These findings will offer new insight into the mediating role of the prefrontal cortex in the affective facets of social behavior that may underlie the profound behavioral disturbances observed in schizophrenia.
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15 .
Adi Mizrahi
Hebrew University of Jerusalem, Neurobiology Department
The role of newborn inhibitory neurons in memory formation of the olfactory system in the mouse
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| The olfactory system of mice is a good model to study sensory perception and to dissect mechanisms of learning and memory. Mammalian olfaction is behaviorally critical and also retains a unique property of structural plasticity in its first relay station, the olfactory bulb (OB). The OB encompasses a "developmental niche" such that newborn inhibitory neurons continue to develop well into adulthood. Both the phenomenon of adult neurogenesis and the functional architecture of the OB suggest a new form of network-based plasticity that might sub serve sensory perception. This putative mechanism continually shapes the connectivity between different functional compartments (sensory percepts) that have been changed (experienced) by the animal. Thus, in this proposal we aim to uncover a new mechanism for experience dependant plasticity in odor perception.
In order to test this mechanism experimentally, we will combine behavior and transgenic transduction of newborn neurons that develop into the OB during learning. Using a line of transgenic mice expressing tagged olfactory receptor neurons we will be able to correlate the density and fine morphological structure of newborn neurons with the functional architecture of the bulb. This study will begin to unravel the functional organization of the inhibitory neurons of the olfactory bulb and provide new insights into general mechanisms of learning and memory in the mammalian brain.
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Third Year
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1 .
Inna Slutsky
Tel Aviv University School of Medicine, Physiology Department
Reversal of Age-Dependent Memory Decline by Magnesium Ion
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| Memory is profoundly affected by aging. However, the endogenous mechanisms needed to retain memory capacity remain elusive. Our recent work suggests that the concentration of magnesium in cerebrospinal fluid ([Mg]CSF) is a key regulator of synaptic plasticity and memory. In intact animals, increasing Mg consumption elevates [Mg]CSF, reversing age-associated decline of memory. This is achieved mechanistically by retaining the synaptic network in a "juvenile" configuration. As a significant portion of the human population, particularly the aging, suffers from a Mg deficiency, this work suggests that increasing Mg consumption might be beneficial for improving learning and memory in humans. |
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2005 - 2006
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First Year
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1 .
Yoram Bonneh & Misha Tsodyks
Weizmann Institute, Neurobiology Department
Investigation of the cause and consequence of sensory hyper-sensitivity in autism.
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| Despite many reports of severe sensory disturbances in people with autism spectrum disorder (ASD), such as hyper and hypo- sensitivity and sensory or perceptual overload, very little is known about the responsible brain mechanisms. Possible causes include over excitatory local sensory networks with high gain on the input, poor top-down attentional modulation of sensory processing and/or large fluctuations of arousal that modulate sensory processing. We propose to investigate the underlying cause and abnormal mechanisms associated with the sensory disturbances in ASD in a detailed study that combines a physiological measure of arousal or autonomic activity (galvanic skin response, GSR) with psychophysical evaluation of early visual, auditory and tactile mechanisms that underlie sensory gain, such as sensitivity, discrimination and adaptation. The GSR measure will allow testing of low-functioning children who do not cooperate but show startle response and even aversion to certain sensory stimuli in a way similar to "fear conditioning". We will also study multi-modal responses which reflect sensory load and their relation to fluctuations of arousal as cases of severe crossmodal interference have been reported. Understanding of the mechanisms that underlie the severe sensory disturbances in autism could lead to the development of early diagnosis tools, "sensory diets" as well as rehabilitation methods. |
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2 .
Ariel Knafo
Hebrew University of Jerusalem, Psychology Department
The molecular genetic architecture of prosocial behavior: Polymorphisms and individual differences, using a multimethod approach including laboratory games.
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| Prosocial behavior, beyond its obvious importance to societal functioning, has implications for individuals' relationships, behavioral adjustment, wellbeing, and mental health. We propose to investigate the genetic origins of individual differences in prosocial behavior. 270 sibling pairs who have participated in a former study and whose DNA has been obtained and analyzed together with a wide range of psychosocial indicators will participate.
We adopt a multi-method approach to assessing prosocial behavior. In addition to well-established personality self-report scales we will obtain sibling reports on prosocial behavior and individuals' self-report on the importance of prosocial and other values in their life. More importantly, two resource allocation tasks, with monetary rewards as the stimulus, will assess costly (therefore realistic) prosocial behaviors.
Several candidate genes, with established links to neuropsychological functioning, will be analyzed. Among these are MAOA and TPH2, formerly implicated in aggression, a behavior negatively related to prosocial behavior.
The association of different polymorphisms to the diverse measures of prosocial behavior will be examined, for the first time in conjunction with the motivations that underlie it, indexed by participants' value priorities. Through understanding the molecular genetic architecture of prosocial behavior, this interdisciplinary study will advance knowledge regarding this important behavior. |
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3 .
Ilan Lampl
Weizmann Institute, Neurobiology Department
Membrane potential up and down states: mechanisms of generation and their role in shaping neuronal response to sensory stimulation.
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| Intracellular recordings from anesthetized and awake animals show that the membrane potential of many cortical neurons is bi-stable, fluctuating rapidly between two potential states ("up and down states"). Since cortical firing mechanism is believed to be reliable, it was speculated that cortical states might be the primary source of trial-to-trial variability of response. Furthermore, it is suggested that cortical states underlie high cognitive behaviors such as persistent activity during working memory and modulation of attention. In the absence of stimulation, cortical states are highly correlated even between distant cells and are dependent on cortical synaptic activity. Upon sensory stimulation, the dynamics of the two state fluctuations change dramatically, with the potential spending more time in the up state. Moreover, the responses of a cortical neuron are strongly dependent upon the immediate state at the time of response. Nevertheless, the mechanisms underlying these complex interactions between cortical states and sensory inputs are still unknown. Through a series of intracellular recording experiments on neurons from the barrel cortex of anesthetized rats, we aim to reveal the cellular, synaptic and network mechanisms that generate cortical states and to study how these mechanisms govern responses to sensory stimulation. Revealing these mechanisms will have significant implications for our understanding of information processing in the primary sensory areas and high level of cognitive processes. |
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4 .
Shai Shoham
Herzog Hospital Jerusalem, Research Department
Dietary lithium supplementation for delaying brain aging processes.
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| The present project explores effects of dietary lithium (Li) supplementation on astrocytic and neuronal markers of aging and on cognitive decline in aging mice. In preliminary work we found that dietary Li supplementation of 0.25% (2.5gr/Kg diet) for one month attenuated astrocytic markers of aging in the hippocampus of adult C57BL mice without affecting body weight. In the present project, in experiment 1, senescence accelerated mice (SAMP8 strain) are allocated to receive 0.0%, 0.1%, or 0.2% lithium, from 2 to 8 months of age. Experiment 2 tests effects of Li in C57BL mice receiving high-fat diet. There are three lithium levels: 0.0%, 0.1%, and 0.2% and two fat levels 6% and 15%, 6 groups total, receiving dietary treatments from 7 to19 months of age. Experiment 3 tests effects of age at onset, and duration of treatment with Li added to high fat diet, from 7, 10, or 13 months of age. Potential Li-induced renal toxicity is tested by immunostaining of water channels in kidney sections. Li dose is adjusted to achieve non-toxic treatment. Attenuation of markers of aging in hippocampus and of cognitive deficits is expected to lay the foundation for Li supplementation to delay cognitive decline in aging. |
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5 .
Drorit Saar
University of Haifa, Brain and Behavior Department
Mechanisms underlying learning induced enhancement of synaptic transmission: quantal analysis study.
|
| The purpose of the proposed research is to describe the mechanisms by which learning-induced synaptic enhancement is generated and maintained in the mammalian cortex.
Rats that are trained with odor-discrimination tasks demonstrate dramatic increase in their capability to acquire memory of new odors, once they have learned the task (rule learning). We have previously shown several training-related forms of long-term synaptic modifications in the intra-cortical connection in the rat piriform cortex, which are preserved in brain slices. These include reduced paired-pulse facilitation (PPF) (Saar et al., 1999), reduced rise time of EPSPs (Saar et al., 2002), decreased predisposition for long-term potentiation (LTP) and increased predisposition for long-term depression (LTD) (Lebel et al., 2001).
Here, we will examine possible pre- and post-synaptic mechanisms that may underlie the observed synaptic modifications. Whole-cell patch clamp recordings from visualized pyramidal neurons in layer II of the piriform cortex will be used to study learning-induced modifications in spontaneous and evoked quantal synaptic events. The study will include detailed analysis of excitatory and inhibitory synaptic transmission. Also, the role of PKA and PKC-dependent second messenger systems in generating and maintaining these long-term synaptic modifications will be studied.
The proposed experimental paradigm, in which learning-induced physiological modifications will be studied quantitatively at the cellular level, offers a unique framework for describing basic mechanisms that underlie learning in the mammalian brain. |
| close |
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6 .
Miki Bloch
Tel Aviv University, Psychiatry Department
Gonadal steroid manipulation and personality characteristics: association with mood fluctuations and in vitro fertilization outcomes
|
| Biological susceptibility related to interactions between the hypothalamic pituitary gonadal (HPG) axis and other neuromodulators, has been hypothesized to account for gender differences in the prevalence of mood disorders. The current study's primary aim is to investigate the association between neuroendocrine fluctuations and mood disorders by monitoring mood states over distinct hormonal phases during in-vitro-fertilization (IVF) treatment. The secondary goal of this study is to explore psychological profiles and coping mechanisms of women undergoing IVF, and to identify the ones that are associated with successful psychological adaptation to the process and a successful biological outcome. Participating women will be recruited among women who are being treated at the Tel-Aviv Sourasky Medical Center Fertility Unit. The sample size (n=210) was determined by power analysis computations. IVF protocols include controlled manipulation of ovarian steroids (progesterone and estrogen), resulting in uniquely well-specified hormonal phases (baseline, hypogonadal, follicular and luteal). Participants' mood and subjective well-being during these distinct phases will be monitored in 2 different IVF protocols. Data will include biological measurements (reproductive hormones, prolactin, androgens, cortisol, neurosteroids, follicle number, pregnancy tests and fetal pulse on week 10) and psychological measurements (SCID interview, MMPI, BSI, Speilberger state and trait anxiety inventories, CES-D, Fordyce subjective well-being visual analogue scale, Markstrom ego-strength scale and the COPE inventory). |
| close |
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7 .
Yossi Chalamish
Weizmann Institute, Neurobiology Department
The conrol of visual imagery and attention under hypnotic suggestion: an fMRI study of the human visual cortex.
|
| A fundamental question in human visual system studies is the mapping of cortical areas directly associated with visual experience. Typical attempts to dissociate the response to outside visual stimulation from the perceptual state involved studying brain regions associated with binocular rivalry. (Tong and Kanwisher, Neuron, Logothetis) and visual imagery (Ishai, Kanwisher).
Here we propose a novel approach in which hypnotic suggestion will be used to dissociate external visual states from their perceptual manifestation through vivid imagery and its control.
During the present year we examined the hypnotizable traits of 87 volunteers (using the standard Stanford hypnotizable test), and have gathered a selected group of 7 volunteers with high hypnotizable traits.
In psychophysical tests this group are able to present, during hypnotic condition, a positive visual hallucinations (see images that do not exist), and negative visual hallucinations(ignore images that are placed in the center of their visual field).
Our next step is to use the hypnotic suggestions while scanning the high hypnotizability subject's brains in functional magnetic resonance imaging system. Three main lines of research will be pursued: a. producing vivid imagery in the absence of visual stimulation. b. Producing the sensation of blank field despite the presence of an external visual stimulation. c. Producing vivid imagery of one category of objects , (e.g. faces), when the external stimuli contain another category, (e.g. houses).
the use of hypnotic suggestion will provide a powerful new methodology that will allow a more effective control over visual imagery, and by that allow better identification of the cortical mechanisms involved in conscious visual awareness, and those which are "reflexively" activated by the external visual stimuli. It is also hoped to define the nature of the imagery, and try to reveal how it emerge in extreme pathologic cases of hallucinations in several psychiatric and organic disorders.
The power of our project is that it merges experts from two disciplines - that of hypnotic suggestions on the one hand, and that of functional mapping on the other. The expertise of Dr. Chalamish and Dr. Solomonovitch in hypnosis, and that of Prof. Malach in functional mapping of the human visual system, provides an exciting opportunity to develop a rigorous "neuroanatomy"of conscious awareness
|
| close |
|
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8 .
Michal Taler & Irit Gil-Ad
Felsenstein Medical Research Center,
Evaluation of the effect of various antidepressants on brain IGF-I and IGFII and their receptors expression in normal and stressed rats. Relevance to antidepressants-induced neurotrophic activity.
|
| Insulin like growth factors ( IGFs) I and II are potent neurotrophic and survival factors in the brain, acting by activation of specific receptors. Previous studies have demonstrated that IGF-I possesses a potent neuroprotective effect, and plays a role in brain growth, neural plasticity and cognition. Recent evidence suggests that depression is associated with decreased neural plasticity and disrupted information processing. Antidepressants were found to facilitate synaptic connections and neuroplasticity, as also evidenced by their induced-stimulation of trophic elements such as BDNF and CREB. However, the information on the effect of antidepressants on the IGF system in the brain is scarce. The aims of the following study are to elucidate, in normal and stressed rats, the effect of subchronic administration of antidepressants derived from different classes: (serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin and norepinephrine reuptake inhibitors (SNRIs) and atypical antidepressants), on the expression of IGF I and II and on their receptors in the prefrontal cortex, hippocampus and hypothalamus. We also wish to determine the effect of these antidepressants on serum IGFI and II levels in controls and stressed rats. Finally we wish to shed light on the possible role of the central IGF system in depression, and to broaden our information on the antidepressants-induced neurotrophic activity. |
| close |
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9 .
Mark Weiser
Sheba Medical Center,
Studying the prodrome of psychosis using a military setting
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| The prodrome of psychotic illnesses is classically defined as the period of time between the beginning of behavioral change and the onset of psychotic symptoms. Although depressed mood, social withdrawal, subtle thought disturbance, disturbances in sleep and confusion have been suggested to precede active psychosis, to date it is not clear what proportion of patients have behavioral changes before the onset of psychosis, and how early these changes occur. In addition, there is no sensitive and specific cluster of manifestations that can be utilized as clinically applicable diagnostic markers.
We propose to perform a study of the symptoms immediately preceding the first psychotic episode in military recruits. The study will take advantage of the fact that in the military, recruits live in close quarters and are under scrutiny both by their buddies and by their commanding officers. Furthermore, the military has very low tolerance for abnormal behavior, and referral to psychiatric assessment is compulsory in recruits with behavioral abnormalities.
We propose to identify recruits immediately after being hospitalized due to their first psychotic episode. Using a structured interview, we will examine the now psychotic recruit and her/his family members, army buddies and immediate commanding officers. The aim of this multi-informant examination will be to identify how many patients had identifiable abnormal behavioral manifestations prior to their first psychotic episode and what these manifestations were. Furthermore, we will attempt to classify these manifestations into clinically identifiable "symptom clusters". In order to ascertain the specificity of the symptoms appearing before the onset of psychosis, we will administer the same structured interview to control recruits matched for age, gender and type of military service.
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10 .
Uri Polat
Tel Aviv University, Faculty of Medicine
Relationships between information processing, decisions and cognitive reward in major depression
|
| Cardinal signs of Major Depressive Disorder (MMD) are impairment of cognitive tasks (CT) and unhedonic symptoms that have recently been suggested to be mediated by an impairment of the Brain Reward System (BRS). Our proposal is to psychophysically study the link between these symptoms, information processing, and the reward-demanding/gain-based decision making tasks that rely on CT. We will explore how patients and control subjects adapt their decision criteria to varying contextual and statistical conditions to operate different combinations of CT. The connection to the reward system will be explored by manipulating the probability of appearance of a certain stimuli configuration and/or by changing the type of explicit external rewards. The information processing will be explored using temporal masking. Our pilot results, using a basic contrast filling-in experiment, show that MDD seem to have conservative criteria regardless of the context of the input signals. The conservative criteria may suggest that the filling in process is absent, probably due to reduced excitation between neurons. Alternatively, it may suggest that they are unable to match their internal representation to the different stimuli information and rewards, in order to reach a more optimal decision - pointing to a possible connection to the impaired BRS. |
| close |
|
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11 .
Marina Pavlovskaya
: Loewenstein Hospital, Neurophysiology Department
Low level visual processing in unilateral neglect syndrome: contrast detection and contrast matching study
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| Uninilateral spatial neglect (USN) is characterized by a failure to perceive stimuli on the contralesional side. Extinction is another phenomenon, commonly associated with USN, where patients are able to detect the contralesional stimulus when presented unilaterally, but fail under bilateral stimulus stimulation. Accumulating evidence for an elaborated processing of "neglected" visual stimuli suggests that low-level visual processing remains intact and the failure of perception occurs due to a high-level "gating" mechanism. However, the nature of this gating mechanism that has a large impact on understanding USN as well as normal perception is currently unknown. Here we propose to explore the nature of this gating mechanism by studying low-level visual processing in USN patients such as involved in contrast sensitivity, perceived contrast and vernier acuity. If the failure of perception in USN is due to "gating", then stimuli that pass the gate should be perceived normally in terms of low-level visual properties, e.g. with the correct contrast, orientation and visual acuity. On the other hand, if USN is due to attenuated processing on the neglected side, then such visual properties should be affected. Preliminary results in contrast matching support the first hypothesis by showing that when they see, they see it right, i.e. with the correct perceived contrast. |
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12 .
Netta Levin & Ehud Zohary
Hebrew University of Jerusalem, Neurobiology Department
Activation patterns in the visual cortex following optic neuritis - An fMRI study
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| The goal of our work is studying cortical plasticity in the human brain, following peripheral insults to the visual system.
With the maturation of noninvasive imaging techniques such as functional MRI, the functional organization of the visual system in humans can now be revealed, including the changes that occur in pathological cases. We have previously used phase mapping methods to get elaborate retinotopic maps of the early visual areas. Utilizing this technique we compared those maps in normal subjects and in a patient suffering from a topographically restricted vascular damage (scotoma) to the retina. We also studied the differential effects of an inflammatory disease of the optic nerve (optic neuritis) on the cortical activation patterns along the hierarchy of the visual system.
The degree to which cortical plasticity can be seen following damage to the visual system, and its functional relevance is a main topic of interest with possible clinical implications. Age related macular degeneration (AMD), the leading cause of late blindness in the developed world, typically obliterates foveal vision and thus can serve as a classical model for a greater understanding of cortical reorganization. Early visual areas (V1-V4) are organized according to a retinotopic mapping principle, with a gross over-representation of the fovea. This naturally raises the question what happens to this vast cortical expanse when the fovea is destroyed. Furthermore, if it is recruited for analysis of visual input from undamaged retinal locations, is it manifest in better behavioral performance.
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13 .
Michal Hershfinkel
Ben Gurion University of the Negev, Department of Morphology
The molecular mechanism linking zinc deficiency to learning and memory disorders.
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| A hallmark of mild zinc deficiency, common in both developed and undeveloped
countries, is impairment of learning and memory and the appearance of eating disorders
most notably anorexia nervosa. This deficit, monitored in human and animal models, is
typically accompanied by neuronal loss. Despite the fact that zinc deficiency is
widespread, the signaling mechanisms linking zinc to neuronal survival during crucial
stages of development are unknown. We have identified a zinc sensing receptor (ZnR) in
epithelial cells which our preliminary results indicate is also active in the brain. The ZnR
is a Gq-coupled receptor that triggers intracellular signaling pathways such as MAP and
PI3-kinase, which are crucial for cell survival. Furthermore, ZnR plays a key role in
regulation of ion transport via the Na+/H+ exchanger (NHE1) which in epithelial cells is
also known to regulate cell survival. We hypothesize that zinc, acting through the ZnR,
has a signaling role in the brain, promoting the activation of cell signaling cascades and
ion transporters that promote neuronal survival. In this proposal, combining biochemical
methods and live imaging of brain slices, we will study the role of the brain-ZnR in the
regulation of two major transport systems: the Na+/K+/2Cl- (NKCC) co-transporter and
the Na+/H+ exchanger (NHE). These transporter proteins are important for ion and pH
homeostasis and, thereby, for neuronal survival. By functionally activating or silencing
ZnR, we will characterize the specific role of this receptor in regulating these transporters.
Subsequently, application of kinases and transporter inhibitors and an NHE1 knockout
model will allow us to determine of the precise role of this isoform, which is particularly
crucial for cell survival. The results of these experiments will provide novel insight into
the molecular mechanisms linking zinc deficiency to the impairment of learning and
memory and may provide important Insight towards the treatment of anorexia nervosa.
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14 .
Avraham Zangen
Weizmann Institute, Neurobiology Department
Neurochemical characterizations of a genetic and an environmental rat model for depressive behavior.
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| Depression is among the most prevalent forms of mental illness. Although the etiology of this disease is poorly understood, it has become clear that the risk for depression is partially genetic. Currently available antidepressants have some efficiency in the control of depressive symptoms, but improvement in terms of latency of onset, side effect profile and especially treatment of non-responders is needed. Moreover, we lack objective diagnostics tests identifying individuals with depression or determining which antidepressant treatment would be most effective for a given individual. Such improvements may come after better understanding of neurochemical and genetic factors underlying the disease. Such research requires controlled measurements of gene expression and neurochemical factors within specific relevant brain regions. Therefore, an animal model for depressive behavior is needed. Most of the models for depression are based on the assumption that depression is a response to acute or chronic stress and ignore the genetic component. We have therefore started to create a genetic animal model based on the core symptoms for depression. We plan to study the genetic contribution and to characterize neurochemical factors that may define depressive behaviors. Our main tools will be gene arrays (and using reward-related brain regions) and microdialysis for monitoring release of monoamines and beta-endorphin. We also intend to use an 'environmental-induced' (chronic mild stress, CMS) animal model for depression and compare the results obtained in the different models of the different components of depressive behavior. We anticipate that our rat model for depression will help the isolation and identification of genetic and neurochemical factors underlying the etiology of this disabling disorder and we hope that our studies will become a basis for future development of a treatment with better outcome and fewer side effects. |
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15 .
Rami Yaka
Hebrew University of Jerusalem, School of Pharmacy
Regulation of GABAa receptor function by ethanol
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| The goal of the proposed study is to explore the molecular mechanisms that regulate the function of the ionotropic ?-aminobutyric acid type A (GABAA) receptors under basal conditions and following exposure to ethanol. The majority of GABAA receptor subtypes in the adult brain are composed of heteropentameric assemblies of ?, ? and ? subunits. Individual GABAA receptor subtypes are associated with distinct neuronal structures and subcellular distributions, and their differential activation is correlated with distinct pharmacological and behavioral phenotypes. Previously we demonstarted a molecular mechanism for the regulation of the phosphorylation state and function of the NMDA receptor and how ethanol modulate its function (Yaka et al., 2002; Yaka et al., 2003a; Yaka et al., 2003c). Based on similarities between the molecular mechanisms that regulate NMDA and GABAA receptors, we will test the hypothesis that regulation of GABAA and NMDA receptors may share common molecular mechanisms.
We will use multiple approaches utilizing immunohistochemical, biochemical and electrophysiological techniques to determine first, the localization of GABAA receptor subunits in areas relevant to addiction, second the signaling pathways and specific kinases that regulate the phosphorylation state and function of the GABAA receptors and finally we will examine how ethanol alter these processes.
Understanding the molecular mechanisms that underlie the regulation of GABAA receptor function will enable us to identify targets for the design of new therapeutic agents that will alter the function of specific populations of GABAA receptors in specific brain areas, involved not only in the development of drug addiction but also in a wide range of neurological disorders associated with modified GABA receptor function such as epilepsy, anxiety and depression. |
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16 .
Simone G. Shamay-Tsoory
University of Haifa, Psychology Department
Characterization of theory of mind and empathy deficits in Schizophrenia: a neuropsychological examination of affective vs. cognitive aspects of social cognition.
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| Patients suffering from schizophrenia show impaired emotional and social behavior, such as misinterpretation of social situations and lack of Theory of Mind (ToM). However, the empathic abilities of these patients has never been examined before and there is conflicting evidence regarding their ability to perform basic ToM tasks. Based on previous findings, it is suggested that the behavioral deficit of schizophrenic patients may be due to impaired empathy and 'affective ToM' abilities, rather than to a general impairment in ToM. Furthermore, it is suggested that empathy and 'affective ToM' deficits are related to prefrontal cortical functioning and to the severity of negative symptoms.
To assess different facets of ToM and empathy, tasks that differ in the level of emotional processing will be administered to schizophrenic patients, age-matched patients with depression and healthy controls. The relation between empathy, 'affective ToM' and prefrontal cognitive functioning will be assessed using Cambridge Neuropsychological Test Automated Battery subtests sensitive to frontal circuits functioning.
The relationship between specific symptoms of schizophrenia, ToM and empathy will also be assessed.
These findings will offer new insight into the mediating role of the prefrontal cortex in the affective facets of social behavior that may underlie the profound behavioral disturbances observed in schizophrenia.
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17 .
Adi Mizrahi
Hebrew University of Jerusalem, Neurobiology Department
The role of newborn inhibitory neurons in memory formation of the olfactory system in the mouse
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| The olfactory system of mice is a good model to study sensory perception and to dissect mechanisms of learning and memory. Mammalian olfaction is behaviorally critical and also retains a unique property of structural plasticity in its first relay station, the olfactory bulb (OB). The OB encompasses a "developmental niche" such that newborn inhibitory neurons continue to develop well into adulthood. Both the phenomenon of adult neurogenesis and the functional architecture of the OB suggest a new form of network-based plasticity that might sub serve sensory perception. This putative mechanism continually shapes the connectivity between different functional compartments (sensory percepts) that have been changed (experienced) by the animal. Thus, in this proposal we aim to uncover a new mechanism for experience dependant plasticity in odor perception.
In order to test this mechanism experimentally, we will combine behavior and transgenic transduction of newborn neurons that develop into the OB during learning. Using a line of transgenic mice expressing tagged olfactory receptor neurons we will be able to correlate the density and fine morphological structure of newborn neurons with the functional architecture of the bulb. This study will begin to unravel the functional organization of the inhibitory neurons of the olfactory bulb and provide new insights into general mechanisms of learning and memory in the mammalian brain.
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18 .
Aviv Weinstein
Sourasky Medical Center, Department of Nuclear Medicine
A pharmaco-genetic and brain imaging study into nicotine-induced dopamine release in cigarette smokers measured with (I-123-)IBZM in single photon emission tomography (SPECT).
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| Dopamine (DA) plays a critical role in nicotine (and other) addiction and this drug is known to release DA in brain areas mediating reward and motivational processes. Although imaging studies show that release of DA follows smoking, little is known regarding how common genetic polymorphisms for three genes associated in some studies with smoking (dopamine D2 receptor, dopamine and serotonin transporter) interact with smoking status and modulate individual differences in nicotine-induced DA release and dopamine receptor occupancy, in vivo.. The current proposal combines brain imaging and genomics ('imaging genomics') towards partially unraveling the complex relationship between smoking phenotype and common polymorphisms. Understanding whether genetic factors contribute to inter-individual variability in smoking is crucial for interpreting imaging results in the context of disease pathology. A unique feature of our research plan is the pre-selection of subjects with specific genetic profiles for three genes DRD2, DAT1 and SERT that should maximize power towards detecting in vivo changes. We hypothesize that a model of vulnerability to addiction based on interactions between genotype, receptor and transporter availability and in vivo nicotine-induced DA release will elucidate some of the fundamental neurochemical and neuro-genetic circuits underlying addiction. |
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Second Year
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1 .
Amir Ayali
Tel Aviv University, Department of Zoology
The development of information processing capabilities in the nervous system
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| The ultimate goal of our work is shedding light on some of the most fundamental principles responsible for the superior information processing capabilities and elevated plasticity of the brain. The rationale behind this study is that basic precursors of these much quested principles might already be recognizable in the dynamical activity of simple invertebrate ganglia and spontaneously constructed networks composed of dissociated ganglion cells. Recently we have developed an in-vitro preparation of dissociated locust ganglion neurons. Cultured neurons spontaneously regenerate neuronal processes and without any external cues self-organize into elaborate networks. As the networks mature neurons cluster, forming ganglion-like structures connected by thick nerve-like bundles of axons. Utilizing advanced multi-electrode-array technology we can accompany the networks' morphological development by careful investigation of the neuronal output at each structural land mark, constructing a parallel schema for development of electrical activity. In preliminary work, using state of the art analysis tools, we show that spontaneous activity of single neurons which is characterized by high regularity and low structural complexity (SC) develops into extremely complex neural bursting events in the highly clustered networks. SC is a direct indication for the potential of the recorded activity or its capacity to carry information. Higher SC is correlated with high information processing capabilities. Thus, our system is a good model for the development of plasticity and information capacity in the nervous system. |
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2 .
Claude Brodski
Ben Gurion University of the Negev, Department of Morphology
Molecular and behavioral analysis of a mouse model for the attention deficit hyperactivity disorder
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| Studying the genetic mechanisms directing the development of cells associated with neuropsychiatric disorders is a promising approach to better understand the pathophysiology of these diseases and to develop improved therapeutic strategies. The mid-hindbrain organizer (MHO) is a structure located at the junction between the developing midbrain and hindbrain, controlling the patterning of the adjacent brain regions.
Using mouse mutants with an aberrantly located MHO, we have provided evidence that the position and size of midbrain dopaminergic and hindbrain serotonergic cell populations in adulthood are controlled by the MHO. Preliminary experiments indicate that the phenotype of these mutants show parallels to the attention deficit hyperactivity disorder (ADHD).
The first objective of the proposed study is to take advantage of this unique mouse model to investigate the molecular mechanisms controlling the development of additional cell populations associated with neuropsychiatric disorders such as the red nucleus and histaminergic neurons. The relevance of histaminergic neurons for ADHD is illustrated by the fact that a histamine receptor antagonist is currently undergoing phase II clinical evaluation for ADHD. The results of our proposed experiments will provide insight into the virtually unknown genetic cascades directing the maturation of these cell populations. In addition, they will advance our understanding of the pathophysiology and suggest potential interventions for ADHD.
The second objective of the project is to complement the molecular biological findings with behavioral analysis of mutants with an aberrantly positioned MHO in order to establish a new mouse model for ADHD. These mutants will complement existing animal models and open new possibilities for the development of novel drugs for the effective treatment of this disorder. The estimated heritability of ADHD is 0.8, indicating that genes play an important role in its etiology. Linking the phenotype of mutants with an aberrantly positioned MHO to symptoms of ADHD would point to specific new candidate genes for genetic studies in humans. |
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3 .
Miri Carmel
Tel Aviv University, Faculty of Medicine
Pharmacogenetics of citalopram treatment in children and adolescent outpatients
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| The goal of this project is to study the pharmacogenetic profile of citalopram, a Selective Serotonin Reuptake Inhibitor (SSRI), for treatment of depression and anxiety in children and adolescents. We will investigate the association between the degree of response to citalopram and the individuals' genotype at several polymorphic sites in candidate genes relevant to the serotonergic system. Additional goals are: to study the pharmacogenetic profile of adverse side effects in children treated with citalopram, and to measure the response of children and adolescents to citalopram in an open-label settings.
Approximately 150-200 children and adolescents, meeting DSM-IV criteria for affective or anxiety disorder, will be recruited. Patients will be treated with citalopram for eight week period and clinical monitoring will be performed weekly. DNA will be extracted and samples will be genotyped for polymorphisms in the following genes: serotonin transporter (5-HTTLPR), tryptophan hydroxylase (TPH), serotonin receptors 5-HTR2A 5-HTR2C and 5HT1Dbeta. Patients showing adequate response by the end of week eight will be compared to those not responding. Comparison between clinical and genetic data will be made using ?2 test. A quantitative analysis (QTL) of the correlation between adverse effects of citalopram therapy and genotypes will be performed.
A gene-based method that would identify the non-responders to an SSRI will be of great clinical utility, prevent patient frustration, and may help decrease adverse effects of pharmacotherapy. |
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4 .
Leon Deouell
Hebrew University of Jerusalem, Department of Psychology
Electrophysiological investigation of interactions between background auditory change detection and auditory and visual processing at the focus of attention
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| While our attention is focused on a task, background processes keep track (i.e., memory traces) of the environment, detecting potentially important changes, and allowing attention to be flexibly allocated. In audition, this process is reflected by the mismatch negativity (MMN) event related potential (ERP). This project will empirically test the claim that the processing and detection of change is related to a superior temporal component of the MMN, while manipulation of attention is related to a frontal component. Current source density (CSD) distributions will be used to index the frontal and temporal components of MMN. Similarity between an unattended deviant event and a target in a concurrently attended sensory stream will be used to create competition for processing resources and affect sensory processing stages. Attentional load of the main task will be used to affect attentional aspects of the mismatch response. Testing the effects of both auditory and visual tasks will also allow us to determine whether auditory spatial processing shares resources with visual spatial processing. Understanding the organization of the mismatch detection process may help not only basic cognitive neuroscience, but also the understanding of several neurological and psychiatric diseases in which this component is impaired. |
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5 .
Gadi Goelman
Hebrew University Medical Center, Medical Biophysics
The Habenular nucleus and its role in coupling serotonergic and dopaminergic systems
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| Previously we have shown enhanced basal-ganglia (BG) - habenular (Hab) connectivity in a rat model of Parkinson's disease (PD). Moreover, we have shown that in PD the Hab is effectively connected to the serotonergic system whereas no such connectivity was observed in control rats. Since many PD patients also exhibit emotional and psychiatric deficits probably related to alteration in their serotonin levels, our findings suggests the existence of a linkage, amplified by the disease, between the dopaminergic and the serotonergic systems that is mediated by the Hab. More specifically, we hypothesize that in healthy state the BG connectivity is segmented into motor, cognitive and limbic functions and the latter is mediated by the Hab. We further hypothesize that in Parkinsonian state the BG loses this ordered connections. We propose to use Manganese Enhanced MRI that is capable of following manganese anterograde transport to test these hypothesizes. We propose to directly inject manganese into the putamen, the caudate and the nucleus accumbens and to follow its transport. Comparison between these transports in Parkinsonian and healthy states is proposed. |
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6 .
Abraham Goldstein
Bar-Ilan University, Brain Research, Interdisciplinary Unit
Electrophysiological correlates of the adult attachment behavioral system
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| Over the past 30 years, attachment theory has generated extensive research on the implications of the attachment system for social and emotional functioning. These studies have delineated the affect-regulatory functions of the attachment system in adulthood and its mediating function in depressive and other psychiatric symptoms. However, most of these studies relied on self-reports or observational methods and have not provided any direct evidence on the neural substrate of attachment-system functioning. The purpose of the proposed research program is to begin to fill in this empirical gap, using electro-encephalographic (EEG) and Event Related Potential (ERP) techniques. A series of studies will investigate patterns of asymmetric hemispheric activity related to individual attachment profiles, as a response to emotional events and attachment-figure availability. This will reveal hyperactivating/deactivating strategies as a result of attachment-figure availability/unavailability and will provide novel physiological information about the individual-differences component of the attachment system. In addition, the proposed research will examine the association between attachment style and the information-processing components of cortical responses to emotional stimuli. This examination will provide crucial information for conceptualizing the attachment system as a neuropsychological affect-regulation device and mapping its implications for affective disorders. |
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7 .
Pnina Green
Tel Aviv University, Laboratory for the Study of Membrane Fatty Acids, Felsenstein Center for Medical Research and Dep. Internal Medicine B, Rabin Medical Center, Beilinson Campus, Petah Tikva
Brain Polyunsaturated Fatty Acids and Depression: Exploration of the "Phospholipid Theory" of Depression in an Animal Model
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| Polyunsaturated fatty acids (PUFA) are essential components of neuronal membrane phospholipids (PL). The two PUFA are docosahexaenoic acid (DHA) of the omega-3 (n-3) family and arachidonic acid (AA) of the omega-6 (n-6) family. Several studies document a negative relationship between the erythrocyte membrane phospholipids n-3 PUFA content and depression, and clinical trials show beneficial effects of n-3 fatty acid (FA) supplementation on the disease manifestations. However, the pathogenetic significance of these findings in not known. Further, it is not universally accepted that erythrocyte and brain FA composition are correlated. In a preliminary study, we compared the brain FA composition in the Flinders Sensitive Line (FSL) rat model of depression and control rats, which were fed identical diets. We found significant differences in several brain areas, suggesting that there are alterations in the FA composition in depressive-like rats that cannot be attributed to dietary influences. The present study is designed to test the hypothesis that depression is associated with disturbed brain PUFA metabolism by exploring in detail relationships between depression (the FSL rat model) and brain PUFA, and between response to several antidepressant treatment modalities and brain PUFA. In addition, relationships between brain PUFA and erythrocyte FA will also be examined. |
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8 .
Daphna Joel
Tel Aviv University, Department of Psychology
Studying the interplay between the orbital cortex and the striatal serotonergic system in a rat model of obsessive compulsive disorder
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| Three neural systems have been implicated in the pathophysiology of obsessive compulsive disorder (OCD): the orbitofrontal cortex, the striatum and the serotonergic system. Yet, the ways in which these neural systems interact to produce obsessions and compulsions in patients is currently unknown. Using a rat model of OCD we have recently found that lesions to the orbital cortex (the rat analogue of the primate orbitofrontal cortex) led to an increase in 'compulsive' behavior that was prevented by a serotonin reuptake inhibitor, and was paralleled by an increase in the density of the striatal serotonin transporter. On the basis of these findings, the present project will test, in the rat model, the hypothesis that pathology of the orbitofrontal cortex leads to a dysregulation of the striatal serotonergic system which is manifested in compulsive behavior. More specifically, we will: 1. Test the effects of an excitotoxic lesion and of a temporary inactivation of the striatum on 'compulsive' behavior; 2. Test the effects of intra-striatal injections of a serotonin reuptake inhibitor on 'compulsive' behavior of orbital-lesioned rats; 3. Assess changes in serotonergic markers in the striatum of orbital-lesioned rats, and their correlations with the extent of 'compulsive' behavior exhibited by the rats. |
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9 .
Rachel Maayan
Felsenstein Medical Research Center, Beilinson Campus, Petah Tikva
Brain DHEA as a neuroprotecter in behavioral disorders
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| We hypothesize that brain dehydroepiandrosterone (DHEA) protects against anti-behavioral disorders, especially the development of depression and anxiety. We propose to test animal models of depression and anxiety using mice with different levels [(1) control/normal, (2) very low and (3) high levels] of DHEA in brain. Methods for nullifying or increasing levels of serum and brain DHEA will be chosen according to the results obtained by biochemical tests measuring the DHEA level.
We assume that:
1. Low levels of brain DHEA will potentiate or increase depressive and anxiolytic behavior.
2. Administering DHEA to Group 2, to reach control levels, will reverse this potentiation.
3. High levels of brain DHEA will protect mice from developing depression and anxiety in the animal model of these behavioral disorders
4. Achieving very low levels of DHEA require investigation of appropriate methods such as removal of synthesizing organs (adrenal and gonads) or blocking mechanisms of DHEA synthesis (including brain).
Evaluating the influence of decreased DHEA levels will be followed by the examination of the influence of brain DHEA-derived neurosteroids, such as estradiol (E2) and testosterone (T) on developing these behavior disorders. |
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10 .
Mouna Maroun
University of Haifa, The Brain and Behavior Research Center, Faculty of Science and Science Education
Mechanisms of long-term extinction in the amygdala-prefrontal cortex circuit
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| Studies into the neural mechanism of fear conditioning and extinction have focused on the amygdala. However, the amygdala has reciprocal connections with the medial prefrontal cortex (mPFC), a brain structure associated with learned extinction. Recent data show that the mPFC is required for the consolidation of long-term extinction memory, probably through potentiation of inputs from the amygdala to the mPFC.
Our working hypothesis is that under normal conditions the mPFC is capable of monitoring the amygdala emotional output to ensure an appropriate response. Under stressful conditions, the relative contribution of the amygdala increases such that the memory that is formed is associated with stronger emotional responses and is less likely to be extinguished. Anxiety disorders and post-traumatic stress disorders (PTSD) are, according to this view, extreme manifestations of the above.
In the proposed project, we will utilize behavioral, pharmacological and biochemical tools to examine the relative contribution of the amygdala and mPFC to the acquisition and consolidation of extinction when acquired under stress. Elucidating these mechanisms will contribute to our understanding of the neural basis of anxiety disorders. |
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11 .
Shula Parush
Hebrew University of Jerusalem, School of Occupational Therapy, Faculty of Medicine
Psychophysiological and behavioral correlates of children with and without Sensory Modulation Disorder (SMD) and their parents
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| Sensory Modulation is the ability to adjusts the quality and speed of neuronal responses to sensory stimuli in order to regulate and organize reactions to sensory input, and maintain optimal arousal (Lane, 2002). The neurophysiological processes hypothesized to be associated with sensory modulation are sensitization and habituation (Dunn, 1997). Mechanisms proposed for these include the elevation or decrease of neuronal thresholds for firing or depletion of neurotransmitters necessary for firing (Reeves, 2001). Hyperresponsivity refers to when neurons fire too easily, disrupting one's ability to override unimportant stimuli (Lane, Miller, & Hanft, 2000). In contrast, hyporesponsivity, may result from neurological thresholds requiring excessive input, similar to the mechanism underlying habituation (Lane, 2002). Sensory Modulation Dysfunction (SMD) describes individuals who routinely demonstrate exaggerated or inappropriate responses to benign sensory input (Bundy & Murray, 2002)
Researchers will investigate psychophysical mechanisms underlying SMD related to the somatosensory system. Further, familial or gender related predispositions to SMD will be investigated by testing children with SMD and their parents.
Fifty children with SMD and 50 matched controls, and their parents, will be tested through Quantitative Sensory Testing, to determine detection thresholds, pain thresholds, suprathresholds, and central sensitization (Meier, Berde, DiCanzio, Zurakovski, & Sethna,1999) for somatosensory sub-modalities ( pain, warmth, cool, vibration, light-touch prickle and pinprick sensations) . |
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12 .
Golan Shahar
Ben Gurion University of the Negev, Department of Behavioral Sciences
Self-criticism as a default set: integrating research on executive functions and task-switching with research on cognitive vulnerability to suicidal depression
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| Integrating the literatures on executive functions and task switching with research on cognitive vulnerability to depression and suicide, we propose that self-criticism, a serious vunerability factor, which has been implicated strongly in suicidal depression (Shahar, 2001, 2003), involves a default mental set (Meiran et al. 2000) entailing a rapid reaction to self-evaluative taks. To test this hypothesis, a task-switching experiment will be carried out involving twenty-five highly self-critical and twenty-five non self-critical patients in full remission from Major Depressive Disorder with Suicidal Featutres. Findings, constituting a first step in research on the neorocognitive underpinning of cognitive vulnerability to psychopathology, promise to account for many of the pathways leading from self-criticism to suicidal depression. |
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13 .
Michael Wagner
Ariel University Center of Samaria, Department of Industrial Engineering
Eye dominance, stereo vision and spatial exploration: A binocular eye-movement measurement approach
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| During fixation, binocular visual axes are assumed to be aligned on the target. Recent studies (Wagner & Ehrenstein 2003; 2004) show that such binocular alignment holds only for 2-5 seconds, until divergent drifts occur, up to magnitudes of 3º within 60 sec. Measuring binocular eye-movements (EyeLink system) revealed asymmetries of eye movement patterns for different fixation procedures. Typically, one eye stays more accurately and steadily at the fixation mark, whereas the other eye is less stable and shows marked excursions from the fixation mark. This indicates an eye dominance mechanism which has, so far, not yet been demonstrated.
The visual system tolerates certain levels of binocular misalignment. These levels are known to be higher in open-field natural scenes, but tend to be lower with near -distance stereoscopic or acuity demanding tasks, resulting in either diplopia or suppression effects. Hence, eye dominance might serve to avoid diplopia in certain viewing conditions, probably by causing suppression of the non-dominant channel.
In stereo vision, vergence typically fluctuates until achieving a proper disparity, appearing perceptually as sufficient image fusion. Recent results indicate that the dominant eye (which is more stable in fixating 2D targets), fluctuates more in stereo vision, being more active in vergence corrections (Wagner & Ehrenstein, 2004). This peculiar finding deserves corroborating research.
Binocular convergence also changes when the search space is defined by linear perspective rather than stereo depth (Wagner & Hochstein 2000). Therefore, binocular eye-movement patterns will be compared during visual exploration in three layers (2D, 2 ½ D-perspective, 3D-stereo) including fixating, smooth pursuit and saccadic exploration tasks. Oculomotor performance will be compared with individual achievement in various optometric tests of (binocular) visual functions.
Results are expected to deepen our understanding of human binocular visual performance, its neural mechanisms and cognitive utilities.
This research will be performed in cooperation with "IfADo" (Leibniz Research Center for Working Environment and Human Factors at the University of Dortmund).
Approval of this research proposal will enable the "IfADo" to partially support this research program. |
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14 .
Kobi Rosenblum
University of Haifa, Brain and Behavior
The role of neuronal translation regulation in taste memory consolidation
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| We are interested in molecular mechanisms underlying neuronal plasticity and memory.
Specifically, we are interested in the molecular machinery subserving the consolidation
process by which short-term memory is converted into long-term memory. Numerous studies demonstrated that long-term memory or long-term potentiation (LTP) is dependent on functional protein synthesis, while short-term memory is not. In addition, a consistent finding in different learning paradigms and brain areas is that mRNA/proteins are induced in correlation with learning or synaptic plasticity. The textbook interpretation of the results obtained with protein synthesis inhibitors together with correlative mRNA/protein induction has been to assume that gene induction is part of the biological hardware of memory consolidation. However, one theoretical possibility is that during memory consolidation the relevant brain area subserving the given learning undergoes regulation on the translation level, and that this regulation induces increase as well as decrease expression of different mRNA populations. Moreover, translation regulation can occur in a spatially restricted manner to induce synapse specific long term alterations in protein expression and may explain synapse specific long term plasticity.
Following our observations that the elongation phase of protein synthesis is modulated in correlation with taste learning in the taste cortex, we aim to identify the possible intrinsic modulations of protein synthesis, that maintain modifications in neuronal connectivity over time to allow memory consolidation.
Up to date there are no studies that define the situation of the translation machinery itself
during learning. In the proposed research we will employ a multidisciplinary approach,
combining cortical-dependent behavior (taste learning), electrophysiology (LTP), imaging
(light and confocal microscopy) and biochemistry to identify regulation processes in the
translation machinery in the relevant brain area/s during learning |
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15 .
Guy Bloch
Hebrew University of Jerusalem, Evolution, Systematics and Ecology
Social regulation of chronobiological plasticity in the honey bee
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| Social influences on the circadian clock are important in various medical and mental
disorders but its biological bases remain poorly explored. Here I propose to study social influences on the clock in the honey bee because it exhibits remarkable chronobiological plasticity, rich social behavior, and its entire genome has recently been sequenced. Thus, complex behavior can be linked to molecular processes. Young bees care for the brood with no circadian rhythms, whereas older bees forage with strong circadian rhythms that are used to anticipate predicted changes in the environment, sun compass navigation, and timing visits to flowers. I hypothesize that social factors such as the presence of old bees, the queen, and the brood that influence the switch from nest activities to foraging, will also influence the development of circadian rhythms in young bees. I propose to test this hypothesis using two state- of- the- art technologies: 1) The EthoVision system to automatically video track individually marked bees in various social environments. 2) The TaqMan® technology to measure brain levels of "clock genes" in single bee brains. The significance of this project is that for the first time a study will explore social
influences on the ontogeny of circadian rhythms and begin to decipher its molecular
underpinnings. Our first year results lend credence to our approach: they showed that the
development of circadian rhythms differed between young bees that developed with foragers or with callows. Given the molecular and functional conservation in the circadian clock and evidence for development of circadian rhythms in other organisms (including human infants), our findings may provide general insights into socially-mediated behavioral plasticity. |
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16 .
Malka Cohen-Armon
Tel Aviv University, Cardiac research Institute
PolyADP-ribosylation of chromatin-bound proteins and memory formation
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| PolyADP-ribosylation is a transient post-translational modification of nuclear proteins, that modifies the interaction between DNA and proteins in the chromatin. This protein
modification is therefore one of the control mechanisms rapdly affecting gene expression. The reaction is catalyzed by polyADP-ribose polymerases (PARPs). PARP-1, the most abundant and highly conserved polymerase is activated by nicked DNA, and takes part in DNA repair.
However, recently we found an alternative mode of PARP-1 activation in the absence of DNA damage. We found that PARP-1 is rapidly activated in electrically stimulated brain cortical neurons by inositol 1,4,5,-trisphosphate (IP3)-induced Ca+2-release into the nucleoplasm. This finding predicted other mecanisms activating PARP-1 in depolarized neuronal cells and neurons expoed to receptor tyrosine kinase stimulation. Recently found direct interaction between phosphorylated ERK2 and PARP-1 may take part in this signal induced activation of PARP-1. All these signaling mechanisms are known to be involved in long-term memory formation. The role of polyADP-ribsylation in memory formation has been tested. In a recent study we found that polyADP-ribosylation during training is necessary for long-term memory formation in Aplysia trained by both associative and non-associative learning. The role of polyADP-ribosylation in memory formation has been attributed to a rapid chromatin relaxation due to polyADP-ribosylation of histone H1. In view of these findings, we intend to further investigate the nuclear mecanisms underlying the role of polyADP-ribosylation in memory formation. Within the framework of this research, we intend: (1) to identify polyADP-ribosylated transcription factors involved in chromatin relaxation and DNAtranscription in response to stimulation associated with learning, (2) to find whether polyADP-ribosylation takes part in gene expression essential for long-term memory formation. For this purpose, genes that their expression is mediated by polyADP-ribosyation will be screened in stimulated cultured brain neurons and in trained rats and mice. A pattern leading to a specific expression of genes during learning will be tested by the chromatin immunoprecipitation (ChIP) assay. The expected significance of this research derives from the discovered essential role of chromatin modification in the formation of long-term memory. |
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17 .
Merav Ahissar
Hebrew University of Jerusalem, Psychology Department
Between perceptual and working memory: the case of dyslexia
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| About 3-15% of the population are reading disabled (RD), namely they suffer from severe and persistent difficulties in acquiring proficient reading abilities in spite of adequate education and intelligence. RDs are characteristically impaired also in reading related abilities including verbal memory, phonological awareness and speech discrimination. A large proportion of RDs also suffer from severe difficulties in basic acoustic (Ahissar et al., 2000) and visual discriminations (Stein & Walsh, 1997). Yet, the nature of the functional relations between RDs' perceptual deficits and their cognitive difficulties is still under debate.
Previous findings in my lab (Ben-Yehudah et al., 2001, Banai & Ahissar, 2002), suggest that poor perceptual processing constrain cognitive abilities through their effect on working memory skills, particularly verbal memory. We found that individuals with the poorest perceptual scores achieve poorest memory scores.
The current study is aimed at testing this hypothesis. It will have two foci:
1) Basic lab research, with teenager RDs; We shall examine whether RDs' performance in perceptual tasks is correlated with speech perception compared with working mmeory tasks. We shall also characterize their related brain activity by mesauring their mismatch negativity (MMN) response to frequency, in order to dissociate between impaired implicit perceptual memory (probed by MMN) and impaired explicit working memory.
2) A perceptual training project with RD teenagers (ages13-15); We shall test whether intensive perceptual (visual and auditory) training for several months will increase dyslexics' memory span. If RDs' memory span will increase, it will be a direct evidence for causal relationships from impaired perception to impaired memory in RDs. We shall further assess the effect of the potential memory change on their cognitive abilities, particularly reading.
This project proposes a new hypothesis to explain the strong correlation found between reading and perceptual skills. The prediction of this hypothesis, that for Reading Disabled individuals perceptual training will enhance verbal memory, is novel. Consequently, the results of this study will have both theoretical implications, regarding the constraints imposed by perceptual processing on memory, and potential immediate applications for a large population of RDs who suffer from severely impaired memory.
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2004 - 2005
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First Year
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1 .
Amir Ayali
Tel Aviv University, Department of Zoology
The development of information processing capabilities in the nervous system
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| The ultimate goal of our work is shedding light on some of the most fundamental principles responsible for the superior information processing capabilities and elevated plasticity of the brain. The rationale behind this study is that basic precursors of these much quested principles might already be recognizable in the dynamical activity of simple invertebrate ganglia and spontaneously constructed networks composed of dissociated ganglion cells. Recently we have developed an in-vitro preparation of dissociated locust ganglion neurons. Cultured neurons spontaneously regenerate neuronal processes and without any external cues self-organize into elaborate networks. As the networks mature neurons cluster, forming ganglion-like structures connected by thick nerve-like bundles of axons. Utilizing advanced multi-electrode-array technology we can accompany the networks' morphological development by careful investigation of the neuronal output at each structural land mark, constructing a parallel schema for development of electrical activity. In preliminary work, using state of the art analysis tools, we show that spontaneous activity of single neurons which is characterized by high regularity and low structural complexity (SC) develops into extremely complex neural bursting events in the highly clustered networks. SC is a direct indication for the potential of the recorded activity or its capacity to carry information. Higher SC is correlated with high information processing capabilities. Thus, our system is a good model for the development of plasticity and information capacity in the nervous system. |
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2 .
Claude Brodski
Ben Gurion University of the Negev, Department of Morphology
Molecular and behavioral analysis of a mouse model for the attention deficit hyperactivity disorder
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| Studying the genetic mechanisms directing the development of cells associated with neuropsychiatric disorders is a promising approach to better understand the pathophysiology of these diseases and to develop improved therapeutic strategies. The mid-hindbrain organizer (MHO) is a structure located at the junction between the developing midbrain and hindbrain, controlling the patterning of the adjacent brain regions.
Using mouse mutants with an aberrantly located MHO, we have provided evidence that the position and size of midbrain dopaminergic and hindbrain serotonergic cell populations in adulthood are controlled by the MHO. Preliminary experiments indicate that the phenotype of these mutants show parallels to the attention deficit hyperactivity disorder (ADHD).
The first objective of the proposed study is to take advantage of this unique mouse model to investigate the molecular mechanisms controlling the development of additional cell populations associated with neuropsychiatric disorders such as the red nucleus and histaminergic neurons. The relevance of histaminergic neurons for ADHD is illustrated by the fact that a histamine receptor antagonist is currently undergoing phase II clinical evaluation for ADHD. The results of our proposed experiments will provide insight into the virtually unknown genetic cascades directing the maturation of these cell populations. In addition, they will advance our understanding of the pathophysiology and suggest potential interventions for ADHD.
The second objective of the project is to complement the molecular biological findings with behavioral analysis of mutants with an aberrantly positioned MHO in order to establish a new mouse model for ADHD. These mutants will complement existing animal models and open new possibilities for the development of novel drugs for the effective treatment of this disorder. The estimated heritability of ADHD is 0.8, indicating that genes play an important role in its etiology. Linking the phenotype of mutants with an aberrantly positioned MHO to symptoms of ADHD would point to specific new candidate genes for genetic studies in humans. |
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3 .
Miri Carmel
Tel Aviv University, Faculty of Medicine
Pharmacogenetics of citalopram treatment in children and adolescent outpatients
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| The goal of this project is to study the pharmacogenetic profile of citalopram, a Selective Serotonin Reuptake Inhibitor (SSRI), for treatment of depression and anxiety in children and adolescents. We will investigate the association between the degree of response to citalopram and the individuals' genotype at several polymorphic sites in candidate genes relevant to the serotonergic system. Additional goals are: to study the pharmacogenetic profile of adverse side effects in children treated with citalopram, and to measure the response of children and adolescents to citalopram in an open-label settings.
Approximately 150-200 children and adolescents, meeting DSM-IV criteria for affective or anxiety disorder, will be recruited. Patients will be treated with citalopram for eight week period and clinical monitoring will be performed weekly. DNA will be extracted and samples will be genotyped for polymorphisms in the following genes: serotonin transporter (5-HTTLPR), tryptophan hydroxylase (TPH), serotonin receptors 5-HTR2A 5-HTR2C and 5HT1Dbeta. Patients showing adequate response by the end of week eight will be compared to those not responding. Comparison between clinical and genetic data will be made using ?2 test. A quantitative analysis (QTL) of the correlation between adverse effects of citalopram therapy and genotypes will be performed.
A gene-based method that would identify the non-responders to an SSRI will be of great clinical utility, prevent patient frustration, and may help decrease adverse effects of pharmacotherapy. |
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4 .
Leon Deouell
Hebrew University of Jerusalem, Department of Psychology
Electrophysiological investigation of interactions between background auditory change detection and auditory and visual processing at the focus of attention
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| While our attention is focused on a task, background processes keep track (i.e., memory traces) of the environment, detecting potentially important changes, and allowing attention to be flexibly allocated. In audition, this process is reflected by the mismatch negativity (MMN) event related potential (ERP). This project will empirically test the claim that the processing and detection of change is related to a superior temporal component of the MMN, while manipulation of attention is related to a frontal component. Current source density (CSD) distributions will be used to index the frontal and temporal components of MMN. Similarity between an unattended deviant event and a target in a concurrently attended sensory stream will be used to create competition for processing resources and affect sensory processing stages. Attentional load of the main task will be used to affect attentional aspects of the mismatch response. Testing the effects of both auditory and visual tasks will also allow us to determine whether auditory spatial processing shares resources with visual spatial processing. Understanding the organization of the mismatch detection process may help not only basic cognitive neuroscience, but also the understanding of several neurological and psychiatric diseases in which this component is impaired. |
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5 .
Gadi Goelman
Hebrew University Medical Center, Medical Biophysics
The Habenular nucleus and its role in coupling serotonergic and dopaminergic systems
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| Previously we have shown enhanced basal-ganglia (BG) - habenular (Hab) connectivity in a rat model of Parkinson's disease (PD). Moreover, we have shown that in PD the Hab is effectively connected to the serotonergic system whereas no such connectivity was observed in control rats. Since many PD patients also exhibit emotional and psychiatric deficits probably related to alteration in their serotonin levels, our findings suggests the existence of a linkage, amplified by the disease, between the dopaminergic and the serotonergic systems that is mediated by the Hab. More specifically, we hypothesize that in healthy state the BG connectivity is segmented into motor, cognitive and limbic functions and the latter is mediated by the Hab. We further hypothesize that in Parkinsonian state the BG loses this ordered connections. We propose to use Manganese Enhanced MRI that is capable of following manganese anterograde transport to test these hypothesizes. We propose to directly inject manganese into the putamen, the caudate and the nucleus accumbens and to follow its transport. Comparison between these transports in Parkinsonian and healthy states is proposed. |
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6 .
Abraham Goldstein
Bar-Ilan University, Brain Research, Interdisciplinary Unit
Electrophysiological correlates of the adult attachment behavioral system
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| Over the past 30 years, attachment theory has generated extensive research on the implications of the attachment system for social and emotional functioning. These studies have delineated the affect-regulatory functions of the attachment system in adulthood and its mediating function in depressive and other psychiatric symptoms. However, most of these studies relied on self-reports or observational methods and have not provided any direct evidence on the neural substrate of attachment-system functioning. The purpose of the proposed research program is to begin to fill in this empirical gap, using electro-encephalographic (EEG) and Event Related Potential (ERP) techniques. A series of studies will investigate patterns of asymmetric hemispheric activity related to individual attachment profiles, as a response to emotional events and attachment-figure availability. This will reveal hyperactivating/deactivating strategies as a result of attachment-figure availability/unavailability and will provide novel physiological information about the individual-differences component of the attachment system. In addition, the proposed research will examine the association between attachment style and the information-processing components of cortical responses to emotional stimuli. This examination will provide crucial information for conceptualizing the attachment system as a neuropsychological affect-regulation device and mapping its implications for affective disorders. |
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7 .
Pnina Green
Tel Aviv University, Laboratory for the Study of Membrane Fatty Acids, Felsenstein Center for Medical Research and Dep. Internal Medicine B, Rabin Medical Center, Beilinson Campus, Petah Tikva
Brain Polyunsaturated Fatty Acids and Depression: Exploration of the "Phospholipid Theory" of Depression in an Animal Model
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| Polyunsaturated fatty acids (PUFA) are essential components of neuronal membrane phospholipids (PL). The two PUFA are docosahexaenoic acid (DHA) of the omega-3 (n-3) family and arachidonic acid (AA) of the omega-6 (n-6) family. Several studies document a negative relationship between the erythrocyte membrane phospholipids n-3 PUFA content and depression, and clinical trials show beneficial effects of n-3 fatty acid (FA) supplementation on the disease manifestations. However, the pathogenetic significance of these findings in not known. Further, it is not universally accepted that erythrocyte and brain FA composition are correlated. In a preliminary study, we compared the brain FA composition in the Flinders Sensitive Line (FSL) rat model of depression and control rats, which were fed identical diets. We found significant differences in several brain areas, suggesting that there are alterations in the FA composition in depressive-like rats that cannot be attributed to dietary influences. The present study is designed to test the hypothesis that depression is associated with disturbed brain PUFA metabolism by exploring in detail relationships between depression (the FSL rat model) and brain PUFA, and between response to several antidepressant treatment modalities and brain PUFA. In addition, relationships between brain PUFA and erythrocyte FA will also be examined. |
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8 .
Daphna Joel
Tel Aviv University, Department of Psychology
Studying the interplay between the orbital cortex and the striatal serotonergic system in a rat model of obsessive compulsive disorder
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| Three neural systems have been implicated in the pathophysiology of obsessive compulsive disorder (OCD): the orbitofrontal cortex, the striatum and the serotonergic system. Yet, the ways in which these neural systems interact to produce obsessions and compulsions in patients is currently unknown. Using a rat model of OCD we have recently found that lesions to the orbital cortex (the rat analogue of the primate orbitofrontal cortex) led to an increase in 'compulsive' behavior that was prevented by a serotonin reuptake inhibitor, and was paralleled by an increase in the density of the striatal serotonin transporter. On the basis of these findings, the present project will test, in the rat model, the hypothesis that pathology of the orbitofrontal cortex leads to a dysregulation of the striatal serotonergic system which is manifested in compulsive behavior. More specifically, we will: 1. Test the effects of an excitotoxic lesion and of a temporary inactivation of the striatum on 'compulsive' behavior; 2. Test the effects of intra-striatal injections of a serotonin reuptake inhibitor on 'compulsive' behavior of orbital-lesioned rats; 3. Assess changes in serotonergic markers in the striatum of orbital-lesioned rats, and their correlations with the extent of 'compulsive' behavior exhibited by the rats. |
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9 .
Rachel Maayan
Felsenstein Medical Research Center, Beilinson Campus, Petah Tikva
Brain DHEA as a neuroprotecter in behavioral disorders
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| We hypothesize that brain dehydroepiandrosterone (DHEA) protects against anti-behavioral disorders, especially the development of depression and anxiety. We propose to test animal models of depression and anxiety using mice with different levels [(1) control/normal, (2) very low and (3) high levels] of DHEA in brain. Methods for nullifying or increasing levels of serum and brain DHEA will be chosen according to the results obtained by biochemical tests measuring the DHEA level.
We assume that:
1. Low levels of brain DHEA will potentiate or increase depressive and anxiolytic behavior.
2. Administering DHEA to Group 2, to reach control levels, will reverse this potentiation.
3. High levels of brain DHEA will protect mice from developing depression and anxiety in the animal model of these behavioral disorders
4. Achieving very low levels of DHEA require investigation of appropriate methods such as removal of synthesizing organs (adrenal and gonads) or blocking mechanisms of DHEA synthesis (including brain).
Evaluating the influence of decreased DHEA levels will be followed by the examination of the influence of brain DHEA-derived neurosteroids, such as estradiol (E2) and testosterone (T) on developing these behavior disorders. |
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10 .
Mouna Maroun
University of Haifa, The Brain and Behavior Research Center, Faculty of Science and Science Education
Mechanisms of long-term extinction in the amygdala-prefrontal cortex circuit
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| Studies into the neural mechanism of fear conditioning and extinction have focused on the amygdala. However, the amygdala has reciprocal connections with the medial prefrontal cortex (mPFC), a brain structure associated with learned extinction. Recent data show that the mPFC is required for the consolidation of long-term extinction memory, probably through potentiation of inputs from the amygdala to the mPFC.
Our working hypothesis is that under normal conditions the mPFC is capable of monitoring the amygdala emotional output to ensure an appropriate response. Under stressful conditions, the relative contribution of the amygdala increases such that the memory that is formed is associated with stronger emotional responses and is less likely to be extinguished. Anxiety disorders and post-traumatic stress disorders (PTSD) are, according to this view, extreme manifestations of the above.
In the proposed project, we will utilize behavioral, pharmacological and biochemical tools to examine the relative contribution of the amygdala and mPFC to the acquisition and consolidation of extinction when acquired under stress. Elucidating these mechanisms will contribute to our understanding of the neural basis of anxiety disorders. |
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11 .
Shula Parush
Hebrew University of Jerusalem, School of Occupational Therapy, Faculty of Medicine
Psychophysiological and behavioral correlates of children with and without Sensory Modulation Disorder (SMD) and their parents
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| Sensory Modulation is the ability to adjusts the quality and speed of neuronal responses to sensory stimuli in order to regulate and organize reactions to sensory input, and maintain optimal arousal (Lane, 2002). The neurophysiological processes hypothesized to be associated with sensory modulation are sensitization and habituation (Dunn, 1997). Mechanisms proposed for these include the elevation or decrease of neuronal thresholds for firing or depletion of neurotransmitters necessary for firing (Reeves, 2001). Hyperresponsivity refers to when neurons fire too easily, disrupting one's ability to override unimportant stimuli (Lane, Miller, & Hanft, 2000). In contrast, hyporesponsivity, may result from neurological thresholds requiring excessive input, similar to the mechanism underlying habituation (Lane, 2002). Sensory Modulation Dysfunction (SMD) describes individuals who routinely demonstrate exaggerated or inappropriate responses to benign sensory input (Bundy & Murray, 2002)
Researchers will investigate psychophysical mechanisms underlying SMD related to the somatosensory system. Further, familial or gender related predispositions to SMD will be investigated by testing children with SMD and their parents.
Fifty children with SMD and 50 matched controls, and their parents, will be tested through Quantitative Sensory Testing, to determine detection thresholds, pain thresholds, suprathresholds, and central sensitization (Meier, Berde, DiCanzio, Zurakovski, & Sethna,1999) for somatosensory sub-modalities ( pain, warmth, cool, vibration, light-touch prickle and pinprick sensations) . |
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12 .
Golan Shahar
Ben Gurion University of the Negev, Department of Behavioral Sciences
Self-criticism as a default set: integrating research on executive functions and task-switching with research on cognitive vulnerability to suicidal depression
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| Integrating the literatures on executive functions and task switching with research on cognitive vulnerability to depression and suicide, we propose that self-criticism, a serious vunerability factor, which has been implicated strongly in suicidal depression (Shahar, 2001, 2003), involves a default mental set (Meiran et al. 2000) entailing a rapid reaction to self-evaluative taks. To test this hypothesis, a task-switching experiment will be carried out involving twenty-five highly self-critical and twenty-five non self-critical patients in full remission from Major Depressive Disorder with Suicidal Featutres. Findings, constituting a first step in research on the neorocognitive underpinning of cognitive vulnerability to psychopathology, promise to account for many of the pathways leading from self-criticism to suicidal depression. |
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13 .
Michael Wagner
Ariel University Center of Samaria, Department of Industrial Engineering
Eye dominance, stereo vision and spatial exploration: A binocular eye-movement measurement approach
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| During fixation, binocular visual axes are assumed to be aligned on the target. Recent studies (Wagner & Ehrenstein 2003; 2004) show that such binocular alignment holds only for 2-5 seconds, until divergent drifts occur, up to magnitudes of 3º within 60 sec. Measuring binocular eye-movements (EyeLink system) revealed asymmetries of eye movement patterns for different fixation procedures. Typically, one eye stays more accurately and steadily at the fixation mark, whereas the other eye is less stable and shows marked excursions from the fixation mark. This indicates an eye dominance mechanism which has, so far, not yet been demonstrated.
The visual system tolerates certain levels of binocular misalignment. These levels are known to be higher in open-field natural scenes, but tend to be lower with near -distance stereoscopic or acuity demanding tasks, resulting in either diplopia or suppression effects. Hence, eye dominance might serve to avoid diplopia in certain viewing conditions, probably by causing suppression of the non-dominant channel.
In stereo vision, vergence typically fluctuates until achieving a proper disparity, appearing perceptually as sufficient image fusion. Recent results indicate that the dominant eye (which is more stable in fixating 2D targets), fluctuates more in stereo vision, being more active in vergence corrections (Wagner & Ehrenstein, 2004). This peculiar finding deserves corroborating research.
Binocular convergence also changes when the search space is defined by linear perspective rather than stereo depth (Wagner & Hochstein 2000). Therefore, binocular eye-movement patterns will be compared during visual exploration in three layers (2D, 2 ½ D-perspective, 3D-stereo) including fixating, smooth pursuit and saccadic exploration tasks. Oculomotor performance will be compared with individual achievement in various optometric tests of (binocular) visual functions.
Results are expected to deepen our understanding of human binocular visual performance, its neural mechanisms and cognitive utilities.
This research will be performed in cooperation with "IfADo" (Leibniz Research Center for Working Environment and Human Factors at the University of Dortmund).
Approval of this research proposal will enable the "IfADo" to partially support this research program. |
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