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2011 - 2012 |
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First Year |
1
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Sharon Anavi-Goffer
Departments of Behavioral Sciences and Molecular Biology, Ariel University Center
Cannabinoid-induced ADHD: CB1 or CB2 receptor-mediated?
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| Therapeutic effects of Cannabis sativa in patients with either or both Tourette Syndrome (TS) and Attention-Deficit Hyperactivity Disorder (ADHD) suggest the core involvement of the endocannabinoid system in these disorders. The goal of this proposal is to study the role of cannabinoid CB1 receptor in ADHD. Our preliminary data show that postnatal treatment with SR141716A, a CB1 receptor antagonist, or with HU-308, a CB2 receptor agonist, induces ADHD-like behavior that last into adulthood. In addition, HU-308 induces motor tics at a late age in mice, resembling symptoms of TS. Our specific aims are to: 1. Determine the cannabinoid receptor expression level and (2) its functional signaling in brain areas associated with ADHD, in our model of SR141716A-induced ADHD. CB1 and CB2 receptor expression will be determined in the right and left cortex, basal ganglia, brain stem and cerebellum. 3. Compare by magnetic resonance imaging (MRI) the two models for ADHD and after treatment with Δ9-THC. We will search for selective changes in the brain structure induced by SR141716A vs. HU-308 and compare the structural changes after treatment with Δ9-THC. 4. Compare the behavior of wild type mice with this of CB1 knockout mice using our paradigm for SR141716A-induced ADHD. Positive results will indicate an alternative molecular target other than or as well as the CB1 receptor. Localizing the specific changes in the brain structure will pinpoint on abnormalities that are donated by the endocannabinoid system to the development of TS and/or ADHD. These results will pave the way for supporting individual therapy for TS and ADHD patients with selective cannabinoid-based drugs. |
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2
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Karen Banai
Communication Sci and Disorders, Haifa University
The effects of stimulus uncertainty on auditory perceptual learning
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| The effects of stimulus uncertainty induced by randomly interleaving multiple stimulus conditions (roving), on auditory perceptual learning and its generalization are poorly understood. Whereas the generalization of learning of distorted speech seems to benefit from training under roving conditions, roving appears to slow or altogether prevent learning of non-speech acoustic discriminations. We now suggest that irrespective of stimulus type (speech, non-speech), stimulus uncertainty forces listeners to use explicit and effortful comparison mechanisms on a trial by trail basis, rather than using stimulus specific memory traces, thus slowing learning. On the other hand because those comparison mechanisms are not stimulus specific, we expect that generalization of learning will be broader when stimulus uncertainty is introduced into the training set. To test this hypothesis, we will train listeners on auditory duration discrimination or on syllable discrimination under roving and non-roving conditions and test the generalization of learning to the untrained discrimination as well as to auditory memory and attention tasks. If stimulus uncertainty has similar effects in the speech and non-speech domains, we expect that in both cases learning will be slower but will generalize more broadly following training with a roving regimen than following training with a non-roving one. |
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3
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Ran Barzilay
Laboratory of Neurosciences, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University
Evaluation of mesenchymal stem cells based treatment in rodent models of Schizophrenia
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| Schizophrenia is a neurodevelopmental disorder affecting around 1% of the population, manifesting with positive symptoms such as psychosis and delusions, negative symptoms such as social withdrawal and cognitive decline. Current antipsychotic treatments for schizophrenia offer patients partial solution for the positive symptoms, and, moreover, limited improvement in treating negative symptoms and cognitive deficits. Schizophrenia is known for years to involve dysregulation of neurotranmitters in the brain, specifically dopamine and glutamate. However latest studies have shown that the pathophysiology of schizophrenia also involves neurodegeneration, dysregulation of neurotrophic factors availibility and impaired neurogenesis. The latter are thought to play a major role in the pathophysiology underlying the negative symptoms.
In our lab we have been working with adult bone marrow mesenchymal stem cells as a source for cell based regenerative therapy. In previous experiments, transplantation of these stem cells showed efficacy in treating neurodegenerative diseases such as Parkinson's and Huntington's diseases, by exerting neuroprotection and inducing neurogenesis. In the proposed study we wish to examine the efficacy of these cells for treating rodent Schizophrenia models. We hypothesize that stem cell based -regenerative treatment for schizophrenia holds huge potential as novel cellular intervention in this disabling disorder. |
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4
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Tali (Avital) Bitan
Department of Communication Sciences and Disorders, Haifa University
Effects of age and sleep on learning regular and irregular morphological rules
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| Previous studies have hypothesized that children differ from adults in the learning mechanisms underlying second language acquisition. The proposed study will examine to what extent the consolidation of artificial morphological rules depends on sleep. Adults and children (9-10yrs) learn to make plural inflections in an artificial language in which inflections differ in frequency and in the level of morpho-phonological regularity. In Experiment #1 participants are trained either in the morning or in the evening, and their performance is tested 12 and 24 hours post training. In Experiment #2 participants are trained in the evening, followed by a night of polysomnographic recordings and a test in the morning. We expect that Offline improvement in adults will be smaller and more sleep dependent compared to children. These results would support our hypothesis that children rely more on procedural learning mechanisms during second language acquisition. We also predict that Offline improvement in regular inflections would be correlated with the amount of REM sleep, while irregular inflection be correlated with Slow-Wave-Sleep, suggesting they rely more on procedural and declarative learning respectively. The results are expected to shed light on differential reliance of adults and children on different learning mechanisms in the acquisition of linguistic rules. |
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5
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Claude Brodski
Department of Morphology, Ben-Gurion University of the Negev
The role of the transcription factor Otx2 in manic and depressive-like behavior
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| One of the major reasons for the limited success in developing novel treatments for bipolar disorder is the absence of suitable animal models for this highly heritable disease. Recently, the transcription factor Otx2 has been suggested as a susceptibility gene for bipolar disorder. We found that Otx2 mouse mutants which show an imbalance of monoaminergic neurotransmission model behavioural aspects reminiscent of bipolar disorder with a high inter- and intraindividual variability which
could be reversed by chronic exposure to lithium.
We will test the face validity of Otx2 gain- and loss of function mutants as a model for bipolar disorder and study manic and depressive like behaviours in paradigms established to assess in animals, despair, hedonia/anhedonia, anxiety, sleep pattern and aggression. In addition, we will test the predictive validity of our models by investigating whether chronic exposure to mood stabilizing drugs reverses behavioural abnormalities.
Our findings will critically advance our understanding of the genetic, developmental and neurobiological basis underlying manic- and depressive-like behaviour. In addition, we expect to provide a tool to investigate a particular aspect of the pathophysiology of this devastating disease, and, will serve a rationale towards the
development of novel mood stabilizers. |
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6
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Ehud Cohen
Department of Biochemistry and Molecular Biology, the Institute for Medical Research Israel – Canada (IMRIC), the Faculty of Medicine, Hebrew University of Jerusalem
Exploring the Roles of Cyclophilins as possible linkers of Aging and Late Onset Neurodegenerative Disorders
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| Aberrant protein aggregation is a common cause of late-onset neurodegenerative
disorders such as prion maladies and Alzheimer’s disease (AD). Mutations in the protease Presenilin-1 (PS1) are accountable for most familial AD cases, among these, substitutions of prolines P264 and P267 in the motif PXXP. Similarly, the substitution of either P102 or P105, of the prion protein (PrP), causes the familial disorder, Gerstmann-Sträussler-Scheinker syndrome (GSS). We found that these proline substitutions prevent folding chaperones of the cyclophilin family, from assisting PrP folding, leading to its aggregation and to disease.
These strikingly similar mutations in different proteins which cause either AD or GSS raise the prospect that a common mechanism underlies the development of the two maladies and suggests that an aging associated decline of cyclophilin activity enables their onset late in life. We propose to study the role of cyclophilins as linkers of aging and neurodegeneration. Employing the nematode C. elegans we will study the mutual relations between aging and cyclophilin activity while mammalian cells will be used to follow the cellular localization and aggregation of PS1 mutants following cyclophilin inhibition. This study is expected to point at new research avenues for the development of neurodegeneration therapies through aging manipulation. |
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7
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Ravid Doron
Department of Education and Psychology, Open University
Efficiency and toxicity of a novel herbal treatment for anxiety disorders and depression
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| Anxiety disorders and depression are major public health concerns world-wide. Finding adequate treatments for these disorders is of the utmost importance. The conventional pharmacological treatment is associated with a wide variety of side effects, a fact which have prompted the research of alternative treatments. The aim of this study is to evaluate the anxiolytic and anti-depressant effects of a novel herbal treatment developed in our laboratory. We have recently found that this treatment was effective in reducing anxiety and depressive-like behaviors and hormonal reactions in mice, following exposure to chronic stress early in life. This project will determine the lowest effective dose of the herbal treatment, by examining the behavioral, biological and endocrinological effects of the treatment, as well as its' possible side-effects. Our proposed herbal compound has the potential to be highly efficacious in treating anxiety disorders and depression while causing minimal to no side-effects and thus may prove to be an excellent candidate as a novel treatment for anxiety and depression in humans. Furthermore, revealing the endocrinological and brain mechanisms at the basis of this potential new treatment will help us further our understanding regarding the biological mechanisms underlying anxiety and depression, which are still not fully understood. |
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8
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Tzvi Ganel
Department of Psychology, Ben-Gurion University of the Negev
The neural basis of object impossibility
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| The human visual system enables an accurate and fast perception of the 3D world. Impossible objects constitute a class of visual illusions that rely on erroneous perception of depth in which 2D line drawings seem to represent objects that could not exist in real 3D space.
Previous studies have typically used long-term memory repetition priming to explore the cognitive and neural representations of impossible objects. Priming has been consistently found for structurally possible, but not for impossible object, which has been used to suggest that impossible objects cannot produce coherent 3D representations in memory. In the present study we propose to compare between short and long-lag fMRI adaptation to investigate if qualitative differences exist between perceptual and long-term memory representations of impossible objects. In Experiment 1, subjects will perform same/different classifications for pairs of possible and impossible objects. In Experiment 2, a similar task will be used, but now half of the pairs will be primed and the other half will be new. This investigation would further the understanding of the neural representation of 3D space in object-responsive areas along the visual cortex. |
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9
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Daniel Kaganovich
Cell and Developmental Biology Department, Institute of Life Sciences, Hebrew University of Jerusalem
Determine the basis for the neuronal cell-type specificity of aggregation-induced toxicity: Examining the effect of neural stimulation and activity on protein folding stress and oxidative stress tolerance in neurons
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| Neurodegenerative diseases constitute a class of illnesses caused by pathological protein aggregation in the brains of affected individuals. Although these disorders are invariably characterized by the death of highly specific sub-populations of neurons in the brain, protein aggregation occurs in all cells, which indicates that neurodegenerative disease states arise only when aggregates manifest a toxic gain-of-function in particular cellular environments. The starting point for an investigation of the origins of neurodegenerative disease must therefore be a thorough understanding of the cell-biological features that are unique to neurons, which make them particularly sensitive to aggregation-induced toxicity. The purpose of the studies described in this proposal is to test the hypothesis that neural activity sensitises neurons to protein folding an oxidative stress, making them uniquely sensitive by aggregation-induced damage. A better understanding of the molecular basis of aggregation-induced toxicity in neurons will then be applied to answering the fundamental question of why specific subsets of neurons are affected in neurodegenerative disease, and what accounts for the aging-induced onset of pathology. To achieve all this, I will use a system of aggregation-induced stress and toxicity reporters, developed in previous work, to monitor real-time protein misfolding stress in Aplysia pre-synaptic and post-synaptic neural circuits. |
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10
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Raphael Lamprecht
Department of Neurobiology and Etiology, Haifa University
The roles of AMPA receptor trafficking regulatory proteins in fear memory formation and maintenance in lateral amygdala
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| Long-term memory formation is believed to involve alterations of synaptic efficacy. Studies have shown that GluR1 containing AMPA receptors are inserted into synapses following stimuli leading to synaptic plasticity and that GluR2/GluR3 receptors replace existing synaptic AMPA receptors continuously and may act to maintain synaptic strength. Fear conditioning leads to the insertion of GluR1 containing AMPA receptors into synapses in lateral amygdala (LA), a process essential for fear memory formation. In addition, it was shown that GluR2 containing AMPA receptors in synapses in LA are needed for the maintenance of fear memory. The cellular mechanisms that mediate between synaptic activation during fear learning and specific AMPA receptor subunits insertion into LA synapses during consolidation and maintenance are not clear. The association of AMPA receptors with different interacting proteins may lead to distinct outcomes such as insertion, stabilization or removal of AMPA receptors from the synapse and consequently to memory consolidation, maintenance or erasure. This research program aims toward elucidating the role of AMPA receptors interacting proteins in regulating AMPA receptors level in LA synapses and in fear memory consolidation and maintenance. Toward that end, we will utilize specific peptide to disrupt the interaction between PSD-95 and the AMPA receptor auxiliary subunit stargazin shown to be important for activity regulated insertion of GluR1 into synapses in slices and peptides disrupting the interaction between GRIP or PICK with GluR2 shown to be involved in the insertion and removal of GluR2 from synapses. Elucidating the molecular mechanisms leading to AMPA receptor trafficking will contribute to our understanding of key cellular processes mediating between fear learning and alteration in synaptic AMPA receptor repertoire in LA needed for fear memory formation and maintenance. Moreover, it can facilitate the development of therapeutically agents for patients prone to excessive fear and might help to prevent some of the debilitating consequences of fear learning. |
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11
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Izhak Michaelevski
Faculty of Life Sciences, Tel-Aviv University
Identification of Key Regulatory Proteins in Formation of Spatial Memory
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| Spatial memory is dependent on the hippocampus, which is particularly vulnerable to aging being involved in age-related cognitive deficits. This vulnerability has implications for the impairment of navigation capacities in older people, who may show up to 80 % drop in performance of spatial tasks with advancing age. Molecular studies have revealed that protein de novo synthesis is absolutely required for formation of long-term spatial memory. Although numerous signaling molecules have been proposed to link synaptic activities with transcription regulation, there is no systematic understanding of these mechanisms. The current application proposes an extensive proteomic and transcriptomic study of hippocampus for spatial memory related paradigms. A quantitative analysis of protein phosphorylation over time will be linked to microarray data via in-silico analysis to predict transcription factors and key regulatory proteins involved in controlling this process. During the second phase of the research, we will test the biological relevance of the identified factors, taking advantage of in vivo transduction with viral vectors to validate key regulator proteins in electrophysiological and behavioral paradigms. |
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12
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Yarden Opatowasky
The Mina and Everd Goodman Faculty of Life Science, Bar-Ilan University
Structural investigations of axon-guidance signaling pathways
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| The accurate formation of neuronal networks during development is crucial for brain function and is controlled by axon attractive and repulsive cues. In most cases, extracellular guidance factors activate cell-surface receptors, which are presented on the tips of the navigating axons. Following the secretion of the guidance factor Slit, Roundabout (Robo) receptors mediate axon-guidance responses in several critical nervous system junctions. Consistent with the central role that the Slit/Robo signaling pathway has in developmental neurobiology, recent studies implicate this pathway in several pathological conditions of the nervous system, such as Parkinson's disease, macular degeneration, schizophrenia, autism, dyslexia and more.
Our research aims at gaining a mechanistic understanding of Robo activation and its downstream signaling, and here we present a detailed two-year plan to investigate Robo regulation using x-ray crystallography. We have already achived well-difracting crystals of one critical Robo region in my laboratory, and we are currently focusing on its structure determination at atomic resolution. We are also working on the crystallization of another Robo regulatory segment and a downstream effector. The expected data will provide a structural basis for the activation mechanisms underlying Robo signaling and will facilitate the development of drugs for the treatment of several neuropathological conditions. |
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Second Year |
1
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Amir Goldbourt
Chemistry, Tel-Aviv University
A molecular view of 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. It was hypothesized that lithium exerts its therapeutic effect by binding to the enzyme myoinositol monophosphatase (IMPase), thereby reducing inositol levels in the blood and lowering the hyperactive phosphatidyl-inositol cell signaling pathway. Despite the fact that several crystal structures of the IMPase enzyme have been solved, lithium has not been directly observed in any of them, and its binding mode has been indirectly deduced. The objective of this proposal is to unravel the molecular basis for the inhibition of IMPase by lithium, by using magic-angle spinning solidstate nuclear magnetic resonance (MAS SSNMR) spectroscopy. We propose to use MAS SSNMR experiments that will elucidate the structure of the lithium binding site in IMPase. Our method includes direct detection of lithium, correlation between lithium and additional atoms in its surrounding (e.g. protons, carbons), and structural characterization of its environment. Once completed, our results will also facilitate the studies of other lithium targets, that may also be associated with both the therapeutic and adverse effects of lithium. |
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2
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Eran Meshorer
Genetics, Hebrew University of Jerusalem
Stress-induced chromatin-related transcriptional memory in the mammalian brain.
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| Chromatin structure plays important roles in the mechanisms of transcriptional memory. Acetylcholinesterase (AChE) is known to display long-lasting changes in expression and alternative splicing patterns in the brain, but the molecular mechanisms that underlie these changes remain largely obscure. Here I propose to investigated the expression levels of the different 5’ variants of AChE following repeated forced swim stress (FSS) in the mouse brain and to study the changes in chromatin structure of the corresponding promoters. To this end, we identified 2 alternative 5’ exons that are downregulated 2 weeks following FSS. Examination of their chromatin structure using chromatin immunoprecipitation (ChIP) with antibodies
against histone modifications revealed reduced levels of H3K9 acetylation and elevated levels of H3K9 tri-methylation at the corresponding promoter. We further propose to apply HDAC inhibitors following FSS in order to examine the potential reversal of these effects. Thus, this proposal seeks to identify the transcriptional changes of AChE 5’ alernative transcripts, identify the chromatin changes that support
this long-term transcriptional memory and examine the possibility of the reversal of these effects with HDAC inhibitors. These studies will therefore have profound implications for the study of stress-induced brain pathologies and for potential stress and/or memory-related therapy. |
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3
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Oren Schuldiner
Molecular Cell Biology, Weizmann Institute
The role of theJun Kinase (JNK) pathway in developmental Axon pruning.
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| Axon pruning is essential for sculpting mature circuits during the development of both vertebrate and invertebrate nervous systems. Understanding the molecular mechanisms that regulate axon pruning should provide a broad insight into axon elimination during development, disease and after injury.
Developmental axon pruning of Drosophila mushroom body (MB) γ neurons is a unique model system to study pruning due to its stereotypic occurrence, and the genetic tools available. A forward genetic screen in the lab identified basket, the Drosophila JNK, as required for axon pruning of MB γ neurons. The JNK pathway is implicated with a wide variety of cellular processes including apoptosis and synapse formation. It is not well understood how different extracellular signals converging on the JNK pathway can induce specific outcomes. Here we propose to uncover the expression of basket on the RNA and protein levels, to shed light on the upstream activation cascade leading to its activation and to identify the downstream players activated by basket phosphorylation and responsible for inducing the pruning program. Understanding JNK signaling and determining its role in integrating extracellular signals into axon fragmentation with precise spatial and temporal control
should provide important molecular insights of axon pruning and JNK signaling. |
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4
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Rami Yaka
Drug Research Inst, Hebrew University of Jerusalem
The role of oxidative stress in cocaine addiction.
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| A variety of mechanisms has been suggested for cocaine toxicity, including the possibility that cocaine induces an increase in oxidative stress (OS) due to excessive oxidation of dopamine (e.g. dopamine quinine), or by redox cycling of cocaine oxidized metabolites. However, the association between oxidative status in the brain and cocaine induced-behavior is poorly understood. Previously we have shown that administration of the unique antioxidant tempol, attenuate cocaine-induced oxidative damage in principle areas of the brain reward system. Moreover, we found that tempol reduced the development and expression of cocaine psychomotor sensitization. We hypothesized that preventing drug-induced oxidative damage by antioxidants or antioxidants-like molecules will result in reversing the drug-induced neuroadaptations which will ultimately lead to prevention of the development and expression of cocaine addiction.
Using state of the art immunohistochemical, biochemical and behavioral tools, we will explore the ability of different exogenous antioxidants to attenuate oxidative damage induced by cocaine administration both ex-vivo and in vivo in the brain reward system. We will examine whether antioxidants can reduce the rewarding properties of cocaine, and finally we will identify the molecular targets that mediates the ability of antioxidants to reduce cocaine-induced behaviors.
We predict that treatment with antioxidants such as tempol, will overturn the oxidative damage induced by administration of cocaine and will lead to the prevention of cocaine reward and addiction. Since no approved pharmacotherapy is available to treat cocaine addiction, if positive, the results of the present study will provide a new approach for the development of new class of drugs with defined mechanism of action and a similar profile as the antioxidant tempol, which will help to fight drug addiction. |
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Third Year |
1
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Leon Deouell
Psychology, Hebrew University of Jerusalem
In the eyes of the beholder: The correlation between induced Gamma band responses and eye movements.
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| Synchronous high frequency neural activity is seen now as a fundamental mechanism for creating ad-hoc neuronal networks of different scales, which represent objects, concepts, beliefs and thoughts. The most immediate ways to look at neural activity in humans is electroencephalography (EEG), a non-invasive measure of neural activity. The most frequently investigated high frequency EEG phenomenon is the induced gamma band response (iGBR), which is typically seen as a broad band power increase, 200-300 ms after a visual or auditory stimulus appears. Until recently, the iGBR was linked to the formation of coherent object representations through synchronous neural oscillations.
However, in a new study we presented conclusive evidence showing that the iGBR is not related to neural oscillations, but rather reflects miniature involuntary saccadic eye
movements. A remaining puzzle, in light of the new findings, is the robust effect of
cognitive manipulations on the iGBR. The present proposal aims to understand this
correlation by examining in detail how different types of stimulation affect involuntary eye movements and how these parameters affect the iGBR. This will provide novel understanding of involuntary eye movements and will allow true assessment of neural oscillations reflected in the EEG, hitherto obscured by the effect of eye movements. |
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2010 - 2011 |
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First Year |
1
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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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2
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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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3
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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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4
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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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5
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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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6
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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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7
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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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8
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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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9
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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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10
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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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Second Year |
1
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Galia Avidan
Psychology, Ben-Gurion University
Organizational principles of human cortical eye fields and their role in visual Perception
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2
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Irit Lichter-Levin
Sourasky Medical Center, Sourasky Medical Center
Brain mechanisms underlying free recall versus recognition retrieval processes
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3
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Son Preminger
Brain Research, Weizmann Institute of Science
Human self-initiated motivated behavior: functional neuroanatomy, plasticity and potential for rehabilitation
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4
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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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5
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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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6
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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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7
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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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8
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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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9
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Anat Maril
Psychology, Hebrew University Jerusalem
Subsequent memory effects & the process of internal generation in prefrontal cortex
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10
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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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11
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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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12
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Nurit Gronau
Department of Psychology, Open University
The role of global contextual factors in visual object perception: an fMRI study
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13
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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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14
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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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15
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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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16
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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
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Einat Shneor Labensohn
Hadassah College, Jerusalem
Cortical reorganization following damage to the optic chiasm: Neuroimaging studies
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Third Year |
1
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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
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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 |
1
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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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13
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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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14
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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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15
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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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16
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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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17
.
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?
|
| 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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18
.
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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19
.
Yifat Prut
Department of Physiology, The Hebrew University
Motor correlates of entrainment to rhythmic auditory cues in humans
|
| 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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20
.
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
|
| 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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21
.
Maoz Shamir
Department of Psychology, Ben-Gurion University
Centralized versus collective decision mechanisms in the brain
|
| 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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22
.
Anna Sterkin
Goldschleger Eye Research Institute, Tel Aviv University
Establishing electrophysiological markers to probe abnormal levels of neural interactions underlying learning and memory deficits
|
| 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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23
.
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
|
| 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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24
.
Kobi Rosenblum
Department of Neurobiology and Ethology, University of Haifa
Identifying, analyzing and manipulating cortical neuronal networks underlying sensory memory formation and recall
|
| 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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25
.
Dr. Leon Deouell
Department of Psychology, Hebrew University
In the eyes of the beholder: Correlation between induced gamma-band responses and eye movements
|
| 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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26
.
Edi Barkai, David Golomb and Israel Sekler
Biology & Neurobiology, University of Haifa
Learning-induced modifications in inhibitory synaptic transmission: mechanisms and functional significance
|
| 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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27
.
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
|
| 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 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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28
.
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
|
| 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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29
.
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
|
| 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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30
.
Prof. Ehud Zohary
Department of Neurobiology, The Hebrew University
Cortical plasticity in the adult human visual system following retinal damage caused by Macular Degeneration
|
| 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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31
.
Rakefet Ackerman
Department of Psychology, Ben-Gurion University
The heuristic basis for the sense of understanding of younger and older adults
|
| 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 |
| close |
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32
.
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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33
.
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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34
.
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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35
.
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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36
.
Hagit Magen
School of Occupational Therapy, The Hebrew University
Perceptual and attentional processes in individuals with sensory modulation disorder: An EEG study
|
| 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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37
.
Johanna Schumann
Department of Neurobiology & Ethology, University of Haifa
The role of the NMDA receptor complex in cocaine psychomotor sensitization
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38
.
Einat Shneor Labensohn
Department of Neurology, The Hebrew University
Cortical reorganization following damage to the optic chiasm: Neuroimaging studies
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39
.
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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40
.
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
|
| 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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Second Year |
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.
|
| 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
|
| 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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|
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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
|
| 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. |
| close |
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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
|
| 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 |
|
First Year |
1
.
Dr. Amir Amedi
Sensory Physiology and Perception
Hebrew University of Jerusalem, Faculty of Medicine and Program of Cognitive Science
Cognitive neuroscience of mental imagery versus perception in the three topographical senses
|
| 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
.
Dr. Sharon Anavi-Goffer
Schizophrenia
Ariel University Center of Samaria, Behavioral Sciences and Molecular Biology
A role for cannabinoid CB2 receptor in schizophrenia
|
| 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
.
Dr. Galia Avidan
Sensory Physiology and Perception
Ben Gurion Univesrity of the Negev, Psychology Department
Investigating the organization principles of human cortical eye-fields and their role in visual perception
|
| 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. |
| close |
|
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4
.
Dr. Miki Bloch
Depressive and Bipolar Disorders
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
|
| 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. |
| close |
|
|
5
.
Dr. Yoav Gothilf
Depressive and Bipolar Disorders
Tel Aviv University, Neurobiology Department
Light entrainment of the circadian clock: regulation of period2 in the zebra-fish model
|
| 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 |
|
|
6
.
Dr. Tzuri Lifschytz
Depressive and Bipolar Disorders
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
|
| 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. |
| close |
|
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7
.
Dr. Anat Maril
Memory & Learning
Hebrew University of Jerusalem, Psychology and Cognitive Sciences
Subsequent memory effect and the process of internal generation in anterior prefrontal cortex
|
| 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
.
Dr. Yehuda Pollak
Attention Deficit Disorder
Shaare Zedek Medical Center , Psychology
Risk-taking and decision-making under uncertainty in adolescents with attention-deficit and hyperactivity disorder
|
| 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
.
Dr. Irit Shapira-Lichter
Memory & Learning
Sourasky Medical Center, Functional Brain Center
Brain mechanisms underlying free recall versus recognition retrieval processes: a multimodal approach
|
| 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. |
| close |
|
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10
.
Dr. Rami Yaka
Drug Abuse
Hebrew University of Jerusalem, Pharmacology
Identification of new drug targets for cocaine addiction using a proteomics approach
|
| 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. |
| close |
|
|
11
.
Dr. Leon Deouell
Sensory Physiology and Perception
Hebrew University of Jerusalem, Psychology
In the eyes of the beholder: the correlation between induced gamma band responses and eye movements
|
| 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. |
| close |
|
|
12
.
Dr. Rakefet Ackerman
Memory & Learning
Ben Gurion Univesrity of the Negev, Psychology
The heuristic basis for the sense of understanding in younger and older adults
|
| 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 |
| close |
|
|
13
.
Dr. Zehavit Kariv-Inbal
Alzheimer's Disease and other Dementias, Memory & Learning
Tel Aviv University, Department of Neurobiology
Prevention and reversal of the pathological effects of apoE4 by diet
|
| 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. |
| close |
|
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14
.
Dr. Hagit Magen
Autism/ Pervasive Developmental Disorder
Hebrew University of Jerusalem, Department of Psychology
Perceptual and attentional processes in individuals with sensory modulation disorder: an EEG study
|
| 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. |
| close |
|
|
15
.
Dr. 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 |
1
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Dr. Irit Akirav
Anxiety Disorders including Post-Traumatic Stress Disorder, Alcoholism
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
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Dr. Ron Amir
Peripheral Neuropathy
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
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Dr. Yaniv Assaf
Degenerative Disorders
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
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Dr Ohad Ben-Shahar
Degenerative Disorders
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
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Dr. Claude Brodski
Attention Deficit Disorder
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
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Dr. Rena Cooper-Kazaz
Depressive and Bipolar Disorders
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
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Dr. Ruth Defrin & Karni Ginzburg
Anxiety Disorders including Post-Traumatic Stress Disorder
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
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Dr. Daniel Gitler
Epilepsy
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
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Dr. David Gurwitz
Depressive and Bipolar Disorders
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
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Dr. Raphael Lamprecht
Alzheimer's Disease and other Dementias, Memory & Learning
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
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Dr. Yonatan Loewenstein
Neuroscience
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
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Dr. Mouna Maroun
Chemical Dependency, Memory & Learning
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
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Dr. Marina Pavlovskaya
Sensery Physiology and Perception, Memory & Learning
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
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Dr. Ronit Pinkas-Kramarski
Basic Neurobiology
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
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Dr. Uri Polat
Depressive and Bipolar Disorders
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
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Dr. Hamutal Slovin
Memory & Learning
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
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Dr. Michael Wagner
Sensory Physiology and Perception
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
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Edi Barkai, David Golomb and Israel Sekler
Memory & Learning
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
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Prof. Hagit Cohen
Depressive and Bipolar Disorders, Anxiety Disorders including Post-Traumatic Stress Disorder
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
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Dr. Reuven Stein
Genetic Effects
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
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Dr. Hadas Okon-Singer
Developmental Disorders
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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22
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Dr. Amir Perelberg
Basic Neurobiology
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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23
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Dr. Shlomo Wagner
Memory & Learning
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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24
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Dr. Talma Hendler
Brain Research
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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Third Year |
1
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Dr. Anat Barnea
Memory & Learning
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
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Prof. Ehud Zohary
Brain Research
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
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Dr. Inna Slutsky
Memory & Learning
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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First Year |
1
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Dr. Irit Akirav
Anxiety Disorders including Post-Traumatic Stress Disorder, Alcoholism
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
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Dr. Ron Amir
Peripheral Neuropathy
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
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Dr. Yaniv Assaf
Degenerative Disorders
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
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Dr Ohad Ben-Shahar
Degenerative Disorders
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
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Dr. Claude Brodski
Attention Deficit Disorder
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
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Dr. Rena Cooper-Kazaz
Depressive and Bipolar Disorders
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
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Dr. Ruth Defrin & Karni Ginzburg
Anxiety Disorders including Post-Traumatic Stress Disorder
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
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Dr. Daniel Gitler
Epilepsy
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
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Dr. David Gurwitz
Depressive and Bipolar Disorders
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
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Dr. Raphael Lamprecht
Alzheimer's Disease and other Dementias, Memory & Learning
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
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Dr. Yonatan Loewenstein
Neuroscience
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
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Dr. Mouna Maroun
Chemical Dependency, Memory & Learning
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
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Dr. Marina Pavlovskaya
Sensery Physiology and Perception, Memory & Learning
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
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Dr. Ronit Pinkas-Kramarski
Basic Neurobiology
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
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Dr. Uri Polat
Depressive and Bipolar Disorders
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
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Dr. Hamutal Slovin
Memory & Learning
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
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Dr. Michael Wagner
Sensory Physiology and Perception
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
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Edi Barkai, David Golomb and Israel Sekler
Memory & Learning
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
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Dr. Hagit Cohen
Anxiety Disorders including Post-Traumatic Stress Disorder
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 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
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Dr. Reuven Stein
Genetic Effects
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
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Dr. David Anaki
Sensery Physiology and Perception
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
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Dr. Tzuri Lifschytz
Depressive and Bipolar Disorders
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
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Dr. Guy Horev
Basic Neurobiology
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
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Dr. Amir Perelberg
Basic Neurobiology
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
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Dr. Michael Tsoory
Basic Neurobiology
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
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Dr. Shlomo Wagner
Memory & Learning
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 |
1
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Dr. Orna Almog
Depressive and Bipolar Disorders
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
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Dr. Yair Bar Haim
Anxiety Disorders including Post-Traumatic Stress Disorder
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
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Dr. Dorit Ben-Shalom
Autism/ Pervasive Developmental Disorder
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
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Dr. Alon Chen
Anxiety Disorders including Post-Traumatic Stress Disorder
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
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Dr. Yael Chertkow-Deutsher
Anxiety Disorders including Post-Traumatic Stress Disorder
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
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Dr. Doron Gothelf
Genetic Effects, Schizophrenia
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
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Dr. Amir Karniel
Memory & Learning
Ben Gurion University of the Negev, Biomedical Engineering
Motor Memory - does it address the past or the future?
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| 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? |
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8
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Dr. Noga Kronfeld-Schor
Depressive and Bipolar Disorders
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)
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| 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
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Dr. Gil Levkowitz
Developmental Disorders, Parkinson's Disease
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
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Dr. Jeannette Schaeffer
Memory & Learning
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
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Dr. Anat Barnea
Memory & Learning
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
.
Prof. Ehud Zohary
Brain Research
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
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Dr. Alexandra Kavushansky
Anxiety Disorders including Post-Traumatic Stress Disorder
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
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Dr. Inna Slutsky
Memory & Learning
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 |
1
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Dr. Opher Donchin
Memory & Learning
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
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Dr. Yoram Gutfreund
Sensory Physiology and Perception
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
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Dr. Dana Cohen
Memory & Learning
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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1
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Dr. Anna Sterkin
Depressive and Bipolar Disorders
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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2006 - 2007 |
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First Year |
1
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Dr. Amir Karniel
Memory & Learning
Ben Gurion University of the Negev, Biomedical Engineering
Motor Memory - does it address the past or the future?
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| 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? |
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2
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Dr. Doron Gothelf
Developmental Disorders, Basic Neurobiology
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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3
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Dr. Gil Levkowitz
Basic Neurobiology
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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4
.
Dr. Jeannette Schaeffer
Memory & Learning
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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5
.
Dr. Yael Chertkow-Deutsher
Anxiety Disorders including Post-Traumatic Stress Disorder
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
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Dr. Leon Deouell
Cognition
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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7
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Dr. Noga Kronfeld-Schor
Depressive and Bipolar Disorders
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)
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| 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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8
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Dr. Alon Chen
Anxiety Disorders including Post-Traumatic Stress Disorder
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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9
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Dr. Orna Almog
Depressive and Bipolar Disorders
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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10
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Dr. Yair Bar Haim
Anxiety Disorders including Post-Traumatic Stress Disorder
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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11
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Dr. Dorit Ben-Shalom
Autism/ Pervasive Developmental Disorder
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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12
.
Dr. Anat Barnea
Brain Research
The Open University, Neurobiology Department
Neurobiological aspects of migratory eriphera 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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13
.
Prof. Ehud Zohary
Brain Research
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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14
.
Dr. Anat Barnea
Brain Research
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
.
Dr. Ariela Gordon-Shaag
Sensery Physiology and Perception, Nerve and Synapse Transmission
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
.
Dr. Alexandra Kavushansky
Anxiety Disorders including Post-Traumatic Stress Disorder
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
.
Dr. Hadas Okon-Singer
Epilepsy
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 |
1
.
Ph.D Yoram Bonneh & Misha Tsodyks
Brain Research & Autism/ Pervasive Developmental Disorder
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
.
Ph.D Ariel Knafo
Brain Research
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
.
Ph.D Ilan Lampl
Sensory Physiology and Perception
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
.
Ph.D Shai Shoham
Sensory Physiology and Perception
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
.
Ph.D Drorit Saar
Memory & Learning
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
.
M.D. Miki Bloch
Depressive and Bipolar Disorders
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
.
M.D. Yossi Chalamish
Basic Neurobiology
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
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8
.
Ph.D Michal Taler & Irit Gil-Ad
Depressive and Bipolar Disorders, Basic Neurobiology
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
.
M.D. Uri Polat
Depressive and Bipolar Disorders
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. |
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10
.
Ph.D Marina Pavlovskaya
Sensory Physiology and Perception
: 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
.
Ph.D Michal Hershfinkel
Degenerative Disorders, Memory & Learning
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
.
Ph.D Avraham Zangen
Anxiety Disorders including Post-Traumatic Stress Disorder
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
.
Ph.D 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
.
Ph.D Simone G. Shamay-Tsoory
Schizophrenia
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
.
Ph.D Adi Mizrahi
Memory & Learning
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 |
1
.
Dr. Inna Slutsky
Memory & Learning
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 |
1
.
Ph.D Yoram Bonneh & Misha Tsodyks
Brain Research & Autism/ Pervasive Developmental Disorder
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
.
Ph.D Ariel Knafo
Brain Research
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
.
Ph.D Ilan Lampl
Brain Research
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
.
Ph.D Shai Shoham
Brain Research
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
.
Ph.D Drorit Saar
Brain Research
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 |
|
|
6
.
M.D. Miki Bloch
Depressive and Bipolar Disorders
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 |
|
|
7
.
M.D. Yossi Chalamish
Basic Neurobiology
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 |
|
|
8
.
Ph.D Michal Taler & Irit Gil-Ad
Memory & Learning, Degenerative Disorders
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 |
|
|
9
.
M.D. Mark Weiser
Behavioral Disorders
Sheba Medical Center,
Studying the prodrome of psychosis using a military setting
|
| 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.
|
| close |
|
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10
.
M.D. Uri Polat
Depressive and Bipolar Disorders
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 |
|
|
11
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Ph.D Marina Pavlovskaya
Sensory Physiology and Perception
: 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
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Dr. Netta Levin & Ehud Zohary
Sensory Physiology and Perception, Degenerative Disorders
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
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Ph.D Michal Hershfinkel
Degenerative Disorders, Memory & Learning
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
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Ph.D Avraham Zangen
Anxiety Disorders including Post-Traumatic Stress Disorder
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
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Ph.D 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
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Ph.D Simone G. Shamay-Tsoory
Schizophrenia
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
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Ph.D Adi Mizrahi
Memory & Learning
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
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Ph.D Aviv Weinstein
Drug Abuse
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 |
1
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Dr. Amir Ayali
Basic Neuroscience
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
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Dr. Claude Brodski
Attention Deficit Disorder
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
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Dr. Miri Carmel
Biochemical Genetics
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
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Dr. Leon Deouell
Memory & Learning
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
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Dr. Gadi Goelman
Memory & Learning
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
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Dr. Abraham Goldstein
Brain Research
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
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Dr. Pnina Green
Depressive and Bipolar Disorders
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
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Dr. Daphna Joel
Behavioral Disorders
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
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Dr. Rachel Maayan
Depressive and Bipolar Disorders, Anxiety Disorders including Post-Traumatic Stress Disorder
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
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Dr. Mouna Maroun
Anxiety Disorders including Post-Traumatic Stress Disorder
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
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Dr. Shula Parush
Sensory Physiology and Perception
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
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Dr. Golan Shahar
Depressive and Bipolar Disorders
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
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Dr. Michael Wagner
Sensory Physiology and Perception
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
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Dr. Kobi Rosenblum
Sensory Physiology and Perception
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
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Dr. Guy Bloch
Brain Research
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
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Dr. Malka Cohen-Armon
Memory & Learning
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
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Dr. Merav Ahissar
Memory & Learning
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 |
1
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Dr. Amir Ayali
Basic Neuroscience
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
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Dr. Claude Brodski
Attention Deficit Disorder
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
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Dr. Miri Carmel
Biochemical Genetics
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
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Dr. Leon Deouell
Memory & Learning
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
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Dr. Gadi Goelman
Memory & Learning
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
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Dr. Abraham Goldstein
Brain Research
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
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Dr. Pnina Green
Depressive and Bipolar Disorders
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
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Dr. Daphna Joel
Behavioral Disorders
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
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Dr. Rachel Maayan
Depressive and Bipolar Disorders, Anxiety Disorders including Post-Traumatic Stress Disorder
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
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Dr. Mouna Maroun
Anxiety Disorders including Post-Traumatic Stress Disorder
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
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Dr. Shula Parush
Sensory Physiology and Perception
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
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Dr. Golan Shahar
Depressive and Bipolar Disorders
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
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Dr. Michael Wagner
Sensory Physiology and Perception
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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