Altered event related potentials during visual emotional stimulation in posttraumatic stress disorder Saar-Ashkenazy R. 1 2 3, Guez J. 3 4, Shalev H. 5, Friedman A. 1, Cohen J. 6* Department of Cognitive Neuroscience and, Ben-Gurion University of the Negev, Beer-Sheva, Israel 2 Department of Psychology and the School of Social-work, Ashkelon Academic College, Israel 3 Department of Psychology, Achva Academic College, Israel 4 Beer-Sheva Mental Health Center, Israel 5 Department of Psychiatry, Soroka University Medical Center Beer-Sheva, Israel 6 Sharett Institute of Oncology, Hadassah Medical Organization, Jerusalem, Israel 1
Background: Disrupted emotional reactivity and modulation are central features of the long-term psychological consequences of traumatic events. Since symptoms exhibited by posttraumatic stress disorder (PTSD) patients directly reflect impaired perceptual, attentional, and emotionalmemory processes, PTSD has become an obvious target for neurophysiological assessment in the emotional processing domain. In the current study we aimed to test the hypothesis that abnormal emotional responsiveness in PTSD is reflected in altered brain electrical activity, as measured via event-related potentials (ERPs). Methods: ERPs were recorded from 14 PTSD and 14 control subjects while viewing emotionladen pictures (positive, neutral and negative). Response-time was collected. Results: Behavioral measures indicated that both controls and PTSD patients perceived the pictures similarly on the scales of valence and arousal as rated "offline", i.e. following EEG recording. RT collected "online", i.e. during EEG recordings, showed a slowing of response to negative stimuli in both groups, with PTSD patients showing a generally slower response, irrespective of emotional content. ERP analysis revealed three emotional responsive ERP components in controls within a timewindow of ~300-1000 ms. In contrast to these findings, PTSD patients showed no modulation of any of the three components identified in controls, i.e. showed similar brain-responses across all emotional categories; while these were not significantly different from those of controls, they were larger in magnitude and resembled that of negative stimuli in controls. Conclusions: We interpret these findings in the context of a tendency towards (negative-) overgeneralization in PTSD.
CNS and systemic effects of multi-target drug, VAR compound combined with fortified high calorie/energy diet in mouse model of Amyotrophic Lateral Sclerosis Golko S, Weinreb O., Amit T. Youdim MBH. Eve Topf Center of Excellence, Technion- Faculty of Medicine, Haifa, Israel Objectives: Amyotrophic Lateral Sclerosis (ALS) is a multifactorial disease that arises from a combination of several pathologies that act through concurring damage inside motor neurons and muscles. Based on this, we have designed novel therapeutic strategy that considers simultaneous manipulation of multiple
targets to strengthen the basal energy status in ALS. In the current study, we have examined the beneficial effects of the combination therapy, the iron chelator-monoamine oxidase inhibitor, VAR10303 (VAR) with high calorieenergy supplemented diet (CED) in SOD1-G93A mutant transgenic ALS (mSOD1) mice. Methods & Results: We have demonstrated that VAR (0.5 and 2.5 mg/kg, p.o.) /CED combined treatment, starting at disease symptomatic stage, significantly delayed the onset of motor dysfunction and showed a superiority in extending the lifespan of mSOD1 mice. These effects were accompanied by a significant regulation of the mitochondrial function and proteins, including up-regulation of the mitochondrial biogenesis master regulator, PPARγ/PGC1α and elevation of the mitochondrial respiratory chain enzymes, NADH (complex I) and succinate dehydrogenase (complex II) in the gastrocnemius (GNS) muscles of VAR-treated mSOD1 mice. Furthermore, VAR/CED combined treatment markedly attenuated neuromuscular junction denervation and motoneuron loss in the GNS muscles of mSOD1 mice. In addition, VAR treatment was significantly prevented H O -induced cytotoxicity, reduced free radical generation and apoptotic markers levels, and increased mitochondrial membrane potential (JC-1) in C C murine myoblast cells. 2
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Conclusions: Our findings showed that the multi target VAR can improve motor dysfunction and muscle mitochondrial function/biogenesis in mSOD1 mice, and thus may be used as effective therapeutic approach for ALS.
Fibroblast growth factor 2 (FGF2) is a novel target gene for alcohol use disorder Even-Chen Oren *, Shaham Ohad , Barak Segev 1
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School of Psychological Sciences Tel Aviv University the Sagol School of Neuroscience, Tel Aviv University 1
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Background: Alcohol use disorder (AUD) is a chronic relapsing disorder, characterized by preoccupation with obtaining alcohol and a narrowing of the behavioral repertoire toward excessive and compulsive alcohol consumption. Repeated alcohol intake leads to neuroadaptations in the reward system, which results in tolerance, reward dysfunction and compulsive alcohol seeking and intake. Nevertheless, mechanisms underlying this disorder are poorly understood. Recently, the growth factor FGF2 has been implicated in learning and memory processes including relapse of fear memories, as well as in the actions of psychostimulants in the CNS. The purpose of the present study was to characterize the involvement of FGF2 and its main receptor, FGF receptor 1 (FGFR1) in AUD. Specifically, we aimed to: 1. determine the responsiveness of the Fgf2 and Fgfr1 genes to alcohol exposure in rodents; and 2. test the effect of recombinant FGF2 (rFGF2) administration on alcohol-related behaviors. Results: Sub-chronic alcohol treatment lead to upregulation of Fgf2 and Fgfr1 mRNA levels in several addiction-related brain regions including the dorsal hippocampus, dorsal striatum (DS) and ventral tegmental area (VTA). Interestingly, while Fgfr1 was upregulated after 24h-withdrawal, Fgf2 was upregulated shortly after alcohol administration. In addition, voluntary alcohol consumption led to long-lasting increases in Fgf2 and Fgfr1 expression in the DS. Furthermore, we tested the effect of rFGF2 on alcohol-conditioned place preference
(CPP), measuring alcohol reward and seeking. We found that rFGF2 abolished the expression and facilitated the extinction of alcohol-CPP. Conclusion: The present study provides the first evidences for the involvement of FGF2 in AUD. Furthermore, our results suggest that alcohol exposure induces neuroadaptations in the FGF2 pathway, and that FGF2 administration suppresses alcohol seeking. Together our finding suggests that FGF2 is a novel target gene for AUD.
New multi-functional drug approach for the treatment of brain injury Missing: presenting author 1
Harel A * 1
Medicortex Finland Oy
Traumatic brain injury (TBI) is one of the main causes of mortality among military personnel, children, young adults and athletes. Background: TBI is manifested by early events and delayed secondary alterations. The latter include: mitochondrial dysfunction, lipid degradation and peroxidation and BBB disruption. This is followed by intracellular calcium influx and activation of proteases, resulting in axonal swelling, disconnection and degeneration. Pro-inflammatory factors are produced and secreted by immune system cells, promoting the development of the inflammatory process. These events result in neurological deficits. Many clinical trials testing drugs for TBI have been conducted but failed to show significance at their primary endpoint. Since the degenerative process is mediated by multiple biological reactions, agents that target a single pathway are ineffective. Therefore, an intervention that simultaneously targets multiple factors is more effective in halting the secondary degeneration. Results: Medicortex presents a novel family of new chemical entities that cross the BBB, each possessing a penetrating head with a chemical spacer and two or more of the following properties: binding of free metal ions, anti-oxidation, anti-inflammation, and/or anti-bacterial. The lead compounds will be selected according to their solubility, stability and toxicity. In vitro and in vivo studies are conducted in order to explore the efficacy of the molecules as neuroprotective agents under different insults and to attenuate neural damage, utilizing animal models of cortical impact brain injury. The first compound, TBI-466, was tested by repeated injection at different concentrations and was found to be safe. Conclusions: Taken together, Medicortex's multi-functional drug agents will target biochemical pathways occurring at different time points post-injury, thereby attenuating and even preventing secondary TBIassociated neurological dysfunction and neuronal cell death.
True deviance sensitivity in awake freely moving rats Missing: corresponding author Missing: presenting author
Nelken I.
Polterovich A. , Jankowski M. , 1
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Dept. of Neurobiology and the Edmund and Lily Safra Center for Brain Sciences, Hebrew University, Je 1
Stimulus-specific adaptation (SSA) is the decrease in responses to a common stimulus that does not generalize, or only partially generalizes, to other stimuli. SSA is usually measured using oddball sequences, in which a common (standard) tone and a rare (deviant) tone are randomly intermixed. The larger responses to a tone when deviant, however, need not necessarily represent true deviance sensitivity. A common test for deviance sensitivity uses a 'deviant among many standards' control sequence, where many
different tones serve as the 'standard', thus eliminating the deviance of the deviant. When the response to the same tone when deviant (against a single standard) is larger than the responses to the same tone in the control sequence, it can be concluded that true deviance sensitivity occurs. An even stricter control is the 'deviant alone' condition, in which all presentations of the standard are replaced by silence. In anesthetized rats, responses in the deviant alone condition are typically largest, while the responses to deviants and to the same tones in the control condition are comparable. We recorded local field potentials and multiunit activity from auditory cortex of awake, freely-moving rats, using telemetry. We observe highly significant SSA (deviant>standard) in the awake state. Moreover, the responses to a tone when deviant were significantly larger than the responses to the same tone in the control condition. In fact, responses to tones when deviant were even significantly larger than in the deviant alone condition. These results establish the presence of true deviance sensitivity in primary auditory cortex in the awake state.
The role of circulating small non-coding RNAs as possible biomarkers predicting response and adverse events in depressed and anxious children and adolescents treated with fluoxetine Amitai M
*, Apter A , Chen A
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Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel Department of Stress Neurobiology and Neurogenetics, Max-Planck Institute of Psychiatry, Munich, Ge Department of Psychological Medicine, Schneider Children’s Medical Center of Israel, Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 1
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Depression andanxiety disorders are among the most common childhood psychiatric disorders.Selective serotonin reuptake inhibitors (SSRIs) are generally consideredfirstline treatment for both depression and anxiety in this age group.However, it has been reported that 30%–40% of all patients who receive asufficient dose and duration of treatment fail to respond. Moreover, SSRI useis frequently associated with serious adverse events (SAE), includingactivation symptoms, manic switch and increased suicidal behavior. These areparticularly relevant in pediatric populations because of concerns about thesuicide threat of SSRIs, resulting in a black-box warning. Currently there are nomethods of identifying in advance the response of children and adolescents to SSRI treatment. The purpose of thecurrent study is to examine the role of circulating small non-coding RNA (ncRNA)as a promising candidate biomarker for SSRI treatment response and SAE inchildren and adolescents treated for depression and anxiety disorders. Methods: Eighty children andadolescents patients who met DSM-IV criteria for major depressivedisorder (MDD) or anxiety disorders participated in the study. Their age rangedfrom 6 to 18 (14.12 ± 2.30) years. The patients were treated with fluoxetine 2040mg/day for 8 weeks. Preliminary results:The overall response rate was 56%. 10% responded with SAE. Out of the study sample we selected 13remitters and 13 nonresponders and 10 children with SAE (activation symptoms,manic/hypomanic switch, increased suicidality), and analyzed expressionprofiles in peripheral blood at admission and after 8 weeks of treatment using smallncRNA sequencing. Data is currently being analyzed and differential levels ofcirculating small ncRNA will be further confirm in a separate cohort of patients.Parallel studies in animal models are currently conducted in order to provide adeeper mechanistic understanding on the involvement of small ncRNAs in depressed and anxious children andadolescents.
Characterization of four ASD mouse models reveals common behavioral phenotypes and common dysregulation in distinct transcriptional networks in the striatum Missing: presenting author 1
Oded O. , Shohat S , Reuveni E , Shifman S. , Elliott E * 1
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Faculty of Medicine, Bar Ilan University Institute of Life Sciences, Hebrew University 2
In the last decade it has become clear that hundreds of genes are involved in the etiology of ASD. While ASD could be divided to genetically exclusive subtypes, the disorder is still characterized by common behavioral deficits. Therefore, it is probable that these different genetic aberrations affect common molecular mechanisms. As of now, little is known on the biological processes that are in common between ASDs of distinct genetic etiologies. Many genetic and nongenetic mouse models have been produced in the pursuit of understanding how different genetic etiologies cause ASD. We have performed locomotion and anxiety-related behavioral phenotyping and whole-transcriptome analysis from the striatum of four widely used autism models: CNTNAP2 KO, Shank3 KO, Chr16p11.2 del, and BTBR. In our behavioral testing, we found common dysregulations in locomotor activity, anxiety-like activity, and risk-assessment activity in most of these autism mouse models. Considering that the striatum is involved in locomotion and risk assessment, we performed RNA-seq analysis from the striatum of all four mouse models, and found that 31 genes were commonly upregulated in the BTBR, Shank3 and Chr16p11.2 del mouse models, including, including IGF-2 and IGFBP2. Using WGCNA analysis, we further found multiple gene networks that correlate with both genotype and risk assessment behavior in the four animal models. This study demonstrates that common behavioral and molecular phenotypes can be deciphered in multiple autism mouse models.
Voltage imaging in the live mouse brain with enhanced Rhodopsin based voltage sensors Adam Y A *
, Zhao Y
1 2 3
, Mostajo-Radji MA
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, Arlotta P
7 2 3
, Campbell RE
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, Cohen
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Dept of Chemistry and Chemical Biology Harvard University Cambridge, MA Dept of Chemistry University of Alberta Edmonton, AB Dept of Stem Cell and Regenerative Biology 1
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Optical detection of action potentials in the intact mammalian brain will open new frontiers in neuroscience research. Archaerhodopsin-based voltage sensors exhibit voltage-sensitive fluorescence, with a sensitivity and speed of response far greater than any other protein- or dye-based voltage indicator. Although they perform well in cultured cells, these indicators are difficult to implement in vivo due to their dim fluorescence and poor membrane trafficking. To address these limitations, we designed a series of modified sensors, based on the QuasAr backbone previously developed by our lab. Our panel of constructs included chimeras with other Rhodopsins, different fluorescent fusion proteins and linkers, additional signal peptides as well as rational point mutations. These constructs were then expressed in primary hippocampal neurons and evaluated by measuring their brightness and their signal to noise ratio (SNR) for optically induced action potentials. Constructs that showed significant improvement were then expressed in vivo using in utero electroporation and tested in acute brain slices. Our screen resulted in new variants of QuasAr, which show significantly improved membrane trafficking as
well as brighter fluorescence. By combining features from the best variants, we generated a new construct named QuasAr3 and expressed it in vivo using AAV vectors. When imaged in acute brain slices, QuasAr3 allowed high fidelity recording of single action potentials and sub threshold events at single cells and even at single dendritic processes. Next, we expressed QuasAr3 in the mouse olfactory bulb and imaged periglomerular neurons (PGNs) in anesthetized mice through a cranial window. Under these conditions we were able to optically record spontaneous spiking activity of single PGNs at high SNR in the live brain. Currently we evaluate the performance of QuasAr3 in additional brain regions and develop tools to perform all-optical electrophysiology in the intact mouse brain.
Odors in human cerumen (earwax) Missing: corresponding author
N 1
Agron S , Weiss T , Shushan S , Cohen Atsmoni S , Sobel 1
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Department of Neurobiology, Weizmann institute of science
Human body odor, which is made of volatile organic compounds (VOCs), contains meaningful information on physiological and mental state. Although most investigations into body odor examine axillary odorants in sweat, humans secrete several additional potential odor carriers. One such source is cerumen (earwax). Cerumen is produced by sebaceous glands and ceruminous glands, which are specialized sweat glands located in the external ear canal. The function of cerumen secretion is not fully understood. It is hypothesized to take part in the moistening, cleaning and humidification of the ear canal. There are also inconclusive data regarding its antimicrobial function. Notably, polymorphism in cerumen phenotypes results from polymorphism in a gene central to human odor production (ABCC11). With this in mind, we set out to establish a VOCs profile for human cerumen secreted in various physiological and mental conditions. We obtained cerumen from 11 healthy individuals (6 F, age = 37.8 ± 17.4) by way of suction from the ear canal. We subjected cerumen headspace to VOC analysis using gas chromatography mass spectrometry (GC-MS). A recent comprehensive study of cerumen VOCs identified several compounds (Prokop-Prigge et al., 2014). Here, we identified two additional VOCs that were not describe previously in the literature, as far as we know. 2undecanone, which was demonstrated to act as an insect and animal repellent and 2hexanone. We are continuing to collect data in order to determine whether these compounds are genuinely secreted by humans or are the result of contamination (e.g., cosmetics), and further estimate the variability of these secretions as a function of physiological and mental state.
Versions of time perceptions Ahissar E. 1
*
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Department of Neurobiology Weizmann Institute Rehovot 2
3
Time and space are linked via motion. In mammalian brains such a link is established via sensor motion: external spatial offsets can be determined by receptor temporal delays. The high-resolution temporal coding in this process stands in contrast to the low resolution of perceptual estimation of elapsed time. The difference can be attributed to differences in both functions and underlying mechanisms.
Using perceptual training protocols for rehabilitation – a critical evaluation Ahissar M * 1
1
Psychology & ELSC, HUJI
In the past 20 years we have witnessed great excitement about the potential of intensive training (e.g. working memory, action video games, music) to enhance perceptual, attentional and cognitive skills. This message is exciting as it negates decades of consistent observations that learning is quite specific to the trained context, and trained instances. This claim was not based on a theoretical prediction but on a combination of 2 basic observations. First, experts (e.g. gamers) do better than non-experts in a range of related tasks. Second, several studies found that training leads to a mild improvement in related untrained tasks, suggesting causality. However, the magnitude of the training effect, even following dozens of hours of playing, is at best marginal, and even its significance was contested by studies conducted in different labs. This pattern of cross lab variability is consistent with the claim that training gains reflect the expectations of participants rather than the actual benefit of a specific training procedure (e.g. practice vs no-practice; action versus non-action video games). I will describe our own study of training working memory and auditory skills, which failed to transfer to any untrained tasks. I will analyze several highly-cited studies that report training benefits, and show that transfer was more limited than that claimed (in magnitude and range). As a first step for resolving the dispute in the field, I propose to verify replicability by the contesting labs administering the protocol designed (and carefully followed) by the proponent researchers. I thank ISF and the ISF-Canada collaboration for their support of this study
Targeting a zinc-potassium continuum in neuronal injury as a novel neuroprotective strategy Aizenman E.
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Department of Neurobiology Pittsburgh Institute for Neurodegenerative Disroders University of Pittsburgh School of Medicine 1
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Kv2.1 is the primary voltage-gated delayed-rectifying potassium channel expressed in cortical and hippocampal neurons. Following an injurious stimulus, the function of this channel is necessary for an apoptosis-enabling surge in K+ efflux. This process is activated by the oxidative liberation of intracellular zinc, and following the dual phosphorylation of Kv2.1 by the kinases p38 and Src at two distinct intracellular residues of the channel. This process triggers rapid Kv2.1 channel insertion into the plasma membrane via interactions with the SNARE proteins SNAP-25 and syntaxin 1A. Indeed, impeding Kv2.1-mediated K+ efflux by disrupting the above regulatory signals has proven to be neuroprotective in various in vitro models of neuronal cell death. Importantly, heterologous expression of the Kv2.1 syntaxin-binding domain was found to effectively reduce the apoptotic potassium current and protect neurons against activated microglia-induced neurotoxicity. Here, we will describe experiments that narrow down the syntaxin-binding region of Kv2.1 to nine C-terminal amino acids, and the use of a cell
permeant peptide based on this sequence that shows promising neuroprotective properties in vitro and in vivo. Funded by NIH grant NS043277
Origins of task-specific sensory-independent organization in the visual and auditory brain: neuroscience evidence, open questions and clinical implications Heimler B. , Striem-Amit E. , Amedi A. 1 2
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Medical Neurobiology, IMRF, Faculty of Medicine, Hebrew University of Jerusalem The Edmond and Lily Safra Center for Brain Research, the Hebrew University of Jerusalem Department of Psychology, Harvard University, Cambridge, MA 02138 USA The Cognitive Science Program, The Hebrew University of Jerusalem, Jerusalem 91220, Israel Sorbonne Universite, Universite Pierre et Marie Curie, Universite Paris, Institut de la vision 1
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Evidence of task-specific sensory-independent (TSSI) plasticity from blind and deaf populations has greatly contributed to our understanding of brain organization. However, the principles determining the origins of this plasticity remain unclear. I will present recent data suggesting that a combination of the connectivity bias and sensitivity to taskdistinctive features might account for TSSI plasticity in the sensory cortices as a whole, from the higher-order occipital/temporal cortices to the primary sensory cortices. I will discuss current theories and evidence, open questions and related predictions. Finally, I will present preliminary results suggesting the way predictions coming from TSSI plasticity can be eventually implemented within rehabilitation programs to maximize the efficiency of visual and auditory recovery.
Body odor conveys information about trustworthiness Amir D *, Endevelt-Shapira Y , Sobel N 1
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Neurobiology Department, Weizmann Institute of Science, Rehovot, Israel
Chemosignaling serves an important function in human communication. Here we test the hypothesis that a person’s body odor carries information about their trustworthiness. We used the trust game, a commonly applied behavioral economics paradigm, to measure trustworthiness. 57 subjects (25F, 26±3.3) played the role of the trustee, and the average amount of money that was sent back to the investor served as an index of their trustworthiness. Subsequently, 10 male subjects (28.4±2.3) spanning the trustworthiness distribution served as body odor donors and slept with a t-shirt for two nights. 35 subjects (21F, 25.2±3.1) rated these odors for trustworthiness, pleasantness and intensity. Analysis of the rankings revealed two significant correlations: In male raters, there was a correlation between actual trustworthiness and perceived trustworthiness (ρ=0.63, p10% of trials, 18-of-23 observers tested) were included in the analysis. Results: Spontaneous eyeblinks, although less frequent, were very similar to microsaccades in their modulation pattern in response to transient stimuli, demonstrating inhibition and rebound, which were dependent on the contrast and spatial-frequency of the stimuli. The average blink-RT, measured as the latency of the first blink, following its release from inhibition, was longer for lower contrast and higher spatial-frequency, and was highly correlated with psychophysical measures of contrast sensitivity. When two types of stimuli were presented in random order, repetition (e.g. sound after a sequence of sounds) decreased the blink RT, while change (e.g. sound “surprise” after a sequence of visual-patches) increased it. Conclusion: Eyeblinks, like microsaccades, are linked to an inhibitory mechanism that presumably turns-off oculomotor events while processing previous events, thus providing an indirect but precise measure for internal processing speed, which can also be used to uncover perceptual saliency and surprise.
Neural changes underlying non-reinforced behavioral change Botvinik Nezer R. *, Assaf Y. , Schonberg T. 1 2
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Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel Department of Neurobiology, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel 1
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Background A unique manipulation named the cue-approach task was recently developed to influence choices without external reinforcement or context changes. In the task, the mere association between an auditory cue and a button press in a one-hour session leads to preference changes lasting at least two months. Consistent results have been obtained in multiple samples demonstrating behavioral change of preferences towards various types of items (e.g. snacks, faces, fractals). The success of the cue approach task in changing behavior challenges current theories of valuebased decision-making. The exact neural mechanisms leading to this change are not fully understood. Recent studies have shown that structural plasticity can be observed in the human brain within hours using advanced non-invasive MRI methods. In order to investigate the anatomical plasticity underlying the immediate and maintained behavioral change, we collected a preliminary sample of seven participants that were scanned before, after and one month following cue-approach training. Results Diffusion tensor imaging (DTI, a diffusion MRI framework) analysis revealed training-induced micro-structural changes in pre-hypothesized regions: ventro-medial prefrontal cortex, left and right parietal cortex and left and right hippocampus. These neural changes did not occur in two control subjects, as well as in a control region (inferior occipital cortex) of the experimental subjects. Magnitude of behavioral change highly correlated with the neural changes in each region. Conclusions Our preliminary results suggest that the cue-approach effect is based on memory, attentional and value-based mechanisms. This study will allow us to better understand the mechanism by which preferences are constructed and choices are made, and might also set the ground for extending this unique training to treating different disorders. This research is supported by a grant from the Israel Science Foundation (1798/15)
Contextual facilitation of the neural representation of objects in real-world scenes Brandman T. *, Peelen M.V. 1
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CIMeC - Center for Mind/Brain Sciences, University of Trento
Background: The study of high-level visual processing has largely focused on the division between scene and object processing into two neural pathways. However, scenes and objects are known to contextually interact in visual perception. Thus far, the neural basis of scene-object interaction remains unknown. Using fMRI and MEG, we asked how visual context shapes the neural representation of objects in real-world scenes. Results: Contextually-defined objects were created by degrading the object such that it is identifiable only within its original scene context. A multivariate category-coding analysis of fMRI revealed above-chance decoding of object category (animate/inanimate) for contextually-defined objects, which was significantly stronger than for degraded objects alone or scenes alone. This was found within object-selective areas directly examined, as well
as in a widespread area of the extrastriate visual cortex, using a searchlight analysis. Furthermore, a connectivity analysis revealed that contextbased object representations were correlated with activity in the scene-selective retrosplenial complex, previously implicated in contextual processing. In the MEG, using the same category-coding approach, multivariate analysis of sensors revealed above-chance decoding of object animacy for contextually-defined objects, significantly more than for degraded objects alone or scenes alone, peaking at 300 ms from stimulus onset, relative to 200 ms peak for intact object animacy. Conclusions: Our results provide the first evidence for shaping of neural representation of objects by scene context. We show that the category of an unidentifiable object is disambiguated by contextual scene cues after 300 ms and is represented in the extrastriate visual cortex, and particularly within object-selective areas. Connectivity with the scene-selective cortex further suggests that object and scene selective pathways interact to facilitate the visual representation of objects. Funded by the Autonomous Province of Trento, Call "Grandi Progetti 2012", project ATTEND.
Multi-level Regulation of Neural Stem Cell Biology and Adult Neurogenesis by Protein S Zelentsova K 1
, Abboud-Jarrous G
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, Talmi Z
, Capucha T
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,Burstyn-Cohen T
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Institute for Dental Sciences The Hebrew University of Jerusalem Jerusalem 91120 Israel 2
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Background: The diversity of molecules and intercellular interactions involved in embryonic and adult neurogenesis reflects the complexity of this process. The regulation of neurogenesis in adulthood is crucial for maintaining a balanced homeostasis of the adult brain. However, not all the mechanisms underlying adult neurogenesis are entirely understood. Results: We find that the blood anticoagulant Protein S plays an important regulatory role in adult neurogenesis, and report it’s expression in embryonic and adult neural stem cells. To investigate it's role in adult neurogenesis, we generated mice harboring a neural-specific deletion of Protein S. In these mice, hippocampal neural stem cells undergo increased proliferation as indicated by BrdU incorporation, suggesting Protein S is a negative regulator of adult neural stem cell proliferation. Neurospheres derived from Protein S conditional knockout (cKO) mice give rise to neurons, astrocytes and oligodendrocytes, indicating their multipotency. Invivo, we observe these Protein S-deficient proliferating neural stem cells survive and develop to maturity. Surprisingly, deletion of Protein S results in a decrease in the numbers of young (DCX+) and mature (NeuN+) neurons generated in the adult brain compared to littermate controls, suggesting an instructive role for Protein S in neuronal fate determination. Finally, we reveal that Protein S deletion affects key regulatory signaling pathways known to play a role in neural stem cell biology and neurogenesis. Conclusions: Protein S is a new important regulator of adult neural stem cell proliferation and neuronal specification in the murine hippocampus, affecting key signaling neurogenic pathways. We acknowledge the ISF and the Hebrew University for partial support of this work.
What was there and where? Incidental memory following repeated search in a scene Missing: corresponding author Carlebach N.
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, Zohary E.
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Department of Neurobiology, Alexander Silberman Institute of Life Sciences, Hebrew University Department of Psychology, Hebrew University of Jerusalem, Mount Scopus Jerusalem, Israel The Edmond and Lily Safra Center for Brain Sciences, Hebrew University of Jerusalem 1
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Background: We often search for specific objects (e.g. car keys) whose position is unknown or forgotten, by scanning the visual scene with our eyes. But how well do we remember other, "distractor", objects which were not the target of our search? We studied the quality of incidental memory of non-target objects, focusing on its dependence on the eye movements made during search. Subjects performed multiple searches for various target objects in the same scene, followed by a surprise memory test. The memory test required retrieval of various features of the nontarget objects: recovery of the object's name (semantic memory), recognition of the specific object among category-matched foils (visual memory), and placement of the object at its original location in the scene (position memory). Results: Performance in all memory tasks was enhanced with longer fixation durations on the non-target objects during search for another object. Conclusions: We show that scene memory, including that of non-target objects, incidentally viewed during search, improves with multiple fixations on those objects. Both object identity and position memory are enhanced. These results suggest that object foveation may be necessary and sufficient for its subsequent memory.
Mechanisms underlying modification of human motor and perceptual memories Censor N. * 1
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School of Psychological Sciences and Sagol School of Neuroscience, Tel Aviv University
The adult brain has a remarkable capacity to allow gradually improved performance in newly acquired skills, lasting for lengthy periods of time. Yet it remains largely unknown how systems-level internal representations of existing human memories dynamically change through daily interactions with the external environment, resulting in procedural motor and perceptual learning. We now have improved tools to systematically tackle these questions in humans, utilizing a multidisciplinary approach combining psychophysics, non-invasive brain stimulation and neuroimaging. Inhibitory repetitive transcranial magnetic stimulation (rTMS) guided by a stereotactic navigation system enables to reveal, at the nodal level, the role of primary cortical processing during memory reactivation in strengthening of existing motor memories. At the network level, modulations of task-free fMRI cortico-striatal inter-regional correlations are evident following interference with the reactivated memory. Finally, we will present current and future research directions based on evidence accumulated to date pointing to commonalities between motor and perceptual learning, and discuss potential clinical implications geared to improve learning or eliminate maladaptive memories.
Direct current stimulation – axonal perspective Chakraborty D. , Rahman A. , Bikson M. , Kaphzan H. * 1
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Sagol Department of Neurobiology, University of Haifa, Israel. Department of Biomedical Engineering, The City College of New York, NY, USA. 2
Background: Transcranial direct current stimulation (tDCS) is an effective non-invasive, inexpensive therapeutic technique aimed at treating various neuropsychiatric disorders. Though extensive clinical trials and mechanistic studies have been performed, still the effect of DC field at the cellular level is unknown. It is presumed that tDCS polarizes the cellular membrane, thus altering excitability depending on the direction of the field (anodal or cathodal current). We hypothesize that on the subcellular level the axons are a major target for DCS. We assumed that polarization is maximal at the axon terminals compare to the cell soma, and these terminal polarizations affect excitability which inflicts on connectivity between neurons. To substantiate this we conducted simultaneous dual whole cell recordings from cortical pyramidal cells somas and their corresponding artificial axon terminations (blebs) during DCS. Results: In our experiments we found that "polarization length" changes along development with age. We also found that axon terminal polarization starts to build up at a length of 100mm from the soma, and increasing with distance. Furthermore, the observed terminal polarization affects various intrinsic properties, such as AP duration and conduction velocity that are expected to alter neuronal connectivity. Conclusion: Axons are an important subcellular target for DCS. The orientation and length of the axons are the major parameters in determining the extent of DCS effects. Many of the axonal intrinsic properties are altered by DCS, and these alterations probably modulate synaptic efficacy and connectivity between brain regions.
Tau-derived peptidomimetics as inhibitors of its toxic self-assembly in Alzheimer's disease
Chemerovski-Glikman M. , Frenkel-Pinter M. , Abu Mokh A. , Mdah R. , Gazit E. , Segal D. * 1
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Dept. Molecular Microbiology & Biotechnology, The Interdisciplinary Sagol School of Neurosciences, G
Harmful amyloid oligomers and fibrils of certain disease-specific proteins are the hallmarks of various neurodegenerative diseases, e.g. Aβ and tau in Alzheimer's disease. Inhibiting the misfolding and aggregation of these proteins is an attractive strategy for the development of modifying therapeutics for these maladies. In this study we’ve rationally designed novel peptido-mimetic inhibitors of the self-assembly of tau based on its primary amyloidogenic fragment 'PHF6', which is composed of the amino acids VQIVYK (residues 306-311 of tau). The designed inhibitors are based on modified PHF6 versions to facilitate their binding to the PHF6 core in the full length tau protein. In addition, they include the b-breakers Proline (Pro) and a-aminoisobutyric acid (Aib) to sterically hinder aggregation propensity of the full length tau. Based on these considerations, twelve permutations of the VQIVYK sequence of PHF6 were designed: in six of them each residue, separately, was replaced by Pro (peptides 1-6), while in the other six each residue, separately, was replaced by Aib (peptides 7-12). The 12 modified peptides were examined for their ability to inhibit the aggregation and toxicity of the wild type PHF6 peptide, as a representative of the full length tau protein. ThS fluorescence and circular dichroism results demonstrated that none of the 12 modified peptides undergoes self-assembly under conditions which favor amyloidogenic selfassembly of wild type PHF6. Transmission electron microscopy, dot-blot, and toxicity assays revealed that upon incubation with wild type PHF6, some of the modified peptides effectively inhibit its self-assembly and reduce its cytoxicity in a dose dependent manner. Thus, these beta-breakers may be effective in inhibiting aggregation and toxicity of the full length tau in tauopathies.
Transcriptional networks provide insight into neural circuits for reward, aversion and selective attention Citri A
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Edmond and Lily Safra Center for Brain Sciences Department of Biological Chemistry, Alexander Silberman Institute of Life Science Safra Campus of the Hebrew University, Givat Ram Jerusalem, 91904 1
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In the Citri Lab for Experience-Dependent Plasticity we study how the nervous system encodes experience at the molecular, synaptic and neural circuit levels. A main focus in the lab is to understand how salient experiences are encoded. Studying transcriptional dynamics induced in defined brain nuclei following a battery of rewarding and aversive experiences we recently identified a nearly perfect correlation between robust and specific patterns of transcription and a variety of defined behavioral experiences. The expression dynamics differ between experiences to the extent that the recent behavioral experiences of individual mice can be inferred solely by examining transcriptional dynamics. We believe this approach, which we term “behavioral transcriptomics”, provides an exciting new platform for studying experience-dependent plasticity at the molecular level, and an entry point for identifying the specific function of gene products in encoding features of salient experiences in defined brain nuclei. Furthermore, information obtained from studying dynamic gene regulation informs us regarding the coding of features of experience, and serves as entry points to investigation of neural circuit plasticity.
Cortical plasticity during the formation of parental care Cohen L. * 1
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Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.
The more we learn about sensory processing in the neocortex, the more it becomes evident how strongly social factors influence processing and storage of information by synaptic plasticity. To shine light on the underlying processes we are studying the influence of social interactions between mice and their pups on parental care formation. On the one hand we are using “retrieval behavior” to study the impact of pup calls onto the structure and function of pyramidal neurons in the auditory cortex of mothers. On the other hand we are investigating, whether and how the auditory cortex circuit of foster mothers changes if they have learned the caretaking solely by social learning. The similarities and differences between the direct and indirect formation of parental care provide valuable insights into social influences and learning and its underpinning in terms of neural circuits. This form of species-specific social behavior will provide valuable insights into synaptic plasticity of cortical circuits in the adult brain. To study cortical synaptic plasticity of pyramidal neurons, the functional identity of a postsynaptic cell and of its individual synaptic inputs needs to be monitored repeatedly to allow the correlation of input and output changes. It is only now with the advent of fast two photon imaging systems and the latest generation of genetically encoded Ca2+ indicators that these questions can be addressed. To achieve this aim we establish new method to express functional and structural indicators in defined single neurons. This allows us to assess the long-term function of single cells and their synapses non-invasively during the formation of species-specific social behavior.
Investigating the effects of tomosyn knock-down in the dentate gyrus on pattern separation Cohen R. *, Ben-Simon Y. , Ashery U. 1
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Sagol School of Neuroscience, Tel-Aviv University
Background: The mossy fibers (MF) synapses connecting the dentate gyrus (DG) granule cells to the CA3 cells (MF-CA3 synapse) have been shown to be essential for spatial pattern separation - a mnemonic-cognitive process, needed for the discrimination of highly overlapping, but not identical, memories. This pathway is also known for its low basal release probability, and high facilitation following a train of stimulations. Tomosyn is a synaptic protein that negatively regulates synaptic transmission, and is highly enriched in the MF-CA3 synapses. Specifically, it interferes with the formation of the SNARE complex, and as a result, the priming step is inhibited and the vesicle release probability (Pr) is reduced. Recent research in our lab has shown that lentiviral knock-down (KD) of tomosyn in the DG increases basal Pr, and greatly reduces the short and long-term synaptic plasticity in the MF synapses. The aim of the current work was to investigate the effects of altering synaptic plasticity of the MF synapse, by tomosyn KD, on animal behavior; using pattern separation as the parameter. To this end lentiviral KD of tomosyn was performed on C57 mice, which were then tested on pattern separation using the contextual fear discrimination task (CFD). Results: Our results indicate a small but significant reduction in pattern separation performance in tomosyn KD animals compared to control animals expressing a scrambled shRNA; as well as a possible slight overall reduction in learning capacity of these mice. Conclusions: The results suggest that the unique synaptic plasticity in the MF, which is known to be tomosyn dependent, is involved in the cognitive process of pattern separation. We now aim to increase the number of cells depleted of tomosyn which are incorporated into memory engrams encoding pattern separation using designer receptors exclusively activated by designer drugs (DREADDs) and stabilized step function opsins (SSFOs).
Studying the adult leech CNS regeneration under electrical stimulation at the single cell level Cohen S.
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*, Shefi O.
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The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar Ilan University Faculty of Engineering, Bar Ilan University Bar Ilan Nanotechnologies and Advanced Materials, Ramat-Gan, 5290002, Israel 1
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Central nervous system (CNS) of adult mammals fail to regenerate following an injury. Invertebrates' CNS, on the other hand, can undergo substantial regeneration with significant functional recovery. Moreover, many invertebrates provide the opportunity to work with identified neurons based on their size, location and characteristic electrical activity pattern within the tissue. Thus, invertebrates serve as a useful model for exploring cell strategies and mechanisms underlying successful CNS regeneration at the single cell level. Electrical stimulation (ES) has been previously
reported as a promoting factor of axonal regeneration in sensory and motor neurons. The effects have been demonstrated mostly in the PNS but there are also experimental evidence for such occurrence in the CNS. For example, low-frequency ES at 20 Hz for a short period was found to be as effective as continuous stimulation over 2 weeks. In this research we aim to study the influence of different ESs on the neuronal growth. We have examined the effects of brief ES (20Hz, 1hr) on the regeneration strategy of the leech CNS at the single cell level over a period of 72 hours. We used an ex-vivo model of the leech ganglia chain. We followed the regeneration process of single cells and compared the regeneration strategy with and without the electrical stimulation. Our preliminary results demonstrated that the dynamics of regeneration and growth rate were affected by the ES. Moreover, the dendritic tree orientation of the regenerated neurons under the ES tended to be more anterior-posterior oriented . The results suggest that ES may (1) contribute for the direction of the spatial orientation of the regenerative axons and (2) influence the normal regeneration time course by interfering in specific time points.
Multiscale interactions in the cerebellar nuclei during natural movement Cohen, D * 1
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The Gonda Brain Research Center, Bar-Ilan University
The cerebellum is thought to play a major role in the production of smooth and coordinated movement, yet, the underlying neuronal mechanisms remain elusive. We chronically recorded and analyzed neuronal activity in the cerebellar nuclei with respect to the actions of freely moving rats. Our data show that cerebellar nuclei neurons dynamically switch between 3 modes of operation: (1) amplification; (2) rectification of local field potential (LFP) oscillations by rhythmic bursting; and (3) non rhythmic firing. The transition between activity modes is non-linearly dependent on the instantaneous LFP power at the theta range during the course of movement. Moreover, manipulation of LFP power by optogenetic stimulation replicated the observed relationship between neuronal activity mode and LFP oscillation power suggesting their causal relationship. Our data highlight a dynamic balance between intrinsic properties of the neuron and the instantaneous extrinsic properties of the network. This statedependent unique LFP-single neuron interaction provides a substrate for a rapid and dynamic control of ongoing movement. The study was financed by a REALNET (FP7-ICT270434) grant from the European Commission.
The time course of consciousness in the Stroop task Dadon G. *, Mesika D. , Lavro D. , Berger A. , Henik A. 1
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ben gurion university of the negev the zlotowski center of neuroscience 2
The time course of conscious cognitive processes is an important factor in understanding cognitive control. The Stroop task, in which participants name the ink color of printed words (Stroop, 1935), is one of the most researched tasks that involves cognitive control. In the current study we examine the time course of facilitation (reaction time for neutral trials minus congruent trials) and interference (reaction time for incongruent trials minus neutral trials) in the Stroop task. Twenty four participants took part in an ERP study. The task was a modified Stroop task in which the interval between the target stimuli (color words) and a mask changed randomly (we had five intervals: 0,16,30,50 and 100ms). Our findings suggest that facilitation and interference start at different poimts in time and might indicate a graded change in consciousness.
Inter-Relationship between Consequences of Brain Mitochondrial Dysfunction and Agents that Promote Mitochondrial Function and/or Autophagy Damri O. , Galila A. * 1 2
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Department of Clinical Biochemistry and Pharmacology and Psychiatry Research Unit, Faculty of Health Mental Health Center, Beer Sheva, Israel 1
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Introduction Mitochondrial (mt.) function is at the nexus of pathways that regulate synaptic plasticity and cellular resilience. The involvement of mt. dysfunction along with increased levels of reactive oxygen species (ROS), accumulating mtDNA mutations and deletions and attenuated autophagy are implicated in psychiatric and neurodegenerative diseases. We have previously induced mild mt. dysfunction using chronic administration of very low rotenone (Rot.) doses, which induce mild respiratory distress. In the present study we aimed to find out whether ROS scavengers and/or autophagy enhancers can ameliorate neuronal mild mt. dysfunction. Results In human neuroblastoma (SH-SY5Y) cells we found: A. A dose-dependent decline of mt. membrane potential following several minutes of exposure to mild to extreme rot. concentrations. B. Semi-chronic treatment with therapeutically-relevant lithium and N-acetyl-cystein (NAC) concentrations rescued SH-SY5Y cells from toxicity induced by semi-chronic very low rot. dose. C. Increased Beclin-1/p62 protein levels ratio were obtained in rot.-treated cells and a further increased ratio was found in the rot.+lithium and rot.+NAC groups. D. ATP levels were below detection limit in the rot.-treated cells; 73% of the control group (no treatment) in cells treated first with rot. and then with lithium, and 100% of the control group in cells treated first with rot. and then with NAC. Discussion The decline of mt. membrane potential following exposure to rot. confirms induction of mt. respiratory distress. The increased Beclin-1/p62 protein levels ratio in rot.-treated cells and the further increased ratio in the rot.+lithium and rot.+NAC groups corroborates with the notion that lithium and NAC augment the cells' effort to cope with rot.-induced toxicity by autophagy enhancement. Overall the results support the notion that ROS scavenging and/or autophagy enhancement can rescue neuronal cells from mt. respiratory damage.
EEG-based Cognitive Load of processing 3D virtual worlds and 2D displays and participants abilities' Dan, Alex , Reiner, Miriam * 1
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Faculty of Education in Science and Technology, Technion
Background We focused on the mental load associated with the learning a paper-folding task using a 2D display compared to a 3D display. The instructor is seen by the learner as a real-time 3D digital “double” or a 2D video. We examined the mental load associated with the simple and complex tasks of following paper folding (origami) instructions and its correlations with participant's abilities. Paper folding abilities were assessed with VZ-2 Brace test. While connected to an electroencephalogram (EEG) system, participants the instructor demonstrating the paper-folding tasks. We recorded alpha and theta oscillations power and calculated Cognitive Load Index as the ratio of the average power of frontal theta (Fz.), and parietal alpha (Pz.) and correlated them with participant's abilities. Results Results showed a significantly higher cognitive load index associated with processing the 2D projection compared to the 3D projection; additionally, changes in the average theta Fz power were larger for the 2D condition compared to the 3D condition. In addition, participants with lower spatial abilities benefited more from the 3D compared to the 2D display. Conclusions Implications are in understanding cognitive processing associated with 2D and 3D worlds, and in employing stereoscopic 3D technology over the 2D displays in designing emerging virtual and augmented reality application.
Age and sex-dependent effects of Olanzapine on weight gain and binge eating behavior in juvenile and adolescent rats
Dar S , Shbiro L , Gil-Ad I 1 2
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, Weizman A
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, Weller A , Taler M 1 2
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Psychology Department Gonda Brain Research Center, Bar-Ilan University Laboratory of Biological Psychiatry Felsenstein Medical Research Center Sackler Faculty of Medicine, Tel Aviv University Research Unit, Geha Mental Health Center 1
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Second generation antipsychotics (SGA) such as Clozapine and Olanzapine (OZ) are effective in reducing positive symptoms of schizophrenia patients but often induce weight gain, severe obesity and metabolic symptoms that are related to increased cardiovascular diseases and hypertension. For years, SGA were given to schizophrenic patients as young as 8 years of age without specific approval and a strong research basis. Because OZ remains superior to other SGA that show less weight gain liability, understanding OZ-induced weight gain mechanisms is crucial. Results from animal model studies have not always been consistent. They are limited to adults and although in humans there are no gender differences in metabolic effect, results are mostly limited to female rats. Here, we compared the effects of chronic OZ treatment in juvenile and adolescent male and female rats. Body weight and food intake were monitored for 3 weeks, and a binge eating test was performed to assess palatable food intake. OZ significantly induced weight gain in juvenile female rats, and tended to increase weight gain in adolescent female rats. In male rats, OZ significantly reduced weight gain in adolescents, and tended to reduce weight gain in juveniles. Interestingly, across sex, OZ had no effect on daily food intake, but significantly reduced juvenile rats’ binge meal size, while increasing adolescent rats’ bingeing behavior. Weight gain results obtained from juvenile females, but not adolescent, rats replicate previous studies in adult rats. Reduced weight gain in OZ treated male rats is consistent with reports in adult rats showing increased body fat compensated by lean body mass reduction. Contrary to the pattern of weight gain results, our binge results seem to correlate well with the clinical observations reported in humans. Thus we suggest a novel approach to modeling OZ induced weight gain and increased craving of palatable food. Central candidate mechanisms are currently being examined. NIPI
Rac1 GTPase and PAK activities in lateral amygdala constrain fear memory formation Das A. , Dines M. , Lamprecht R. * 1
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Sagol Department of Neurobiology, University of Haifa, Haifa Israel,
[email protected] Sagol Department of Neurobiology, University of Haifa, Haifa Israel,
[email protected] Sagol Department of Neurobiology, University of Haifa, Haifa Israel,
[email protected] 1
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Fear conditioning leads to long-term fear memory formation and is a model for studying fear-related psychopathologies conditions such as phobias and posttraumatic stress disorder. Long-term fear memory formation is believed to involve alterations of synaptic efficacy mediated by changes in synaptic transmission and morphology in lateral amygdala (LA). Rac GTPase is a member of the Rho GTPases family molecular switches that cycle between an inactive GDP-bound state and an active GTP-bound form to regulate downstream effectors. Rac GTPase and its downstream effector p21-activated kinase (PAK) are involved in key neuronal functions such as neuronal morphogenesis and transmission. Rac1 is involved in neuronal morphogenesis and intimately involved in the regulation of dendritic spines structure and formation and known to regulate proteins that affect actin polymerization and nucleation.To assess possible roles of Rac GTPase and PAK in fear memory formation in LA, we used a photoactivatable form of Rac1 (PA-Rac1) that can interact and activate its effector proteins when stimulated with light and PAK specific inhibitor. Stimulation of PA-Rac1 in LA by light led to phosphorylation of PAK. PA-Rac1 activation in LA during fear conditioning learning trials impaired long-term but not short-term fear memory formation. Inhibition of PAK in LA by microinjection of PAK inhibitor IPA-3 30 minutes before fear conditioning enhanced long-term but not short-term fear memory formation. Our results demonstrate that Rac GTPase and PAK activities constrain the formation of fear memory in LA. Thus, the level of Rac GTPase and PAK in LA during and following fearful experience will determine whether it will be consolidated into long-term memory or not. Moreover, our research shows that Rac GTPase and PAK proteins may serve as targets for pharmacological treatment of fear and anxiety disorders.
Quantitative Analysis and Classification of Human Pyramidal Cells Deitcher Y , Eyal G , Atenekeng Kahou GA , Telefont M , Mansvelder HD , de Kock CPJ , Segev I * 1 2
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Edmond and Lily Safra Center for Brain Sciences, the Hebrew University of Jerusalem, Jerusalem Departments of Neurobiology, the Hebrew University of Jerusalem, Jerusalem Brain Mind Institute, Ecole Polytechnique Fèdèrale de Lausanne, Lausanne, Switzerland Department of Integrative Neurophysiology, VU University Amsterdam, Netherlands 1
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Dendritic morphology is a key factor in determining information processing at the single cells and network levels. In the present study, we have characterized unique human data, consisting of 60 3D reconstructed pyramidal cells from L2/3 of the human temporal cortex. For each cell, 32 features were extracted for characterization of the morphological properties of each cell in our database. Systematic classification of the L2/3 human pyramidal neurons population showed a gradual depth-dependent change in morphological features in these neurons. The gradual depthdependent change is found in multiple features, such as the degree of ramification of the apical and basal dendritic tree. Out of 32 different features, 18 features show a significant (p6 in a 10 point scale) and recovered almost completely within 20 days, with no observed differences between genotypes. We therefore next subjected the apoE3 and apoE4 WT mice to a less severe trauma, utilizing the mTBI paradigm. The overall response of the mice was indeed milder (initial NSS=~4), yet the recovery was also similar between apoE4 and apoE3 mice. The mice were then subjected to a second insult on day 7. Following this, apoE4 WT mice had a significantly higher NSS compared to the apoE3 WT mice. In addition, apoE4 WT mice showed a significantly slower recovery over the next days. In conclusion, these findings suggest that the synuclein deficiency masks any differential effects of apoE4 on the recovery from head trauma. However, in apoE WT mice, like in humans, apoE4 increases the susceptibility and impairs the recovery from mild head injury.
Exploring the preservation of specificity in 'visual' areas of the human congenitally blind brain using the EyeMusic Sensory Substitution Device and fMRI imaging Maidenbaum S. *, Abboud S. , Dehaene S. 1 2
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, Amedi A.
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Medical Neurobiology, IMRIC, Hebrew University of Jerusalem ELSC, Hebrew University of Jerusalem CEA, I2BM, NeuroSpin center, Gif sur Yvette, France Collège de France, Paris, France INSERM, Cognitive Neuro-imaging Unit, Institut Fédératif de Recherche (IFR) 49, Gif sur Yvette, Fran Cognitive Science, Hebrew University of Jerusalem 4Sorbonne Universités UPMC 06, Institut de 1
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Background:Over the past decade a series of 'visual' brain regions with preferred specificity for certain categories of stimuli have been located and researched. For example, the Visual Word Form Area (VWFA) shows preferential selectivity for the letter shapes and the Visual Number Form Area (VNFA) shows selective preference for the number shapes. What happens to these regions in congenital blindness? How large a part does vision take in driving and creating this preference? what is the contribution of shape biases to its formation and whether visual processing underlies it? These questions are especially intriguing in the case of the above categories, which only became relevant very recently on an evolutionary time scale yet still show anatomical consistency across human brains. How do we have regions dedicated specifically to letters or numbers if we only started using these concepts several thousand years ago? Here we use congenital blindness as a model for brain development without visual experience. Results: During fMRI, we present blind subjects with shapes encoded via The EyeMusic, a novel visual-to-auditory Sensory Substitution Device which can convey whole scene visual information such as location, shape and color via audition. We find that greater activation is observed in the rITG when subjects process symbols as numbers compared with control tasks on the same symbols. Using resting-state fMRI in the blind and sighted, we further show that the VWFA and VNFA exhibit distinct patterns of functional connectivity with language-processing and quantity areas, respectively. Conclusions: These findings suggest that specificity in the ventral ‘visual’ stream can emerge independently of sensory modality and visual experience, under the influence of distinct connectivity patterns. Finally, we will discuss low-level visual features such as color – will such features also emerge independently of sensory modality and visual experience? To what extent will they do so? European Research Council grant (310809); McDonnell Foundation (220020284); ISF (ISF 1684/08); ELSC
Preclinical drug development strategy for neurodegenerative diseases Mandel S.A. *, Orbach A. 1
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Pharmacology-Teva Pharmaceutical Industries
Converging evidence suggests that thepathophysiology of neurodegenerative diseases (NDDs) begin years, if notdecades, prior to the onset of clinical symptoms, including memory impairment,motor disturbances and non-motor related abnormalities. Significant efforts areput in the development of novel drugs engaging biological targets with apotential for neuroprotection and to address symptomatology with compoundsdirected towards biochemical systems that might contribute to a significantrelief in patient’s quality of life. Despite the promising findings withleading compounds in preclinical animal studies, this has not translated intothe clinical arena. A main challenge is to find the meaningful biologicaltargets for development of modifying/neuroprotective drugs to treat NDDs. In my talk I will present an overview ofdrug discovery and development, with emphasis on the preclinicalpharmacological activities supporting an Investigational New Drug (IND)application. These include non-clinical studies on safety, absorption,distribution and metabolism, brain access to relevant tissues and drug efficacytesting. The case of NDDs presentsunique characteristics to consider at both non-clinical and clinical level suchas their chronic nature, advanced age at onset and co-morbidity with otherconditions associated with aging as digestive and metabolic-relateddisturbances, diabetes and inflammation. Thus, an effective preclinicalstrategy must anticipate difficulties early in drug development and identify thosemolecules with potential of success in the clinics.
Identifying Positive and Negative autobiographical Memories from fMRI scans using feature selection in machine learning techniques Frid A. *, Manevitz L. M. , Nawa E. N. 1 2
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Edmond J. Safra Brain Research Center for the Study of Learning Disabilities, University of Haifa Neurocomputation Laboratory, CRI, University of Haifa CiNet, Center for Information and Neural Networks, NCTA, Osaka, Japan 1
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Background: Recently, Nawa and Ando showed that certain self-driven mental tasks can be classified from whole brain activity patterns in fMRI scans. They showed there that autobiographical memories with positive valences (or negative valences) can be reliably separated from neutral tasks (e.g. backwards counting tasks). However, they partial success in separating the positive valence memories from negative ones, which on the surface seems like a rather delicate distinction. Their methodology there was to use the entire brain as the data. Results: In this work, we show that using the same scan data, the valence of the memories can be reliably classified to positive or negative by using the "relieff" feature selection technique. This technique uses a multivariate neighborhood to judge the importance of features (in analogy with "searchlight" techniques). Classification results within patients using only 1000 voxels: separating memory (negative and positive) task from counting task was 98%, and between the negative and positive memory tasks 82%. Conclusions: 1. Autobiographical memories can be classified automatically by their valences using machine learning techniques when coupled with feature selection techniques on fMRI data. 2. The methodologies used here can be evaluated in the future to investigate the relative importance of voxels for the valence of a memory.
EFFECT OF SEIZURES ON CEREBRAL EXPRESSION OF ESSENTIAL COMPOUND CARRIERS IN THE RAT Mann A. , Ekstein D. , Ben Hur T. , Eyal S. * 1
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Institute for Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel Department of Neurology, Hadassah Hebrew University Medical Center, Jerusalem, Israel 1
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Background: Epilepsy is a brain disease affecting approximately 65 million people worldwide, one third of which are pharmacoressistant. While clear evidence suggests disruption of the electrolytes and neurotransmitter balance in the epileptic brain, the effect of the disease on entry mechanisms of essential compounds, such as folic acid, thyroid hormones and monocarboxylates, are yet to be elucidated. These compounds are known to play an important role in proper cellular function and metabolism and their deprivation is associated with numerous CNS disorders, including depression and cognitive decline. It is therefore our goal was to characterize the effect of seizures on major essential compounds transport pathways into the brain. Results: Our initial analysis demonstrated upregulation of the expression of two evaluated folate transport mechanisms in the CA1, of rats with pilocarpine-induced chronic epilepsy compared to controls. We also observed a statistically insignificant increase in the expression of the monocarboxylate transporter in the CA1 of the same rat group. Conclusions: The altered expression of folate transport mechanisms suggests an effect of seizures on the transport of this essential compound into cerebral cells. Further studies are now being conducted in order to evaluate the impact of seizures on other carriers and its significance. The National Institute for Psychobiology in Israel (NIPI)
Functional microarchitecture of excitatory versus inhibitory neurons in layer 2/3 of mouse auditory cortex Maor I. *, Shalev A. , Mizrahi A. 1 2
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Department of Neurobiology, The Hebrew University of Jerusalem The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem 1
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Structure and function of neural circuits are inherently linked. In the auditory system, early neural stations like cochlea and brain stem are characterized by strict tonotopy, which is used to deconstruct sounds to their basic frequencies. But higher along the auditory hierarchy, as early as primary auditory cortex (A1), tonotopy starts breaking down at local circuits. This architecture is consistent with the argument that neurons in A1 show computations of complex sound features. However, whether and how the functional microarchitecture of A1 supports complex sound feature computations is not known. Moreover, cortical networks are composed of numerous cell types, which may show different architectures that could support different functions. Here, we studied the functional microarchitecture of excitatory versus inhibitory neurons in layer 2/3 of mouse A1 within 150mm3 cortical volumes. We used in vivo two photon targeted cell attached recordings from spatially and genetically identified inhibitory neurons (parvalbumin positive neurons, PVNS) and their excitatory neighbors intertwined within the local circuit. We show that excitatory neurons have heterogeneous functional organization as characterized by a diversity of characteristic frequencies (upto 3 octaves apart) as well as highly diverse pairwise signal correlations (average correlation close to zero). These data support our previous mapping experiments using calcium imaging. Interestingly, and in marked contrast, PVNs exhibited highly homogenous functional organization. PVNs characteristic frequency distribution was narrow and their pairwise signal correlations strongly skewed to positive values (average 0.4) as compared to those of neighboring excitatory neuronal pairs. The distinct functional organization of excitatory and inhibitory cortical neurons reflect the connectivity differences among different cell types and has implications to how sensory information is processed by A1.
Functional processing along the hippocampus longitudinal axis Markus E *, Lee T , Schmidt B , Marrone D 1
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Psychology, Univ of Connecticut Psychology, Wilfrid Laurier Univ 2
The link between the hippocampus and memory and spatial navigation is well known. However the hippocampus is not a homogenous structure. Determining the manner in which different regions work in parallel and/or interact will provide a better understanding of how this system processes memory. I will present LFP oscillations, IEG and behavioral strategies we have used that try and address these issues. The data indicate that both the dorsal and ventral hippocampus are involved in spatial navigation. However there are differences between these regions in processing information. The question of interaction between these regions is less clear with data pointing to both independent and interactive processing. There may be increased integration and cooperation throughout the hippocampus with increased hippocampal task demands.
The effects of anaesthesia on sensory processing: Propofol sedation modulates responses in high-order auditory cortex but not in A1: a single-unit and intracranial EEG study in humans Krom A. J. *, Marmelshtein, A. , Gelbard-Sagiv, H. , Tankus, A. , Hayat, D. , Strauss, I. , Fried, I. , Nir, Y. 1 2
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Sackler School of Medicine, Tel Aviv University Dept of Anaesthesia, Hadassah Ein Karem University Hospital, Jerusalem Sagol School of Neuroscience, Tel Aviv University Functional Neurosurgery Unit, Tel Aviv Medical Center Dept of Anaesthesia, Tel Aviv Medical Center Dept of Neurosurgery, University of California Los Angeles 1
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Background: It is still unclear how, despite diverse molecular and cellular mechanisms, a wide range of anaesthetics all bring about loss of consciousness (LOC), and how responses to identical sensory stimuli compare between wakefulness and anaesthesia. In particular, it is unclear where along the auditory hierarchy sensory processing robustly changes during LOC. Methods: Here, we recorded bispectral index (BIS), scalp electroencephalogram (EEG), intracerebral EEG, and single-unit firing in multiple brain regions of neurosurgical epilepsy patients as they were sedated for routine deplantation of intracranial depth electrodes serving for clinical monitoring. Propofol infusion rate was adjusted gradually over 35-55 minutes to achieve unresponsiveness with spontaneous ventilation (BIS reduced ≈95 to ≈70). Auditory stimuli, including simple 40Hz clicktrains (who's scalp EEG auditory steady-state response (ASSR) is known to reduce with LOC) and words, were delivered intermittently during wakefulness and as sedation deepened. Results: Preliminary results (n=4) suggest that the magnitude, coherence and spatial distribution of the 40Hz intracerebral ASSR changed with depth of anaesthesia, with responses in anterior, inferior, superior and posterior aspects of the temporal lobe attenuating by 7-90% after LOC. In contrast, the local 40Hz ASSR within the primary auditory cortex in one individual was comparable between states of wakefulness and anaesthesia. Single-unit responses to specific words as well as to the 40Hz click trains were identified in one individual implanted with electrodes in the Superior Temporal Gyrus (planum temporale), and these responses were robustly modulated upon increasing sedation and full LOC. More specifically, the late portion of the responses was more sensitive to anesthesia than the early (onset) response. Conclusion: These results suggest that the effects of state-dependent sensory processing may occur mostly beyond primary sensory cortices.
Telling Time: Constraints from Dynamics of Excitability Marom S. * 1
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Physiology, Medicine, Technion
Contemplating brain representation of temporal features, it is instructive to begin by clarifying constraints imposed by mechanisms underlying excitability — the most elementary functional process in neural systems. Analyses of excitability dynamics at the single neuron level, amid stimuli with a range of temporal statistics, will be presented. Theoretical, methodological and functional implications will be discussed.
DIFFERENTIAL EFFECTS OF STRESS ON EXTINCTION AND MEDIAL PREFRONTAL CORTEX PLASTICITY IN THE POST-WEANLING AND ADULT ANIMALS Maroun, M 1
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Sagol Department of Neurobiology University of Haifa Haifa, Israel 2
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Background: The neural circuit linking the medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA) has crucial roles in both the acquisition and the extinction of fear conditioning in both adult and post-weanling pup. We have previously shown that in the adult animal, exposure to acute stress was associated with impaired extinction and inhibition of the induction of long-term potentiation (LTP), the hypothesized cellular model for memory formation. This data hints on the relevance of changes in plasticity to extinction of fear. Results: We recently addressed whether similar effects are evident in the post-weanling pup, and our results show that contrary to the prevailing notion, stress resulted in enhanced extinction and mPFC-LTP.These results show that stress deferentially modulates extinction and plasticity in the post-weanling pup as compared to the adult animal. Conclusions: These findings imply that different attitudes should be taken while treating youngsters/ children suffering from stress-related anxiety disorders. Supported by ISF grant to MM (663/13)
Beta oscillations in the MPTP treated primate: Similar modulations across different populations Matzner A. *, Bar-Gad I. 1
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Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel
Background: Parkinson's disease is characterized by excessive oscillatory activity in the beta band across basal ganglia (BG) nuclei. Estimation of the power spectrum is a common method for identifying oscillations. However, the stochastic nature of neuronal activity leads to severe biases in the estimation of these oscillations in single unit spike trains, arising from biological and experimental factors. Results: We analyzed the effect of factors such as the mean firing rate and the recording duration on the detectability of oscillations and their significance. We demonstrate the biases computationally, formulate them analytically and validate their occurrence in neurons recorded from the globus pallidus internus (GPi), globus pallidus externus (GPe) and subthalamic nucleus (STN) of Parkinsonian non-human primates. Next, we introduce a novel objective measure, the "modulation index", which overcomes these biases, and enables reliable detection and a direct estimation of oscillations from spike trains. The modulation index demonstrates an unbiased detection of beta band oscillations (BBO) in the BG nuclei during Parkinsonism. Using the modulation index we showed that the magnitude of oscillations of individual neurons is similar between the GPi, GPe and STN, whereas the fraction of oscillatory populations is different between the nuclei. Conclusions: Biological and experimental factors dramatically affect the estimation of the magnitude of spike train oscillations, and their detectability. This bias prevents an independent comparison across brain regions, neuronal types and different recording sessions with varying recording durations. The modulation index measure overcomes these biases and enables an unbiased comparison between spike trains. Analysis of BBO in the BG circuits using the modulation index suggests complex interactions between different nuclei, which involve different subpopulations through the BG nuclei that maintain similar levels of oscillation. We thank Anan Moran, Yaara Erez and Hadass Tischler for the experimental data.
fMRI analysis without a design-matrix: a model-free approach Mazor M. , Mukamel R. * 1
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Sagol School of Neuroscience, Tel-Aviv University School of Psychological Sciences, Tel-Aviv University 2
Background: The hemodynamic response function (HRF) is known to vary widely across subjects and brain regions. This fact, which is acknowledged but not commonly taken into account, limits the power and accuracy of model-based approaches to fMRI analysis (including the widely used General Linear Model). Accurate HRF modelling is especially pertinent when using event-related experimental designs and analysis. To circumvent this problem, we propose a novel analysis scheme (Time-Course Consistency; TCC) that is independent of any assumptions regarding the underlying HRF, and is thus invariant to idiosyncratic differences in neurovascular coupling. We also introduce an experimental design (“TWISTER”), which utilizes these advantages . We present the results of a validation experiment that suggests this method performs well, both in terms of sensitivity and specificity. Results:Healthy subjects performed a simple house-face discriminationtask using right/left -hand button presses inside the scanner. By using the TCC analysis scheme with a TWISTER design, we successfully identified the bilateral primary motor hand areas as showing higher sensitivity to the type of motor actions (right or left hand button presses) than to the visual stimuli category (faces or houses), and the bilateral fusiform gyrus as showing an opposite pattern. Importantly, these results were obtained without explicitly modeling the timing of events within each experimental run and without committing to a certain structure of the HRF (i.e., no design matrix). Conclusions: We propose a new framework for the design and analysis of functional MRI data in cognitive research. Being model-free, this method bypasses the need to account for differences in neurovascular coupling between brain regions and across different subjects. This can be particularly useful in the study of populations (such as the elderly) and brain regions (such as sub-cortical regions) that do not adhere to the canonical HRF.
On the role of sensory adaptation in motor control Meir R.
1 2 3 4
*, Harel Y.
, Opper
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Electrical Engineering Technion Haifa 32000 Israel Department of Artifcial Intelligence Technical University Berlin Berlin 10587 Germany 1
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Sensory adaptation is often viewed within ecological theories of perception where it contributes to improve neural coding by taking advantage of the salient statistical features of the environment. While such enhanced encoding is usually considered in an open loop setting, animal behavior typically takes place in closed loop where perception subserves action selection, which itself modifies the perceptual input. Thus, perception and action must be viewed within a perception-action cycle. Based on recent experimental work showing that motor learning leads to task-dependent sensory adaptation, we use Optimal Control Theory to study sensory adaptation within open loop (purely perceptual) and closed loop (control) settings, showing that they lead to different predictions. This implies that sensory adaptation must be considered within a broad behavioral setting incorporating perception and action jointly. In a broader setting, top-down effects, task-dependent and otherwise, have been shown experimentally to contribute to early sensory processing, thereby inspiring the development of a theoretical framework for such phenomena.
The Relation of Sign and Kind of Emotions during Video Clips Watching and EEG Systemic and Informational Characteristics Mekler A. *, Muss A. , Galperina E. , Kruchinina O. 1
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Saint-Petersburg State Pediatric Medical University, Russia,
[email protected] Saint-Petersburg State University, Department of psychology, Russia Saint-Petersburg State Pediatric Medical University, Russia Sechenov Institute Of Evolutionary Physiology And Biochemistry Russian Academy Of Science 1
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Background. There are number of studies on the brain electrical activity during positive and negative emotions. Among them, some studies on the EEG complexity are also known (e.g., Aftanas 1998, Liu, Surina, Nguyen, 2011). This approach discovers the systems changes in brain activity organization during emotions of different kinds. However, to our opinion there is a reason to use more differentiated approach to emotions under study. In our study, we divided emotions into four groups by two oppositions – positive/negative and vital/ethic. The latter allows distinguishing emotions related to basic needs as fear or disgust and those, which are on the highest levels of mind. In our work, we studied systems and informational characteristics of the brain activity in emotions of designated four kinds. For stimulation of emotions, we used short video clips. We conducted a standalone experiment in order to select proper recordings. As a result, several video recordings for each group of emotions were selected. In the main experiment, EEGs were recorded during video clips watching. International system 10-20 was used. For further processing, we used EEGs in the band 0.5 – 70 Hz with removed visually noticeable artifacts and applied notch filter. The following values characterizing systemic and informational processes were calculated – correlation dimension of reconstructed attractor (D2), fractal dimension of the EEG curve (D0), Lempel-Ziv Complexity (LZC) and Shannon’s entropy (SE). Results. Statistical analysis showed significant increasing of D2, LZC, and D0 in any emotional watching state in comparison to relaxed state with open eyes. Also in some leads complexity measures increased in positive emotions in comparison to negative and in ethic emotions in comparison with vital ones. Conclusions. Results of the presented study lead to conclusion that complexity may be a universal value for mental processes as well as for physiological. Study was supported by the RFBR grant #14-06-00248
Large-scale, cell noninvasive in vitro electrophysiological recordings by self-assembled loose-patch-like junctions between cultured neurons and mushroom-shaped microelectrodes Micha E. Spira*
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*, Nava Shmoel , Noha Rabieh , Silviya M. Ojovan , Eilon Maydan , Hadas Erez 4
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Department of Neurobiology, The Alexander Silberman Institute of Life Science. HUJI the Harvey M. Kruger family Center for Nanoscience HUJI The C. Smith Family and Prof. J. Elkes laboratory for collaborative research in Psychobiology HUJI 1,2,3 1,,2,3 1
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Substrate integrated planar microelectrode arrays is the golden grail method for millisecond-resolution, long-term, large-scale, cell-noninvasive electrophysiological recordings from mammalian neuronal networks. Nevertheless, these devices suffer from drawbacks that are solved by spikedetecting, spike-sorting and signal-averaging techniques relaying on estimated parameters, require the user supervision to correct errors, merge clusters and remove outliers. Here we demonstrate that primary rat hippocampal neurons grown on micrometer size gold mushroom-shaped microelectrodes (gMµE) simply functionalized by poly-ethylene-imine/laminin undergo self-assembly processes to form loose patch-like hybrids structures. More than 90% of the formed hybrids record monophasic positive action potentials (APs). Of these, 34.5% record APs with amplitudes above 300 µV and up to 5000 µV. The self-assembled neuron-gMµE configuration improves the recording quality by an order of magnitude in respect to planar MEA. In the presentation we will characterize and analyze the electrophysiological signaling repertoire generated by the neuronsgMµEs configuration, and discuss the prospective to further improve the technology. supported by the EU FP7 Future Emerging Technology program, a “B A L AP” grant o. 3 6
Magnetic nanoparticles for manipulating neuronal growth and differentiation Michal M. , Karni M. , Alon N. , Baranes K. , Levy I. , Yamin T. , Margel S. , Sharoni A. , Shefi O. * 1 2
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Faculty of Engineering, Bar Ilan University Institute for Nanotechnology and Advanced Materials, Bar Ilan University Chemistry, Bar Ilan University Physics, Bar Ilan University 1
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The ability to manipulate neuronal organization and growth has extensive implications in neuronal regeneration and tissue engineering. It has been shown that physical forces play a key role in shaping neuronal structure and in interactions between neurons and their vicinity. In the present study we use magnetic nanoparticles (maghemite, γ-Fe2O3) as mediators to apply physical forces locally and as carriers of neuronal growth factors. We use these nano-complexes in order to locate cells, promote neuronal growth and affect growth orientation. We generated magnetic fields with controlled magnetic flux densities at multiple scales of size and strength. We fabricated a unique device, embedded with micro-patterned pads that can be magnetized selectively. We incubated PC12 cells and primary neurons in medium enriched with iron oxide nanoparticles conjugated to fluorescent tag. Both types of cells uptake the nanoparticles and turned sensitive to the magnetic stimulation with no cytotoxic effect. Plating PC12 cells atop the micro-patterned device has led to an organized network of clusters of cells. Currently we are mathematically modelling nanoparticles uptake by cells and the organization of magnetized cells in response to various external magnetic fields. In addition, we found that covalent conjugation of the magnetic nanoparticles to nerve growth factor (NGF) which is a critical component in nerve tissue development and repair enhanced the typical effect of NGF. Morphometric and molecular measurements revealed that treatment with the nanoparticle-NGF complex leads to a promoted differentiation progression and to more complex dendritic trees. Stability and signaling pathway assays suggest conjugation to NPs as a method to extend the half-life of NGF, thereby increasing its availability and efficiency. Our study presents an emerging magneto-chemical method for the manipulation of neuronal migration and growth opening new directions in non-invasive neuronal repair.
Detecting cell types from neuronal connectomes Mintz G. *, Sompolinsky H. 1 2
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ELSC, Hebrew university in Jerusalem Racach institute of physics, Hebrew university in Jerusalem 2
The field of connectomics promises to quantify the connectivity between all neurons within a tissue volume, such as a single barrel in rodent somatosensory cortex. Given the inevitable variability of the local circuit from one region to a nearby one (e.g., variability across different cortical columns), and across time and individuals, an important goal of connectomics is to extract from small copies of wiring diagrams the underlying statistical connectivity rules. Furthermore, these rules may reveal insight into the structure-function relation of the circuit. I will describe work aimed at detecting cell types from neuronal wiring diagrams. Here we classify cells into types by the statistics of their connectivity to other cells; this classification may or may not coincide with traditional morphological and molecular-genetic classification. We use the Stochastic Block Model (SBM) on directed graphs as a generative model to simulate the connectivity of a local cortical circuit. We use an approximate Bayesian inference method and statistical mechanics to extract from an observed wiring diagram the statistical connectivity rules, as well as the type of each cell in the circuit. We apply the method to a connectome of the rat barrel cortex, estimated from detailed 3D reconstructions of cell morphologies and their locations. Our work can be used to identify some of the key features that determine the ability to extract cell types and other connectivity rules from dense cortical connectomes. We also discuss the necessary corrections that need to be introduced into the model to better account for real data.
A novel chemo-optogenetic model of focal inducible epileptic seizures Mitelman R *, Levy DR , Lampl I , Yizhar O 1
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Department of Neurobiology, Weizmann Institute of Science
Background: Epilepsy is a common, devastating neurological disorder, manifested by synchronized neuronal seizures that start in a small brain area and rapidly spread to remote brain regions, impairing perception, cognition and motor functions. However, studies of epileptic seizures in animal models are limited due to the lack of focal epilepsy models in which seizures can be induced in a highly reproducible manner. Results: We have developed a novel chemo-optogenetic model that enables light-inducible seizures, with high reproducibility at a defined cortical locus. This was achieved by co-expressing chemogenetic an engineered inhibitory receptor (hM4D) along with channelrhodopsin in inhibitory interneurons of the medial prefrontal cortex, by stereotactically injecting adeno-associated virus (AAV) to GAD2-Cre transgenic mice. Seizure activity was monitored by in vivo EEG recording synchronized with camera imaging of the animals. Systemic application of the synthetic ligand (CNO) silences these neurons, thereby causing an initial behavioral and electrical seizure, as expected by silencing of inhibition. After this initial seizure, brief activation of these same neurons with light induces paradoxical, reproducible focal seizures. Systemic pre-treatment of mice with NKCC1 transporter blocker Bumetanide eliminated the induction of seizure activity by light. Conclusions: We present a novel model of focal epilepsy, initiated by local silencing of GABAergic interneurons and reproducibly induced by activation of the same neuronal population. These paradoxical seizures might be explained by changes in the reversal potential of GABA, as a result of re-expression of the NKCC1 transporter, which is not normally expressed in the healthy adult brain. Furthermore, with this model of inducible seizures we will be able to estimate many aspects of epileptic seizures in vivo, such as their spatiotemporal progression and changes in the balance between excitation and inhibition.
System-level organization of the neurovascular unit along the mouse lemniscal pathway
Mitiagin Y. , Blinder P. * 1
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Department of Neurobiology, Faculty of Life sciences, Tel Aviv University Sagol School of Neuroscience, Tel Aviv University 2
Background: The concept of neurovascular coupling, i.e. the relationship between local neural activity and subsequent changes in cerebral blood flow, is widely used in neuroscience. This process enables proper brain function and underpins the mechanism behind functional magnetic resonance imaging (fMRI). Despite such a key role, we still lack a precise understanding of the topological relationships between vascular and cellular “units”. Moreover, contrary to the accepted view, a recent morphological analysis showed no precise topological pattern between vascular and neuronal units. Prompting the question whether the observed topological organization represents a cortical property or a general building principle. Interestingly, studies have found region specific differences in neurovascular coupling and electric activity along the rat lemniscal pathway. There, neuronal units are evident from their cytoarchitecture and represent functional and structural modules, making this pathway suitable for structural studies. Results: Our study found no structurally defined neurovascular unit, nor pattern-like organization of the vasculature along this pathway. However each station along the lemniscal pathway presented unique vascular morphological characteristics.
Immune mechanisms in the progression and treatment of Alzheimer's disease Monsonego A. * 1
1
Ben-Gurion University
Alzheimer’s disease (AD) is the most common form of dementia, with prevalence progressively increasing with aging. Pathological hallmarks of the disease include accumulation of amyloid-beta (Aβ) peptides and neurofibrillary tangles in the brain associated with glial activation, synpatotoxicity and neural loss. In addition, AD involves age-related lymphocyte dysfunctioning, declined immunity, chronic inflammation and impaired brain-immune interactions. The lecture demonstrates cellular and molecular inflammatory changes in the brain caused due accumulation and deposition of Ab. I will then describe immunogenic characteristics of Aβ in human and mice and discuss immunotherapeutic approaches for AD in light of the possibility that cognitive decline is accelerated due peripheral and brain-endogenous immune cell malfunctioning.
The roles of sensory cortical single neurons and the ensemble dynamics during adaptive behavior: Insights from the gustatory cortex Moran A. * 1 2
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Department of Neurobiology, Tel Aviv Univrsity Sagol School for Neuroscience, Tel Aviv University 2
The ultimate goal ofsensory processing in the brain is driving an appropriate behavior to a streamof sensory input. In this scope, sensory cortical single neurons aretraditionally considered to code the physical properties of the external world,such as visual bar orientation, sound frequency or taste identity. It is slowlybecoming clear, however, that sensory cortical neurons are also sensitive to along list of influences including expectations, information from othermodalities, attention, and the stimulus valence. So what is the role of sensorycortical neurons in the context of behavior? To answer this question we recordedsingle neuron responses from the gustatory cortex (GC) of freely behaving ratswhile they initially liked a sweet taste, then learned to dislike it, and thenliked it again, all in as short as 49 hours. We have found that the majority ofGC single neuron responses had changed with experience, thus rejecting the ideaof the sensory cortex only coding physical properties of the external world.Moreover, their response changes across the experiment were not following thebehavior. Recent studies reporting taste-specific ensemble activity states inGC had led us to hypothesize that true tracking of behavior is only appreciatedin the level of the population dynamics. Using hidden Markov models (HMM) werevealed those underlying population activity states and indeed found thattheir dynamics were following behavior with a fidelity not present at thesingle neuron level. This work emphasizes the role of the ensemble and the neuralnetwork in driving cognition and behavior. Much is still unknown, though, aboutboth the plasticity rules governing changes in the single neuron level and themutual roles played by other nuclei in experience based behavior This work was partially funded by the NIH and AM was supported by the Sloan-Swartz Foundation
Large, late population responses to stimulus specific adaptation (SSA) resemble mismatch negativity (MMN) time course Moshitch D. *, Sehrawat K. , Nelken I. 1 2
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Neurobiology, Hebrew University The Edmond and Lily Safra Center for brain sciences, Hebrew University 2
Background: Stimulus-specific adaptation (SSA) is the reduction in the response to a common stimulus that does not generalize, or only partially generalizes, to other, rare stimuli. SSA has been proposed to be a correlate of ‘deviance detection’, an important computational task of sensory systems. Electrophysiological correlates of deviance detection have been studied in depth in humans using a number of brain potentials. The best known of these is mismatch negativity (MMN), which peaks ∼ 150–200 ms after the deviance point. SSA is similar, but certainly not identical to MMN. One known difference between SSA and MMN is the time course of the response. SSA ‘rides’ on the early cortical responses to sounds ∼40 ms after stimulus onset, while MMN is substantially later (∼150–200 ms). This late response is not entirely absent in the single cell level but is highly variable in single trials and thus hard to discriminate from spontaneous activity. Results: Lately we recorded calcium signals using the multicell bolus loading technique. Our readout method is an optical fiber which enables the recording of calcium signals coming from the average spiking activity of a local network of neurons. We recorded the calcium transients in response to pure tones embedded in SSA-evoking and control sequences. We discovered late responses at about100-150 ms after stimulus onset. These responses are reliable, large, and clearlypass the standard tests for deviance detection. Conclusions: We discovered, for the first time, late responses that resemble the MMN potential time course. Our working hypothesis is that a large number of neurons fire at the late time window so that the net average response of the whole population seen in the calcium transients sums up to a large late coherent activity, but that the identity of these neurons shift from trial to trial, so that each single neuron respond inconsistently across trials.
The brain systemic and information processes while listening to different kinds of music Mekler A. *, Spiridonov E. , Muss A. , Kruchinina O. 1
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Saint-Petersburg State Pediatric Medical University, Russia,
[email protected] Saint-Petersburg State University, Department of psychology, Russia Sechenov Institute Of Evolutionary Physiology And Biochemistry Russian Academy Of Science 1
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In presented work, we studied the systemic characteristics of the brain processes in listening to different kinds of music. On the first step, we selected the music extracts by emotions they produce. With this purpose, a number of short fragments of classical music were listened by 30 subjects. Each fragment was evaluated according to Differential Emotions Scale (DES, Izard, 1974). Then we selected those fragments, which induce a small number of emotions listed in the DES. Thus, we got three groups of music fragments – inducing positive emotions, negative “sthenic” and negative “asthenic” ones. During the next stage of the study EEG recordings were made during listening to the selected music fragments. EEG was recorded using international system 10-20 in the frequency range 0.5 – 70Hz and the notch filter at 50Hz. We calculated
numerical values that characterize bran systemic and information processes – correlation dimension of the reconstructed attractor (D2), fractal dimension of the EEG curve (D0), Lempel-Ziv complexity (LZC) and Shannon entropy (SE). Statistical analysis showed the decreasing of the EEG complexity (D2) in any condition of the listening to music in comparison with the relaxed state with open eyes (P3 and P4). In the lead F3 in positive emotions D2 is greater than in negative stenic. In negative stenic is less than in negative astenic in the leads Fp1 and F4. Conclusions. In general, one can say that EEG complexity while listening music that stimulates positive emotions is greater than negative ones and while asthenic emotions is greater than sthenic. Study was supported by the Russian Foundation for Humanities grant #14-06-00925
Examining network connectivity associated with the Sustained Attention to Response Task Naim-Feil, J *, Levit Binnun, N , Freche, Nick , Rubinson, M , Moses, E 1 2
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Physics of Complex Systems, Weizmann Institute of Science Sagol Centre for Neuroscience, Interdisciplinary Centre, Herzliya Sagol Centre for Neuroscience, Interdisciplinary Centre, Herzliya 1
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A key objective of cognitive neuropsychology is to examine the neural architecture that underlies cognitive function. Advances in neuroimaging techniques have suggested that adequate cognition rely on cortical structures which recruit an interconnected network of brain regions. Only recently, neurophysicists suggested a model of network connectivity in which topological measures based on Graph Theory quantify complex networks of the human brain. Therefore, the current study utilized these novel techniques to examine the network metrics associated with cognition and whether network analysis is sensitive enough to index network differences associated with cognition. We administered the Sustained Attention to Response Task (SART) to 29 healthy controls while simultaneously measuring electroencephalography (EEG). Our first objective was to examine whether the globally emergent network properties of the baseline condition (no task) differ from the effortful task condition. Our second objective was to explore whether network analysis is sensitive enough to identify different network dynamics associated with the GO condition (sustained attention) relative to the NOGO condition (response inhibition). Our study demonstrated a significant dampening of network metrics (such as reduced global efficiency) in the baseline condition (no task) relative to both of the active task conditions (GO and NOGO). Furthermore, in the active task condition, we show that the sustained attention (GO) condition was represented as a more widely-distributed, connected, globallyefficient and resilient network than the response inhibition (NOGO) condition which relied on a smaller but more centralized network dynamic.These preliminary findings support network analysis as a useful tool for the quantification of the global networks that are fundamental to cognitive function.
A Feature Conjunction Paradigm in Rats: Preliminary results on choice biases Nelinger G. *, Assa E. , Sabrialabed S. , Ahissar E. 1
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Neurobiology dept., Weizmann Institute of Science, Rehovot, Israel Biochemisty dept., Hebrew University of Jerusalem, Rehovot, Israel 2
Background: Feature integration into objects has been proposed to require the focusing of attention on a specific location. Acquisition of individual features, in contrast, was suggested to rely on low level mechanisms, via gradually convergent changes of motor and sensory variables leading to a steady-state. The current research seeks to examine the role of low-level immediate feedback and convergence in feature conjunction, using a novel object identification task. Results: Rats were trained to associate different objects with different reward locations. The three objects introduced could differ from one another by either shape, texture, or both. Two out of four rats learned the task to a level that allows systematic analysis. We analyze behavioral patterns indicative of perceptual processes, decision biases, whisking strategies and whisker-object interactions. Our rats exhibited two dominant decision biases. The first was locomotion based, which effectively dichotomized the task. The second was training based and reflected reward probabilities encountered during initial training. Analysis of choice behavior, given these biases, suggests that Rat 1 based its decision on texture (rough vs smooth) whereas Rat 2 based its decisions on shape (round vs square). Learning dynamics was similar for the two rats. Both rats exhibited trial-by-trial variability in behavior which can be modeled as fluctuating between two modes: “perceiving” and “introverting”. Analysis of whisking behavior and whisker-object interactions are in process. Thus far we found no correlation between the gross temporal aspects of object exploration and sipper selection (durations and latencies) and perception. Conclusion (so far): Our behavioral analysis suggests that two out of the four rats learnt and performed the perceptual task to some extent, while exhibiting significant choice biases. It is not yet clear whether they can employ feature conjunction or are limited to single-feature perception.
Stimulus variability and separability: Impacts of Inhibition Netta Haroush *, Shimon Marom 1 2
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Department of Physiology, Faculty of Medicine, Technion—Israel Institute of Technology, Haifa, Israe Network Biology Research Laboratories, Faculty of Electrical Engineering, Technion—Israel Institute 1
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IInhibition is fundamental to sensory discrimination. At the level of the sensory envelop, inhibition is perceived as sharpening contrast amongst various stimulus properties. However, in these peripheral organs, the anatomy of neural circuits is highly structured. As activity propagates to lessstructured, higher relay stations, the impact of inhibition is less established. Here we take a synthetic approach---using multi-site recordings from a large random network of cortical neurons--- to investigate the effects of synaptic inhibition on response variability and on the separability amongst different spatial input sources. We show that synapticdis-inhibition quenches response variability, and as a consequence, sharpens separability amongst different stimulation loci. This sharpening effect, however, is only observed when temporal relations amongst first spikes of individual neurons are considered. At the population rate level, the impact of disinhibition on separability is not significant. We offer interpretations of these observations in the context of network topology and activity noise. This work was founded by the European Union's Seventh Framework Programme [FP7/2007-2013] under gra
Spatio-temporal characteristics of population responses evoked by microstimualtion and optogenetic stimulation in the barrel cortex Nivinsky S. *, Yizhar O. , Slovin H. 1
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The Gonda Multidisciplinary Brain Research Center, Bar-Ilan Univ., Ramat Gan, Israel Dept. of Neurobiology, Weizmann Institute of Science, Rehovot, Israel 1
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Background: Intra-cortical microstimulation (ICMS) is a widely used technique where short pulses of low amplitude currents that are delivered to cortical tissue excite nearby axons and cell bodies. Optogenetics uses light to manipulate target cells expressing microbial rhodopsin proteins. Although both these methods allow excitation of neural circuits, the spatio-temporal patterns of cortical neuronal responses evoked by ICMS and optogenetic stimulation are not well understood. We set out to investigate the effects of ICMS and ChR2-mediated stimulation on population activity in the rat barrel cortex, using voltage-sensitive dye (VSD) imaging. Results: In the ICMS experiments we used biphasic square pulses at low-frequency (LFS), high-frequency (HFS) and single-pulse stimulation. Our results show different population responses, in both time and space, to LFS and HFS. For optogenetic experiments, we expressed ChR2 in cortical pyramidal neurons. Experiments were done 3 or 8 weeks from viral
injection. The combination of optical stimulation with the VSDI presented some difficulties: blue laser stimulation generated an optical artifact and possibly photobleaching of the voltage-sensitive dye. Therefore, for optogenetic stimulation we focused on the evoked VSD response after laser stimulation offset. Similar to ICMS, optostimulation evoked cortical activation that spread several mm from the stimulation site. However, the recruitment pattern of the cortical network depended strongly on the time from viral expression. Conclusion: We found that ICMS at HFS was less effective in cortical activation compared to ICMS at LFS, which may result from axonal conduction suppression. In addition, population responses evoked by short optogenetic stimulation (10ms), following 8 weeks of viral expression, were similar to those of ICMS at HFS. The slow closing dynamics of the channel (~17ms) and higher expression of the virus after 8 weeks may lead to this similarity.
An efficient coding theory for a dynamic trajectory predicts non-uniform allocation of grid cells to modules in the entorhinal cortex Weiss Mosheiff N. 1, Agmon H. 2, Moriel A. 1, Burak Y. 2 1* 1 Racah Institute of Physics, The Hebrew University of Jerusalem 2 Edmond and Lily Safra Center for Brain Sciences, Racah Institute of Physics, HUJI
Background Recent experiments established that grid cells in the entorhinal cortex are functionally organized in discrete modules with uniform grid spacing. The ratios of grid spacing approximately form a geometric series. This result is in agreement with recent theories, which postulate that grid cells implement an efficient code for the animal’s position. However, the experimental data suggests also that the number of cells decreases sharply with grid spacing, in marked disagreement with existing theories. Results We postulate that the entorhinal cortex is adapted to represent a dynamic quantity (the trajectory of the animal in space), while taking into account the temporal statistics of this variable. We first develop a theory for efficient coding of a variable that dynamically follows the statistics of a simple random walk. A central prediction of the theory is that module neuron population sizes should sharply decrease with the increase of grid spacing, in agreement with the trends seen in the experimental data. Another prediction is that the ratios of grid spacing approach a constant value in the modules with small spacing. The predicted ratio is 2, which is consistent with experimental data and with previously proposed models. We identify a simple, near optimal scheme for readout of the grid cell code by neural circuitry, in which model place cells linearly sum inputs from grid cells, using an exponential temporal kernel, whose decay time depends on the spacing of the presynaptic grid cell. This readout scheme requires persistence over varying timescales, ranging from ~1ms to ~1s, depending on the grid cell module. Conclusions We propose that the sharp decrease in module population sizes, with increase of the grid spacing, is an outcome of the efficient coding hypothesis, if the dynamic nature of motion in space is taken into account. We acknowledge support from the Israel Science Foundation and from the Gatsby Charitable Foundation.
Intra-cranially recorded (ECoG) activity reflects reinstantiation of visual memories during retrieval in human high order visual cortex Norman Y.[i], Yeagle EM[ii], Golan T.1, Harel M.1, Mehta AD.2 Malach R.1 [i] Department of Neurobiology, Weizmann Institute of Science, Rehovot, 76100, Israel.[ii] Department of Neurosurgery, Hofstra North Shore LIJ School of Medicine, and Feinstein Institute for Medical Research, Manhasset, New York , 11030.
Intra-Cranially Recorded (ECoG) Activity Reflects Reinstantiation Of Visual Memories During Retrieval In Human High Order Visual Cortex. Yitzhak Norman[1], Erin M. Yeagle[2], Tal Golan[1], Michal Harel[1], Ashesh D. Mehta[2] and Rafael Malach[1] [1] Department of Neurobiology, Weizmann Institute of Science, Rehovot, 76100, Israel. [2] Department of Neurosurgery, Hofstra North Shore LIJ School of Medicine, and Feinstein Institute for Medical Research, Manhasset, New York , 11030. One of the central hypotheses in memory research is that memory retrieval consists of the reinstatement of encoding-related activity (Tulving, 1972). Several studies in humans have shown similarity between neural activity during encoding of individual items and retrieval of the same items (Gelbard-Sagiv et al., 2008; Nyberg et al., 2000; Zhang et al., 2015). We investigated such encoding-recall relationship using intracranial ECoG recordings in eight epileptic patients. Subjects viewed pictures of famous people and places, and after a short distraction task, were instructed to freely recall items from each category. Our results show a clear dissociation between encoding and free recall in early visual cortex recordings. However, a significant relationship was found between the power of broad-band gamma during encoding of individual pictures, and the spontaneous recall of these pictures in high, content selective, visual areas. In particular, electrodes in the Fusiform Face Area (FFA) showed the strongest encoding-recall correlation, with increased gamma activity only during recall of pictures containing faces. These results show that free recall of visual images involves a selective replay of visual content in high visual areas in the absence of early visual cortex activation.
Elucidating the activation mechanism of TRPA1 by cannabinoids Noy G. , Priel A. * 1
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Institute for Drug Research (IDR), Faculty of Medicine, The Hebrew University of Jerusalem
Background: Cannabinoids, endogenous and exogenous, have a dramatic effect on the pain pathway. To date, the most common use of these natural substances has been for analgesic purposes. However, little is known on their cellular and molecular mechanism(s) inducing pain relief. A possible mechanism that recently emerged from different physiological and pathophysiological studies, points to the somatosensory TRP channels as potential targets of cannabinoids. Two main TRP channels are expressed on pain fibers: TRPV1 and TRPA1. TRPA1 is considered the main chemo-sensor, involved in detecting and responding to a wide variety of noxious stimuli by electrophilic and non-electrophilic compounds. Although compounds of the cannabinoid family are known to the channel, the exact activation mechanism is not known. Results: Here, we describe for the first time the binding site of cannabidiol (CBD), the main non-psychoactive substance in cannabis, on TRPA1. We found that CBD activates TRPA1 through the recently described binding site for potent and selective antagonist A-967079. Using site-direct mutagenesis, calcium imaging and electrophysiology, we identify two residues S873 and L881 (on human TRPA1 protein) to be crucial for CBD activation. Mutagenesis of these amino acids results in a profound decrease in channel activation. Conclusions: Our data demonstrates that cannabinoids have at least one specific binding site on pain evoking TRP channels.
The ProFET Protein Machine Learning Platform Ofer D. , Linial M. * 1
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The Hebrew University of Jerusalem, Israel.
[email protected] Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem
[email protected] 1
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Background: The amount of sequenced genomes and proteins is growing at an unprecedented pace. Unfortunately, manual curation and functional knowledge lags behind. Homologous inference often fails at labeling proteins with diverse functions and broad classes. Thus, identifying high-level protein functionality remains challenging. We hypothesize that a universal, feature engineering approach can yield classification of high-level functions and unified properties when combined with machine learning (ML) approaches, without requiring external databases or alignment. Results: We present a novel bioinformatics toolkit called ProFET (Protein Feature Engineering Toolkit). ProFET extracts hundreds of features
covering the elementary biophysical and sequence derived attributes. These different representations of sequences and amino acids (AA) alphabets provide a compact, compressed set of features. The results from ProFET were incorporated in data analysis pipelines and adapted for multi-genome scale analysis. ProFET was applied on 18 established and novel protein benchmark datasets for a variety of binary and multi-class tasks. The results show state of the art performance. The features’ show excellent biological interpretability. The success of ProFET applies to a wide range of highlevel functions such as subcellular localization, structural classes and proteins with unique functional properties (e.g., neuropeptide precursors, thermophilic, subcellular localization and nucleic acid binding). Conclusions: ProFET allows easy, universal discovery of new target proteins, machine learning with proteins, as well as understanding the features underlying different high-level protein functions. ProFET’s source code and data is freely available at https://github.com/ddofer/ProFET. ProFET has been published in Ofer, D. Linial, M (2015), “ProFET: Feature Engineering Captures High-Level Protein Functions” Bioinformatics, 31:3429-3436.
Long lasting effect of mesenchymal stem cells treatment in BTBR autism model Perets N. , Segal-Gavish S. , Barhum Y. , Morozov D. , Gothelf Y. , Abramov N. , London M. , Choen Y. , Offen D. * 1
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Felsenstein Medical Research Center, Tel Aviv University, Israel School of Chemistry, Tel Aviv Universit BrainStorm Cell Therapeutics, Petach Tikva, Israel Neurobiology, Hebrew University, Israel School of Chemistry, Tel Aviv University 1
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Background: Autism spectrum disorders (ASD) are neurodevelopmental disabilities characterized by severe impairment in social communication skills and cognitive flexibility. We have previously shown that mesenchymal stem cells (MSC) can benefit autistic-like symptoms of the BTBR autism mice model when transplanted to the lateral ventricles of the brain. In the current experiment we tested the long lasting effect of naive MSC and MSC that secrete neurotrophic factors (MSC-NTF cells). Methods: BTBR male mice were transplanted with MSC (n=11) or with MSC-NTF cells (n=10) to the lateral ventricles at ages of 6-8 weeks. For control we used BTBR injected with DMEM (n=10). One and six months post operation, mice were analyzed by several behavioral tests and MRI. Results: BTBR mice treated with human MSC or MSC-NTF showed significantly improvement in social test and repetitive behaviors, one and six month post transplantation (p < 0.01). Measuring the male to female ultrasonic vocalizations we found that MSC-NTF treated mice were significantly better than control group, one and six month post treatment (p < 0.01), while the MSC-treated groups show high, yet non-significant, improvement one and six months post treatment. In reversal water T-maze exam, MSC-NTF were significantly better in first reversal trial (P < 0.05) but this improvement was not seen after 6 months and was not seen for MSC treated mice. Eight months post treatment differences could be seen in diffusion tensor MRI (DTI) analysis, between MSC treated and control group in the hippocampus, striatum and cerebellum while MSC-NTF had significant changes in superior cerebellar peduncle compared to the control group. Conclusions: One injection of MSC, and even more, MSC-NTF improve the autistic-like symptoms of BTBR mice. Some of the behavioral benefits were seen long after the transplantation, suggesting for nonreversible changes that benefit especially the social behaviors.
A novel caspase-6 inhibitor as a potential therapy for Alzheimer disease Offen D. *, Aharony I. , Fisher E. , Kopolovich D. , Ben-Zur T. 1
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Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University
Background: Alzheimer's disease (AD) is a devastating neurodegenerative illness which affects cognitive and emotional processes in the elderly. Caspase-6, a member of the caspase family of apoptosis regulators, was found to possess a significant role in AD pathogenesis. It is involved in multiple pathways, including synaptic impairment, microtubule system malfunction, protein degradation failure and axonal degeneration. Therefore, caspase-6 is considered to be an up-stream modulator of AD pathogenesis and as a result, a viable therapeutic target for the treatment of AD. In this study, the primary objective was to test whether a compound based on caspase-6 inhibition influences behavioral outcomes in an animal model of AD Results: We designed a natural substrate-based caspase-6 peptide inhibitor, designated ED11. It was shown to inhibit caspase-6 in an extra-cellular caspase-6 luminescence-based assay in a dose-dependent manner. Furthermore, the IC50 value of caspase-6 protein cleavage inhibition by ED11 was determined as 12.12nM, comparable to the potent synthetic inhibitor zVAD-FMK. In addition, ED11 did not influence PARP or spectrin cleavage by caspase-3, indicating its selectivity for caspase-6. After providing in-vivo evidence of the ability of ED11 to penetrate the blood-brain barrier, we evaluated ED11's efficacy in-vivo. Seven- month-old 3xTg mice were treated with ED11 using a subcutaneous implanted mini-pump. Behavioral and cognitive abilities were measured by the elevated plus maze (EPM) and Morris water maze (MWM), respectively. ED11 treatment resulted in the regulation of anxiety-related behavior in the EPM and the preservation of learning skills in the MWM. Conclusions: Peptide based caspase-6 inhibition by ED11 was demonstrated to be potent, to be selective and to influence 3xTg mouse model behavior. We believe that ED11 may be used as a tool to further clarify the caspase-6 role in AD and perhaps as a therapeutic compound for the treatment of AD.
Combined gene therapy reduces the neuronal damage in mouse model of focal ischemia Offen D. *, Molcho L. , Egozi A. , Barhum Y. , Ben_Zur T. 1
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Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University
Background: Research into stroke is still fueled by frustration over the shortcomings of available therapeutics. The targeting of a single aspect of this multifactorial-multisystemic disease might contribute to the therapeutic limitations. In an attempt to overcome this, we devised a novel multifactorial-cocktail treatment, using lentiviruses encoding EAAT2, GDH2 and NRF2, that act synergistically to address the the effected excitooxidative axis, thereby reducing extracellular-glutamate and glutamate availability while improving the metabolic state and the anti-oxidant response. Methods: Mice were intrastriatally injected (unilaterally) with lentiviruses carrying Nrf2, GDH2 and EAAT2 genes or with GFP as control. Focal ischemic injury was induced by the injection of ET-1 into the striatum 48 h later. Behavioral tests were performed in order to measure motor function. Results: The evaluation of motor asymmetry by elevated bridge and cylinder tests, showed motor deficits two days following ET-1-induce ischemia. However, injection of the viral vectors carrying the Nrf2, GDH2 and EAAT2 genes, demonstrated marked improvements in motor function two days following ET-1 induction. In the elevated beam test, we observed a 20% decrease in the time spent crossing the beam (7.9 secs in the three-genes group vs. 9.9 secs in the GFP group, p,
