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Soreq, H.  2015.  Checks and balances on cholinergic signaling in brain and body function. Trends Neurosci. 38:448-58. Abstract
A century after the discovery of acetylcholine (ACh), we recognize both ACh receptors, transporters, and synthesizing and degrading enzymes and regulators of their expression as contributors to cognition, metabolism, and immunity. Recent discoveries indicate that pre- and post-transcriptional ACh signaling controllers coordinate the identity, functioning, dynamics, and brain-to-body communication of cholinergic cells. Checks and balances including epigenetic mechanisms, alternative splicing, and miRNAs may all expand or limit the diversity of these cholinergic components by consistently performing genome-related surveillance. This regulatory network enables homeostatic maintenance of brain-to-body ACh signaling as well as reactions to nicotine, Alzheimer's disease anticholinesterase therapeutics, and agricultural pesticides. Here I review recent reports on the functional implications of these controllers of cholinergic signaling in and out of the brain.
Shenhar-Tsarfaty, S, Yayon N, Waiskopf N, Shapira I, Toker S, Zaltser D, Berliner S, Ritov Y, Soreq H.  2015.  Fear and C-reactive protein cosynergize annual pulse increases in healthy adults. Proc Natl Acad Sci U S A. 112:E467-71. Abstract
Recent international terror outbreaks notably involve long-term mental health risks to the exposed population, but whether physical health risks are also anticipated has remained unknown. Here, we report fear of terror-induced annual increases in resting heart rate (pulse), a notable risk factor of all-cause mortality. Partial least squares analysis based on 325 measured parameters successfully predicted annual pulse increases, inverse to the expected age-related pulse decline, in approximately 4.1% of a cohort of 17,380 apparently healthy active Israeli adults. Nonbiased hierarchical regression analysis among 27 of those parameters identified pertinent fear of terror combined with the inflammatory biomarker C-reactive protein as prominent coregulators of the observed annual pulse increases. In comparison, basal pulse primarily depended on general physiological parameters and reduced cholinergic control over anxiety and inflammation, together indicating that consistent exposure to terror threats ignites fear-induced exacerbation of preexisting neuro-immune risks of all-cause mortality.
Khouri, L, Nelken I.  2015.  Detecting the unexpected. Current Opinion in Neurobiology. Volume 35 Abstract
Sensory input is inherently dynamic and redundant. Humans and animals alike show a remarkable ability to extract regularities from the sensory scene and dynamically update their responses to the environment. This type of short-term plasticity occurs on time scales ranging from seconds to minutes (and possibly longer). Mismatch Negativity (a component of the human event-related potentials, MMN) and Stimulus Specific Adaptation (a single-neuron analogue, SSA) are two examples of this form of short-term plasticity. Conceptually, both are thought to express a form of surprise and to represent predictive processing. MMN and SSA therefore provide us with handles for investigating this important time scale of short-term plasticity.
Slomowitz, E, Styr B, Vertkin I, Milshtein-Parush H, Nelken I, Slutsky M, Slutsky I.  2015.  Interplay between population firing stability and single neuron dynamics in hippocampal networks.. eLIFE. Abstract
Neuronal circuits' ability to maintain the delicate balance between stability and flexibility in changing environments is critical for normal neuronal functioning. However, to what extent individual neurons and neuronal populations maintain internal firing properties remains largely unknown. In this study, we show that distributions of spontaneous population firing rates and synchrony are subject to accurate homeostatic control following increase of synaptic inhibition in cultured hippocampal networks. Reduction in firing rate triggered synaptic and intrinsic adaptive responses operating as global homeostatic mechanisms to maintain firing macro-stability, without achieving local homeostasis at the single-neuron level. Adaptive mechanisms, while stabilizing population firing properties, reduced short-term facilitation essential for synaptic discrimination of input patterns. Thus, invariant ongoing population dynamics emerge from intrinsically unstable activity patterns of individual neurons and synapses. The observed differences in the precision of homeostatic control at different spatial scales challenge cell-autonomous theory of network homeostasis and suggest the existence of network-wide regulation rules.
Jaffe-Dax, S, Raviv O, Jacoby N, Loewenstein Y, Ahissar M.  2015.  A Computational Model of Implicit Memory Captures Dyslexics' Perceptual Deficits.. The Journal of neuroscience : the official journal of the Society for Neuroscience. 35(35):12116-26. Abstractjaffe-dax_et_al._-_2015_-_a_computational_model_of_implicit_memory_captures_dyslexics_perceptual_deficits_-_journal_of_neuroscience.pdf
Dyslexics are diagnosed for their poor reading skills, yet they characteristically also suffer from poor verbal memory and often from poor auditory skills. To date, this combined profile has been accounted for in broad cognitive terms. Here we hypothesize that the perceptual deficits associated with dyslexia can be understood computationally as a deficit in integrating prior information with noisy observations. To test this hypothesis we analyzed the performance of human participants in an auditory discrimination task using a two-parameter computational model. One parameter captures the internal noise in representing the current event, and the other captures the impact of recently acquired prior information. Our findings show that dyslexics' perceptual deficit can be accounted for by inadequate adjustment of these components; namely, low weighting of their implicit memory of past trials relative to their internal noise. Underweighting the stimulus statistics decreased dyslexics' ability to compensate for noisy observations. ERP measurements (P2 component) while participants watched a silent movie indicated that dyslexics' perceptual deficiency may stem from poor automatic integration of stimulus statistics. This study provides the first description of a specific computational deficit associated with dyslexia.
H, M, et al.  2015.  Reconstruction and Simulation of Neocortical Microcircuitry.. Cell. 163(2):456-92. Abstract
We present a first-draft digital reconstruction of the microcircuitry of somatosensory cortex of juvenile rat. The reconstruction uses cellular and synaptic organizing principles to algorithmically reconstruct detailed anatomy and physiology from sparse experimental data. An objective anatomical method defines a neocortical volume of 0.29 ± 0.01 mm(3) containing ~31,000 neurons, and patch-clamp studies identify 55 layer-specific morphological and 207 morpho-electrical neuron subtypes. When digitally reconstructed neurons are positioned in the volume and synapse formation is restricted to biological bouton densities and numbers of synapses per connection, their overlapping arbors form ~8 million connections with ~37 million synapses. Simulations reproduce an array of in vitro and in vivo experiments without parameter tuning. Additionally, we find a spectrum of network states with a sharp transition from synchronous to asynchronous activity, modulated by physiological mechanisms. The spectrum of network states, dynamically reconfigured around this transition, supports diverse information processing strategies.
Doron, A, Manassi M, Herzog MH, Ahissar M.  2015.  Intact crowding and temporal masking in dyslexia.. Journal of vision. 15(14):13. Abstractintact_crowding_and_temporal_masking_in_dyslexia.pdf
Phonological deficits in dyslexia are well documented. However, there is an ongoing discussion about whether visual deficits limit the reading skills of people with dyslexia. Here, we investigated visual crowding and backward masking. We presented a Vernier (i.e., two vertical bars slightly offset to the left or right) and asked observers to indicate the offset direction. Vernier stimuli are visually similar to letters and are strongly affected by crowding, even in the fovea. To increase task difficulty, Verniers are often followed by a mask (i.e., backward masking). We measured Vernier offset discrimination thresholds for the basic Vernier task, under crowding, and under backward masking, in students with dyslexia (n = 19) and age and intelligence matched students (n = 27). We found no group differences in any of these conditions. Controls with fast visual processing (good backward masking performance), were faster readers. By contrast, no such correlation was found among the students with dyslexia, suggesting that backward masking does not limit their reading efficiency. These findings indicate that neither elevated crowding nor elevated backward masking pose a bottleneck to reading skills of people with dyslexia.
Noblejas, M I, Schechtman E, Adler A, Joshua M, Katabi S, Bergman H.  2015.  Hold your pauses: external globus pallidus neurons respond to behavioural events by decreasing pause activity.. The European journal of neuroscience. 42(7):2415-25. Abstract
Awareness of its rich structural pathways has earned the external segment of the globus pallidus (GPe) recognition as a central figure within the basal ganglia circuitry. Interestingly, GPe neurons are uniquely identified by the presence of prominent pauses interspersed among a high-frequency discharge rate of 50-80 spikes/s. These pauses have an average pause duration of 620 ms with a frequency of 13/min, yielding an average pause activity (probability of a GPe neuron being in a pause) of (620 × 13)/(60 × 1000) = 0.13. Spontaneous pause activity has been found to be inversely related to arousal state. The relationship of pause activity with behavioural events remains to be elucidated. In the present study, we analysed the electrophysiological activity of 200 well-isolated GPe pauser cells recorded from four non-human primates (Macaque fascicularis) while they were engaged in similar classical conditioning tasks. The isolation quality of the recorded activity and the pauses were determined with objective automatic methods. The results showed that the pause probability decreased by 9.09 and 10.0%, and the discharge rate increased by 2.96 and 1.95%, around cue and outcome presentation, respectively. Analysis of the linear relationship between the changes in pause activity and discharge rate showed r(2)  = 0.46 and r(2)  = 0.66 upon cue onset and outcome presentation, respectively. Thus, pause activity is a pertinent element in short-term encoding of relevant behavioural events, and has a significant, but not exclusive, role in the modulation of GPe discharge rate around these events.
Sigalov, N, Maidenbaum S, Amedi A.  2015.  Reading in the Dark: Neural Correlates and Cross-modal Plasticity for Learning to Read Entire Words without Visual Experience.. Neuropsychologia. Abstract
Cognitive neuroscience has long attempted to determine the ways in which cortical selectivity develops, and the impact of nature vs. nurture on it. Congenital blindness (CB) offers a unique opportunity to test this question as the brains of blind individuals develop without visual experience. Here we approach this question through the reading network. Several areas in the visual cortex have been implicated as part of the reading network, and one of the main of these is the VWFA, which is selective to the form of letters and words. But what happens in the CB brain? On the one hand, it has been shown that cross-modal plasticity leads to the recruitment of occipital areas, including the VWFA, for linguistic tasks. On the other hand, we have recently demonstrated VWFA activity for letters in contrast to other visual categories when the information is provided via other senses such as touch or audition. Which of these tasks is more dominant? By which mechanism does the CB brain process reading? Using fMRI and visual-to-auditory sensory substitution which transfers the topographical features of the letters we compare reading with semantic and scrambled conditions in a group of CB. We found activation in early auditory and visual cortices during the early processing phase (letter), while the later phase (word) showed VWFA and bilateral dorsal-intraparietal activations for words. This further supports the notion that many visual regions in general, even early visual areas, also maintain a predilection for task processing even when the modality is variable and in spite of putative lifelong linguistic cross-modal plasticity. Furthermore, we find that the VWFA is recruited preferentially for letter and word form, while it was not recruited, and even exhibited deactivation, for an immediately subsequent semantic task suggesting that despite only short sensory substitution experience orthographic task processing can dominate semantic processing in the VWFA. On a wider scope, this implies that at least in some cases cross-modal plasticity which enables the recruitment of areas for new tasks may be dominated by sensory independent task specific activation.
Furstenberg, A, Breska A, Sompolinsky H, Deouell LY.  2015.  Evidence of Change of Intention in Picking Situations.. Journal of cognitive neuroscience. 27(11):2133-46. Abstract
Intending to perform an action and then immediately executing it is a mundane process. The cognitive and neural mechanisms involved in this process of "proximal" intention formation and execution, in the face of multiple options to choose from, are not clear, however. Especially, it is not clear how intentions are formed when the choice makes no difference. Here we used behavioral and electrophysiological measures to investigate the temporal dynamics of proximal intention formation and "change of intention" in a free picking scenario, in which the alternatives are on a par for the participant. Participants pressed a right or left button following either an instructive visible arrow cue or a visible neutral "free-choice" cue, both preceded by a masked arrow prime. The goal of the prime was to induce a bias toward pressing the left or right button. Presumably, when the choice is arbitrary, such bias should determine the decision. EEG lateralized readiness potentials and EMG measurements revealed that the prime indeed induced an intention to move in one direction. However, we discovered a signature of "change of intention" in both the Instructed and Free-choice decisions. These results suggest that, even in arbitrary choices, biases present in the neural system for choosing one or another option may be overruled and point to a curious "picking deliberation" phenomenon. We discuss a possible neural scenario that could explain this phenomenon.
Ankri, L, Husson Z, Pietrajtis K, Proville R, Léna C, Yarom Y, Dieudonné S, Uusisaari M Y.  2015.  A novel inhibitory nucleo-cortical circuit controls cerebellar Golgi cell activity.. eLife. 4 Abstract
The cerebellum, a crucial center for motor coordination, is composed of a cortex and several nuclei. The main mode of interaction between these two parts is considered to be formed by the inhibitory control of the nuclei by cortical Purkinje neurons. We now amend this view by showing that inhibitory GABA-glycinergic neurons of the cerebellar nuclei project profusely into the cerebellar cortex, where they make synaptic contacts on a GABAergic subpopulation of cerebellar Golgi cells. These spontaneously firing Golgi cells are inhibited by optogenetic activation of the inhibitory nucleo-cortical fibers both in vitro and in vivo. Our data suggest that the cerebellar nuclei may contribute to the functional recruitment of the cerebellar cortex by decreasing Golgi cell inhibition onto granule cells.
Alajem, A, Biran A, Harikumar A, Sailaja B S, Aaronson Y, Livyatan I, Nissim-Rafinia M, Sommer A G, Mostoslavsky G, Gerbasi VR et al..  2015.  Differential Association of Chromatin Proteins Identifies BAF60a/SMARCD1 as a Regulator of Embryonic Stem Cell Differentiation.. Cell reports. 10(12):2019-31. Abstract
Embryonic stem cells (ESCs) possess a distinct chromatin conformation maintained by specialized chromatin proteins. To identify chromatin regulators in ESCs, we developed a simple biochemical assay named D-CAP (differential chromatin-associated proteins), using brief micrococcal nuclease digestion of chromatin, followed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Using D-CAP, we identified several differentially chromatin-associated proteins between undifferentiated and differentiated ESCs, including the chromatin remodeling protein SMARCD1. SMARCD1 depletion in ESCs led to altered chromatin and enhanced endodermal differentiation. Gene expression and chromatin immunoprecipitation sequencing (ChIP-seq) analyses suggested that SMARCD1 is both an activator and a repressor and is enriched at developmental regulators and that its chromatin binding coincides with H3K27me3. SMARCD1 knockdown caused H3K27me3 redistribution and increased H3K4me3 around the transcription start site (TSS). One of the identified SMARCD1 targets was Klf4. In SMARCD1-knockdown clones, KLF4, as well as H3K4me3 at the Klf4 locus, remained high and H3K27me3 was abolished. These results propose a role for SMARCD1 in restricting pluripotency and activating lineage pathways by regulating H3K27 methylation.
Moussaieff, A, Rouleau M, Kitsberg D, Cohen M, Levy G, Barasch D, Nemirovski A, Shen-Orr S, Laevsky I, Amit M et al..  2015.  Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells.. Cell metabolism. 21(3):392-402. Abstract
Loss of pluripotency is a gradual event whose initiating factors are largely unknown. Here we report the earliest metabolic changes induced during the first hours of differentiation. High-resolution NMR identified 44 metabolites and a distinct metabolic transition occurring during early differentiation. Metabolic and transcriptional analyses showed that pluripotent cells produced acetyl-CoA through glycolysis and rapidly lost this function during differentiation. Importantly, modulation of glycolysis blocked histone deacetylation and differentiation in human and mouse embryonic stem cells. Acetate, a precursor of acetyl-CoA, delayed differentiation and blocked early histone deacetylation in a dose-dependent manner. Inhibitors upstream of acetyl-CoA caused differentiation of pluripotent cells, while those downstream delayed differentiation. Our results show a metabolic switch causing a loss of histone acetylation and pluripotent state during the first hours of differentiation. Our data highlight the important role metabolism plays in pluripotency and suggest that a glycolytic switch controlling histone acetylation can release stem cells from pluripotency.
Goll, Y, Atlan G, Citri A.  2015.  Attention: the claustrum.. Trends in neurosciences. Abstract
The claustrum is a mysterious thin sheet of neurons lying between the insular cortex and the striatum. It is reciprocally connected with almost all cortical areas, including motor, somatosensory, visual, auditory, limbic, associative, and prefrontal cortices. In addition, it receives neuromodulatory input from subcortical structures. A decade ago, Sir Francis Crick and Christof Koch published an influential review proposing the claustrum as the 'seat of consciousness', spurring a revival of interest in the claustrum. We review the literature on the claustrum, emphasizing recent discoveries, and develop a detailed hypothesis describing a role for the claustrum in the segregation of attention.
Joshua, M, Lisberger SG.  2015.  A tale of two species: Neural integration in zebrafish and monkeys.. Neuroscience. 296:80-91. Abstract
Selection of a model organism creates tension between competing constraints. The recent explosion of modern molecular techniques has revolutionized the analysis of neural systems in organisms that are amenable to genetic techniques. Yet, the non-human primate remains the gold-standard for the analysis of the neural basis of behavior, and as a bridge to the operation of the human brain. The challenge is to generalize across species in a way that exposes the operation of circuits as well as the relationship of circuits to behavior. Eye movements provide an opportunity to cross the bridge from mechanism to behavior through research on diverse species. Here, we review experiments and computational studies on a circuit function called "neural integration" that occurs in the brainstems of larval zebrafish, primates, and species "in between". We show that analysis of circuit structure using modern molecular and imaging approaches in zebrafish has remarkable explanatory power for details of the responses of integrator neurons in the monkey. The combination of research from the two species has led to a much stronger hypothesis for the implementation of the neural integrator than could have been achieved using either species alone.
Jacoby, N, Ahissar M.  2015.  Assessing the applied benefits of perceptual training: Lessons from studies of training working-memory.. Journal of vision. 15(10):6. Abstracti1534-7362-15-10-6.pdf
In the 1980s to 1990s, studies of perceptual learning focused on the specificity of training to basic visual attributes such as retinal position and orientation. These studies were considered scientifically innovative since they suggested the existence of plasticity in the early stimulus-specific sensory cortex. Twenty years later, perceptual training has gradually shifted to potential applications, and research tends to be devoted to showing transfer. In this paper we analyze two key methodological issues related to the interpretation of transfer. The first has to do with the absence of a control group or the sole use of a test-retest group in traditional perceptual training studies. The second deals with claims of transfer based on the correlation between improvement on the trained and transfer tasks. We analyze examples from the general intelligence literature dealing with the impact on general intelligence of training on a working memory task. The re-analyses show that the reports of a significantly larger transfer of the trained group over the test-retest group fail to replicate when transfer is compared to an actively trained group. Furthermore, the correlations reported in this literature between gains on the trained and transfer tasks can be replicated even when no transfer is assumed.
Pavlovskaya, M, Soroker N, Bonneh YS, Hochstein S.  2015.  Computing an average when part of the population is not perceived.. Journal of cognitive neuroscience. 27(7):1397-411. Abstract
The syndrome of unilateral spatial neglect (USN) after right-hemisphere damage is characterized by failure of salient left-sided stimuli to activate an orienting response, attract attention, and gain access to conscious awareness. The explicit failure processing left-sided visual information is not uniform, however, and patients seem to be more successful performing certain visual tasks than others. The source of this difference is still not clear. We focus on processing of visual scene statistical properties, asking whether, in computing the average size of an array of objects, USN patients give appropriate weight to objects on the left; disregard left-side objects entirely; or assign them an intermediate, lower weight, in accord with their tendency to neglect these objects. The interest in testing this question stems from a series of studies in healthy individuals that led Chong and Treisman [Chong, S. C., & Treisman, A. Statistical processing: Computing the average size in perceptual groups. Vision Research, 45, 891-900, 2005a; Chong, S. C., & Treisman, A. Attentional spread in the statistical processing of visual displays. Perception & Psychophysics, 67, 1-13, 2005b] to propose that processing of statistical properties (like the average size of visual scene elements) is carried out in parallel, with no need for serial allocation of focal attention to the different scene elements. Our results corroborate this suggestion, showing that objects in the left ("neglected") hemispace contribute to average size computation, despite a marked imbalance in spatial distribution of attention, which leads to a reduced weight of left-side elements in the averaging computation. This finding sheds light on the nature of the impairment in USN and on basic mechanisms underlying statistical processing in vision. We confirm that statistical processing depends mainly on spread-attention mechanisms, which are largely spared in USN.
Daikhin, L, Ahissar M.  2015.  Fast Learning of Simple Perceptual Discriminations Reduces Brain Activation in Working Memory and in High-level Auditory Regions.. Journal of cognitive neuroscience. :1-14. Abstractjocn_a_00786.pdf
Introducing simple stimulus regularities facilitates learning of both simple and complex tasks. This facilitation may reflect an implicit change in the strategies used to solve the task when successful predictions regarding incoming stimuli can be formed. We studied the modifications in brain activity associated with fast perceptual learning based on regularity detection. We administered a two-tone frequency discrimination task and measured brain activation (fMRI) under two conditions: with and without a repeated reference tone. Although participants could not explicitly tell the difference between these two conditions, the introduced regularity affected both performance and the pattern of brain activation. The "No-Reference" condition induced a larger activation in frontoparietal areas known to be part of the working memory network. However, only the condition with a reference showed fast learning, which was accompanied by a reduction of activity in two regions: the left intraparietal area, involved in stimulus retention, and in posterior superior-temporal area, involved in representing auditory regularities. We propose that this joint reduction reflects a reduction in the need for online storage of the compared tones. We further suggest that this change reflects an implicit strategic shift "backwards" from reliance mainly on working memory networks in the "No-Reference" condition to increased reliance on detected regularities stored in high-level auditory networks.
Yearim, A, Gelfman S, Shayevitch R, Melcer S, Glaich O, Mallm J-P, Nissim-Rafinia M, Cohen A-HS, Rippe K, Meshorer E et al..  2015.  HP1 is involved in regulating the global impact of DNA methylation on alternative splicing.. Cell reports. 10(7):1122-34. Abstract
The global impact of DNA methylation on alternative splicing is largely unknown. Using a genome-wide approach in wild-type and methylation-deficient embryonic stem cells, we found that DNA methylation can either enhance or silence exon recognition and affects the splicing of more than 20% of alternative exons. These exons are characterized by distinct genetic and epigenetic signatures. Alternative splicing regulation of a subset of these exons can be explained by heterochromatin protein 1 (HP1), which silences or enhances exon recognition in a position-dependent manner. We constructed an experimental system using site-specific targeting of a methylated/unmethylated gene and demonstrate a direct causal relationship between DNA methylation and alternative splicing. HP1 regulates this gene's alternative splicing in a methylation-dependent manner by recruiting splicing factors to its methylated form. Our results demonstrate DNA methylation's significant global influence on mRNA splicing and identify a specific mechanism of splicing regulation mediated by HP1.
Zeharia, N, Hertz U, Flash T, Amedi A.  2015.  New whole-body sensory-motor gradients revealed using phase-locked analysis and verified using multivoxel pattern analysis and functional connectivity.. The Journal of neuroscience : the official journal of the Society for Neuroscience. 35(7):2845-59. Abstract
Topographic organization is one of the main principles of organization in the human brain. Specifically, whole-brain topographic mapping using spectral analysis is responsible for one of the greatest advances in vision research. Thus, it is intriguing that although topography is a key feature also in the motor system, whole-body somatosensory-motor mapping using spectral analysis has not been conducted in humans outside M1/SMA. Here, using this method, we were able to map a homunculus in the globus pallidus, a key target area for deep brain stimulation, which has not been mapped noninvasively or in healthy subjects. The analysis clarifies contradictory and partial results regarding somatotopy in the caudal-cingulate zone and rostral-cingulate zone in the medial wall and in the putamen. Most of the results were confirmed at the single-subject level and were found to be compatible with results from animal studies. Using multivoxel pattern analysis, we could predict movements of individual body parts in these homunculi, thus confirming that they contain somatotopic information. Using functional connectivity, we demonstrate interhemispheric functional somatotopic connectivity of these homunculi, such that the somatotopy in one hemisphere could have been found given the connectivity pattern of the corresponding regions of interest in the other hemisphere. When inspecting the somatotopic and nonsomatotopic connectivity patterns, a similarity index indicated that the pattern of connected and nonconnected regions of interest across different homunculi is similar for different body parts and hemispheres. The results show that topographical gradients are even more widespread than previously assumed in the somatosensory-motor system. Spectral analysis can thus potentially serve as a gold standard for defining somatosensory-motor system areas for basic research and clinical applications.
Kohn, E, Katz B, Yasin B, Peters M, Rhodes E, Zaguri R, Weiss S, Minke B.  2015.  Functional cooperation between the IP3 receptor and phospholipase C secures the high sensitivity to light of Drosophila photoreceptors in vivo.. The Journal of neuroscience : the official journal of the Society for Neuroscience. 35(6):2530-46. Abstract
Drosophila phototransduction is a model system for the ubiquitous phosphoinositide signaling. In complete darkness, spontaneous unitary current events (dark bumps) are produced by spontaneous single Gqα activation, while single-photon responses (quantum bumps) arise from synchronous activation of several Gqα molecules. We have recently shown that most of the spontaneous single Gqα activations do not produce dark bumps, because of a critical phospholipase Cβ (PLCβ) activity level required for bump generation. Surpassing the threshold of channel activation depends on both PLCβ activity and cellular [Ca(2+)], which participates in light excitation via a still unclear mechanism. We show here that in IP3 receptor (IP3R)-deficient photoreceptors, both light-activated Ca(2+) release from internal stores and light sensitivity were strongly attenuated. This was further verified by Ca(2+) store depletion, linking Ca(2+) release to light excitation. In IP3R-deficient photoreceptors, dark bumps were virtually absent and the quantum-bump rate was reduced, indicating that Ca(2+) release from internal stores is necessary to reach the critical level of PLCβ catalytic activity and the cellular [Ca(2+)] required for excitation. Combination of IP3R knockdown with reduced PLCβ catalytic activity resulted in highly suppressed light responses that were partially rescued by cellular Ca(2+) elevation, showing a functional cooperation between IP3R and PLCβ via released Ca(2+). These findings suggest that in contrast to the current dogma that Ca(2+) release via IP3R does not participate in light excitation, we show that released Ca(2+) plays a critical role in light excitation. The positive feedback between PLCβ and IP3R found here may represent a common feature of the inositol-lipid signaling.
Livyatan, I, Aaronson Y, Gokhman D, Ashkenazi R, Meshorer E.  2015.  BindDB: An Integrated Database and Webtool Platform for "Reverse-ChIP" Epigenomic Analysis.. Cell stem cell. 17(6):647-8.
Saadon-Grosman, N, Tal Z, Itshayek E, Amedi A, Arzy S.  2015.  Discontinuity of cortical gradients reflects sensory impairment.. Proceedings of the National Academy of Sciences of the United States of America. 112(52):16024-9. Abstract
Topographic maps and their continuity constitute a fundamental principle of brain organization. In the somatosensory system, whole-body sensory impairment may be reflected either in cortical signal reduction or disorganization of the somatotopic map, such as disturbed continuity. Here we investigated the role of continuity in pathological states. We studied whole-body cortical representations in response to continuous sensory stimulation under functional MRI (fMRI) in two unique patient populations-patients with cervical sensory Brown-Séquard syndrome (injury to one side of the spinal cord) and patients before and after surgical repair of cervical disk protrusion-enabling us to compare whole-body representations in the same study subjects. We quantified the spatial gradient of cortical activation and evaluated the divergence from a continuous pattern. Gradient continuity was found to be disturbed at the primary somatosensory cortex (S1) and the supplementary motor area (SMA), in both patient populations: contralateral to the disturbed body side in the Brown-Séquard group and before repair in the surgical group, which was further improved after intervention. Results corresponding to the nondisturbed body side and after surgical repair were comparable with control subjects. No difference was found in the fMRI signal power between the different conditions in the two groups, as well as with respect to control subjects. These results suggest that decreased sensation in our patients is related to gradient discontinuity rather than signal reduction. Gradient continuity may be crucial for somatotopic and other topographical organization, and its disruption may characterize pathological processing.
Barniv, D, Nelken I.  2015.  Auditory Streaming as an Online Classification Process with Evidence Accumulation.. PLoS One. 10(12): e0144788. Abstract
When human subjects hear a sequence of two alternating pure tones, they often perceive it in one of two ways: as one integrated sequence (a single "stream" consisting of the two tones), or as two segregated sequences, one sequence of low tones perceived separately from another sequence of high tones (two "streams"). Perception of this stimulus is thus bistable. Moreover, subjects report on-going switching between the two percepts: unless the frequency separation is large, initial perception tends to be of integration, followed by toggling between integration and segregation phases. The process of stream formation is loosely named "auditory streaming". Auditory streaming is believed to be a manifestation of human ability to analyze an auditory scene, i.e. to attribute portions of the incoming sound sequence to distinct sound generating entities. Previous studies suggested that the durations of the successive integration and segregation phases are statistically independent. This independence plays an important role in current models of bistability. Contrary to this, we show here, by analyzing a large set of data, that subsequent phase durations are positively correlated. To account together for bistability and positive correlation between subsequent durations, we suggest that streaming is a consequence of an evidence accumulation process. Evidence for segregation is accumulated during the integration phase and vice versa; a switch to the opposite percept occurs stochastically based on this evidence. During a long phase, a large amount of evidence for the opposite percept is accumulated, resulting in a long subsequent phase. In contrast, a short phase is followed by another short phase. We implement these concepts using a probabilistic model that shows both bistability and correlations similar to those observed experimentally.
Harikumar, A, Meshorer E.  2015.  Chromatin remodeling and bivalent histone modifications in embryonic stem cells.. EMBO reports. 16(12):1609-19. Abstract
Pluripotent embryonic stem cells (ESCs) are characterized by distinct epigenetic features including a relative enrichment of histone modifications related to active chromatin. Among these is tri-methylation of lysine 4 on histone H3 (H3K4me3). Several thousands of the H3K4me3-enriched promoters in pluripotent cells also contain a repressive histone mark, namely H3K27me3, a situation referred to as "bivalency". While bivalent promoters are not unique to pluripotent cells, they are relatively enriched in these cell types, largely marking developmental and lineage-specific genes which are silent but poised for immediate action. The H3K4me3 and H3K27me3 modifications are catalyzed by lysine methyltransferases which are usually found within, although not entirely limited to, the Trithorax group (TrxG) and Polycomb group (PcG) protein complexes, respectively, but these do not provide selective bivalent specificity. Recent studies highlight the family of ATP-dependent chromatin remodeling proteins as regulators of bivalent domains. Here, we discuss bivalency in general, describe the machineries that catalyze bivalent chromatin domains, and portray the emerging connection between bivalency and the action of different families of chromatin remodelers, namely INO80, esBAF, and NuRD, in pluripotent cells. We posit that chromatin remodeling proteins may enable "bivalent specificity", often selectively acting on, or selectively depleted from, bivalent domains.