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Elber-Dorozko, L, Loewenstein Y.  Submitted.  Striatal action-value neurons reconsidered. AbstractpdfSupplementary Information
It is generally believed that during economic decisions, striatal neurons represent the valuesassociated with different actions. This hypothesis is based on a large number of electrophysiological studies, in which the neural activity of striatal neurons was measured while the subject was learning to prefer the more rewarding action. Here we present an alternative interpretation of the electrophysiological findings. We show that the standard statistical methods that were used to identify action-value neurons in the striatum erroneously detect the same action-value representations in unrelated neuronal recordings. This is due to temporal correlations in the neuronal data. We propose an alternative statistical method for identifying action-value representations that is not subject to this caveat. We apply it to previously identified action-value neurons in the basal ganglia and fail to detect action-value representations. In conclusion, we argue that there is no conclusive evidence for the generally accepted hypothesis that striatal neurons encode action-values.
Barbash, S, Garfinkel BP, Maoz R, Simchovitz A, Nadorp B, Guffanti A, Bennett ER, Nadeau C, Turk A, Paul L et al..  2017.  Alzheimer's brains show inter-related changes in RNA and lipid metabolism. Neurobiol Dis. 106:1-13. Abstract
Alzheimer's disease (AD) involves changes in both lipid and RNA metabolism, but it remained unknown if these differences associate with AD's cognition and/or post-mortem neuropathology indices. Here, we report RNA-sequencing evidence of inter-related associations between lipid processing, cognition level, and AD neuropathology. In two unrelated cohorts, we identified pathway-enriched facilitation of lipid processing and alternative splicing genes, including the neuronal-enriched NOVA1 and hnRNPA1. Specifically, this association emerged in temporal lobe tissue samples from donors where postmortem evidence demonstrated AD neuropathology, but who presented normal cognition proximate to death. The observed changes further associated with modified ATP synthesis and mitochondrial transcripts, indicating metabolic relevance; accordingly, mass-spectrometry-derived lipidomic profiles distinguished between individuals with and without cognitive impairment prior to death. In spite of the limited group sizes, tissues from persons with both cognitive impairment and AD pathology showed elevation in several drug-targeted genes of other brain, vascular and autoimmune disorders, accompanied by pathology-related increases in distinct lipid processing transcripts, and in the RNA metabolism genes hnRNPH2, TARDBP, CLP1 and EWSR1. To further detect 3'-polyadenylation variants, we employed multiple cDNA primer pairs. This identified variants that showed limited differences in scope and length between the tested cohorts, yet enabled superior clustering of demented and non-demented AD brains versus controls compared to total mRNA expression values. Our findings indicate inter-related cognition-associated differences in AD's lipid processing, alternative splicing and 3'-polyadenylation, calling for pursuing the underlying psychological and therapeutics implications.
Haviv, R, Oz E, Soreq H.  2017.  The Stress-Responding miR-132-3p Shows Evolutionarily Conserved Pathway Interactions. Cell Mol Neurobiol. Abstract
MicroRNAs (miRNAs) are small non-coding RNA chains that can each interact with the 3'-untranslated region of multiple target transcripts in various organisms, humans included. MiRNAs tune entire biological pathways, spanning stress reactions, by regulating the stability and/or translation of their targets. MiRNA genes are often subject to co-evolutionary changes together with their target transcripts, which may be reflected by differences between paralog mouse and primate miRNA/mRNA pairs. However, whether such evolution occurred in stress-related miRNAs remained largely unknown. Here, we report that the stress-induced evolutionarily conserved miR-132-3p, its target transcripts and its regulated pathways provide an intriguing example to exceptionally robust conservation. Mice and human miR-132-3p share six experimentally validated targets and 18 predicted targets with a common miRNA response element. Enrichment analysis and mining in-house and web-available experimental data identified co-regulation by miR-132 in mice and humans of stress-related, inflammatory, metabolic, and neuronal growth pathways. Our findings demonstrate pan-mammalian preservation of miR-132's neuronal roles, and call for further exploring the corresponding stress-related implications.
Bekenstein, U, Mishra N, Milikovsky DZ, Hanin G, Zelig D, Sheintuch L, Berson A, Greenberg DS, Friedman A, Soreq H.  2017.  Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity. Proc Natl Acad Sci U S A. 114:E4996-e5005. Abstract
Epilepsy is a common neurological disease, manifested in unprovoked recurrent seizures. Epileptogenesis may develop due to genetic or pharmacological origins or following injury, but it remains unclear how the unaffected brain escapes this susceptibility to seizures. Here, we report that dynamic changes in forebrain microRNA (miR)-211 in the mouse brain shift the threshold for spontaneous and pharmacologically induced seizures alongside changes in the cholinergic pathway genes, implicating this miR in the avoidance of seizures. We identified miR-211 as a putative attenuator of cholinergic-mediated seizures by intersecting forebrain miR profiles that were Argonaute precipitated, synaptic vesicle target enriched, or differentially expressed under pilocarpine-induced seizures, and validated TGFBR2 and the nicotinic antiinflammatory acetylcholine receptor nAChRa7 as murine and human miR-211 targets, respectively. To explore the link between miR-211 and epilepsy, we engineered dTg-211 mice with doxycycline-suppressible forebrain overexpression of miR-211. These mice reacted to doxycycline exposure by spontaneous electrocorticography-documented nonconvulsive seizures, accompanied by forebrain accumulation of the convulsive seizures mediating miR-134. RNA sequencing demonstrated in doxycycline-treated dTg-211 cortices overrepresentation of synaptic activity, Ca2+ transmembrane transport, TGFBR2 signaling, and cholinergic synapse pathways. Additionally, a cholinergic dysregulated mouse model overexpressing a miR refractory acetylcholinesterase-R splice variant showed a parallel propensity for convulsions, miR-211 decreases, and miR-134 elevation. Our findings demonstrate that in mice, dynamic miR-211 decreases induce hypersynchronization and nonconvulsive and convulsive seizures, accompanied by expression changes in cholinergic and TGFBR2 pathways as well as in miR-134. Realizing the importance of miR-211 dynamics opens new venues for translational diagnosis of and interference with epilepsy.
Lasser-Katz, E, Simchovitz A, Chiu WH, Oertel WH, Sharon R, Soreq H, Roeper J, Goldberg JA.  2017.  Mutant alpha-Synuclein Overexpression Induces Stressless Pacemaking in Vagal Motoneurons at Risk in Parkinson's Disease. J Neurosci. 37:47-57. Abstract
alpha-Synuclein overexpression (ASOX) drives the formation of toxic aggregates in neurons vulnerable in Parkinson's disease (PD), including dopaminergic neurons of the substantia nigra (SN) and cholinergic neurons of the dorsal motor nucleus of the vagus (DMV). Just as these populations differ in when they exhibit alpha-synucleinopathies during PD pathogenesis, they could also differ in their physiological responses to ASOX. An ASOX-mediated hyperactivity of SN dopamine neurons, which was caused by oxidative dysfunction of Kv4.3 potassium channels, was recently identified in transgenic (A53T-SNCA) mice overexpressing mutated human alpha-synuclein. Noting that DMV neurons display extensive alpha-synucleinopathies earlier than SN dopamine neurons while exhibiting milder cell loss in PD, we aimed to define the electrophysiological properties of DMV neurons in A53T-SNCA mice. We found that DMV neurons maintain normal firing rates in response to ASOX. Moreover, Kv4.3 channels in DMV neurons exhibit no oxidative dysfunction in the A53T-SNCA mice, which could only be recapitulated in wild-type mice by glutathione dialysis. Two-photon imaging of redox-sensitive GFP corroborated the finding that mitochondrial oxidative stress was diminished in DMV neurons in the A53T-SNCA mice. This reduction in oxidative stress resulted from a transcriptional downregulation of voltage-activated (Cav) calcium channels in DMV neurons, which led to a reduction in activity-dependent calcium influx via Cav channels. Thus, ASOX induces a homeostatic remodeling with improved redox signaling in DMV neurons, which could explain the differential vulnerability of SN dopamine and DMV neurons in PD and could promote neuroprotective strategies that emulate endogenous homeostatic responses to ASOX (e.g., stressless pacemaking) in DMV neurons. SIGNIFICANCE STATEMENT: Overexpression of mutant alpha-synuclein causes Parkinson's disease, presumably by driving neurodegeneration in vulnerable neuronal target populations. However, the extent of alpha-synuclein pathology (e.g., Lewy bodies) is not directly related to the degree of neurodegeneration across various vulnerable neuronal populations. Here, we show that, in contrast to dopamine neurons in the substantia nigra, vagal motoneurons do not enhance their excitability and oxidative load in response to chronic mutant alpha-synuclein overexpression. Rather, by downregulating their voltage-activated calcium channels, vagal motoneurons acquire a stressless form of pacemaking that diminishes mitochondrial and cytosolic oxidative stress. Emulating this endogenous adaptive response to alpha-synuclein overexpression could lead to novel strategies to protect dopamine neurons and perhaps delay the onset of Parkinson's disease.
Mishra, N, Friedson L, Hanin G, Bekenstein U, Volovich M, Bennett ER, Greenberg DS, Soreq H.  2017.  Antisense miR-132 blockade via the AChE-R splice variant mitigates cortical inflammation. Sci Rep. 7:42755. Abstract
MicroRNA (miR)-132 brain-to-body messages suppress inflammation by targeting acetylcholinesterase (AChE), but the target specificity of 3'-AChE splice variants and the signaling pathways involved remain unknown. Using surface plasmon resonance (SPR), we identified preferential miR-132 targeting of soluble AChE-R over synaptic-bound AChE-S, potentiating miR-132-mediated brain and body cholinergic suppression of pro-inflammatory cytokines. Inversely, bacterial lipopolysaccharide (LPS) reduced multiple miR-132 targets, suppressed AChE-S more than AChE-R and elevated inflammatory hallmarks. Furthermore, blockade of peripheral miR-132 by chemically protected AM132 antisense oligonucleotide elevated muscle AChE-R 10-fold over AChE-S, and cortical miRNA-sequencing demonstrated inverse brain changes by AM132 and LPS in immune-related miRs and neurotransmission and cholinergic signaling pathways. In neuromuscular junctions, AM132 co-elevated the nicotinic acetylcholine receptor and AChE, re-balancing neurotransmission and reaching mild muscle incoordination. Our findings demonstrate preferential miR-132-induced modulation of AChE-R which ignites bidirectional brain and body anti-inflammatory regulation, underscoring splice-variant miR-132 specificity as a new complexity level in inflammatory surveillance.
Barbash, S, Simchovitz A, Buchman AS, Bennett DA, Shifman S, Soreq H.  2017.  Neuronal-expressed microRNA-targeted pseudogenes compete with coding genes in the human brain. Transl Psychiatry. 7:e1199. Abstract
MicroRNAs orchestrate brain functioning via interaction with microRNA recognition elements (MRE) on target transcripts. However, the global impact of potential competition on the microRNA pool between coding and non-coding brain transcripts that share MREs with them remains unexplored. Here we report that non-coding pseudogene transcripts carrying MREs (PSG+MRE) often show duplicated origin, evolutionary conservation and higher expression in human temporal lobe neurons than comparable duplicated MRE-deficient pseudogenes (PSG-MRE). PSG+MRE participate in neuronal RNA-induced silencing complexes (RISC), indicating functional involvement. Furthermore, downregulation cell culture experiments validated bidirectional co-regulation of PSG+MRE with MRE-sharing coding transcripts, frequently not their mother genes, and with targeted microRNAs; also, PSG+MRE single-nucleotide polymorphisms associated with schizophrenia, bipolar disorder and autism, suggesting interaction with mental diseases. Our findings indicate functional roles of duplicated PSG+MRE in brain development and cognition, supporting physiological impact of the reciprocal co-regulation of PSG+MRE with MRE-sharing coding transcripts in human brain neurons.
Simchovitz, A, Heneka MT, Soreq H.  2017.  Personalized genetics of the cholinergic blockade of neuroinflammation. J Neurochem. 142 Suppl 2:178-187. Abstract
Acetylcholine signaling is essential for cognitive functioning and blocks inflammation. To maintain homeostasis, cholinergic signaling is subjected to multi-leveled and bidirectional regulation by both proteins and non-coding microRNAs ('CholinomiRs'). CholinomiRs coordinate the cognitive and inflammatory aspects of cholinergic signaling by targeting major cholinergic transcripts including the acetylcholine hydrolyzing enzyme acetylcholinesterase (AChE). Notably, AChE inhibitors are the only currently approved line of treatment for Alzheimer's disease patients. Since cholinergic signaling blocks neuroinflammation which is inherent to Alzheimer's disease, genomic changes modifying AChE's properties and its susceptibility to inhibitors and/or to CholinomiRs regulation may affect the levels and properties of inflammasome components such as NLRP3. This calls for genomic-based medicine approaches based on genotyping of both coding and non-coding single nucleotide polymorphisms (SNPs) in the genes involved in cholinergic signaling. An example is a SNP in a recognition element for the primate-specific microRNA-608 within the 3' untranslated region of the AChE transcript. Carriers of the minor allele of that SNP present massively elevated brain AChE levels, increased trait anxiety and inflammation, accompanied by perturbed CholinomiR-608 regulatory networks and elevated prefrontal activity under exposure to stressful insults. Several additional SNPs in the AChE and other cholinergic genes await further studies, and might likewise involve different CholinomiRs and pathways including those modulating the initiation and progression of neurodegenerative diseases. CholinomiRs regulation of the cholinergic system thus merits in-depth interrogation and is likely to lead to personalized medicine approaches for achieving better homeostasis in health and disease. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.
Hanin, G, Yayon N, Tzur Y, Haviv R, Bennett ER, Udi S, Krishnamoorthy YR, Kotsiliti E, Zangen R, Efron B et al..  2017.  miRNA-132 induces hepatic steatosis and hyperlipidaemia by synergistic multitarget suppression. Gut. Abstract
OBJECTIVE: Both non-alcoholic fatty liver disease (NAFLD) and the multitarget complexity of microRNA (miR) suppression have recently raised much interest, but the in vivo impact and context-dependence of hepatic miR-target interactions are incompletely understood. Assessing the relative in vivo contributions of specific targets to miR-mediated phenotypes is pivotal for investigating metabolic processes. DESIGN: We quantified fatty liver parameters and the levels of miR-132 and its targets in novel transgenic mice overexpressing miR-132, in liver tissues from patients with NAFLD, and in diverse mouse models of hepatic steatosis. We tested the causal nature of miR-132 excess in these phenotypes by injecting diet-induced obese mice with antisense oligonucleotide suppressors of miR-132 or its target genes, and measured changes in metabolic parameters and transcripts. RESULTS: Transgenic mice overexpressing miR-132 showed a severe fatty liver phenotype and increased body weight, serum low-density lipoprotein/very low-density lipoprotein (LDL/VLDL) and liver triglycerides, accompanied by decreases in validated miR-132 targets and increases in lipogenesis and lipid accumulation-related transcripts. Likewise, liver samples from both patients with NAFLD and mouse models of hepatic steatosis or non-alcoholic steatohepatitis (NASH) displayed dramatic increases in miR-132 and varying decreases in miR-132 targets compared with controls. Furthermore, injecting diet-induced obese mice with anti-miR-132 oligonucleotides, but not suppressing its individual targets, reversed the hepatic miR-132 excess and hyperlipidemic phenotype. CONCLUSIONS: Our findings identify miR-132 as a key regulator of hepatic lipid homeostasis, functioning in a context-dependent fashion via suppression of multiple targets and with cumulative synergistic effects. This indicates reduction of miR-132 levels as a possible treatment of hepatic steatosis.
Yarden, TS, Nelken I.  2017.  Stimulus-specific adaptation in a recurrent network model of primary auditory cortex.. PLoS Comput Biol.. 13(3):e1005437. doi: 10.1371/journal.pcbi.1005437. Abstract
Stimulus-specific adaptation (SSA) occurs when neurons decrease their responses to frequently-presented (standard) stimuli but not, or not as much, to other, rare (deviant) stimuli. SSA is present in all mammalian species in which it has been tested as well as in birds. SSA confers short-term memory to neuronal responses, and may lie upstream of the generation of mismatch negativity (MMN), an important human event-related potential. Previously published models of SSA mostly rely on synaptic depression of the feedforward, thalamocortical input. Here we study SSA in a recurrent neural network model of primary auditory cortex. When the recurrent, intracortical synapses display synaptic depression, the network generates population spikes (PSs). SSA occurs in this network when deviants elicit a PS but standards do not, and we demarcate the regions in parameter space that allow SSA. While SSA based on PSs does not require feedforward depression, we identify feedforward depression as a mechanism for expanding the range of parameters that support SSA. We provide predictions for experiments that could help differentiate between SSA due to synaptic depression of feedforward connections and SSA due to synaptic depression of recurrent connections. Similar to experimental data, the magnitude of SSA in the model depends on the frequency difference between deviant and standard, probability of the deviant, inter-stimulus interval and input amplitude. In contrast to models based on feedforward depression, our model shows true deviance sensitivity as found in experiments.
Zylbertal, A, Yarom Y, Wagner S.  2017.  Synchronous Infra-Slow Bursting in the Mouse Accessory Olfactory Bulb Emerge from Interplay between Intrinsic Neuronal Dynamics and Network Connectivity.. The Journal of neuroscience : the official journal of the Society for Neuroscience. 37(10):2656-2672. Abstract
Rhythmic neuronal activity of multiple frequency bands has been described in many brain areas and attributed to numerous brain functions. Among these, little is known about the mechanism and role of infra-slow oscillations, which have been demonstrated recently in the mouse accessory olfactory bulb (AOB). Along with prolonged responses to stimuli and distinct network connectivity, they inexplicably affect the AOB processing of social relevant stimuli. Here, we show that assemblies of AOB mitral cells are synchronized by lateral interactions through chemical and electrical synapses. Using a network model, we demonstrate that the synchronous oscillations in these assemblies emerge from interplay between intrinsic membrane properties and network connectivity. As a consequence, the AOB network topology, in which each mitral cell receives input from multiple glomeruli, enables integration of chemosensory stimuli over extended time scales by interglomerular synchrony of infra-slow bursting. These results provide a possible functional significance for the distinct AOB physiology and topology. Beyond the AOB, this study presents a general model for synchronous infra-slow bursting in neuronal networks.SIGNIFICANCE STATEMENT Infra-slow rhythmic neuronal activity with a very long (>10 s) duration has been described in many brain areas, but little is known about the role of this activity and the mechanisms that produce it. Here, we combine experimental and computational methods to show that synchronous infra-slow bursting activity in mitral cells of the mouse accessory olfactory bulb (AOB) emerges from interplay between intracellular dynamics and network connectivity. In this novel mechanism, slow intracellular Na(+) dynamics endow AOB mitral cells with a weak tendency to burst, which is further enhanced and stabilized by chemical and electrical synapses between them. Combined with the unique topology of the AOB network, infra-slow bursting enables integration and binding of multiple chemosensory stimuli over a prolonged time scale.
Goldstein, RH, Katz B, Lev S, Binshtok AM.  2017.  Ultrafast optical recording reveals distinct capsaicin-induced ion dynamics along single nociceptive neurite terminals in vitro.. Journal of Biomedical Optics. 22(7):76010.
Barkai, O, Goldstein RH, Caspi Y, Katz B, Lev S, Binshtok AM.  2017.  The Role of Kv7/M Potassium Channels in Controlling Ectopic Firing in Nociceptors.. Frontiers in Molecular Neuroscience. 10:181. Abstract
Peripheral nociceptive neurons encode and convey injury-inducing stimuli toward the central nervous system. In normal conditions, tight control of nociceptive resting potential prevents their spontaneous activation. However, in many pathological conditions the control of membrane potential is disrupted, leading to ectopic, stimulus-unrelated firing of nociceptive neurons, which is correlated to spontaneous pain. We have investigated the role of KV7/M channels in stabilizing membrane potential and impeding spontaneous firing of nociceptive neurons. These channels generate low voltage-activating, noninactivating M-type K(+) currents (M-current, IM ), which control neuronal excitability. Using perforated-patch recordings from cultured, rat nociceptor-like dorsal root ganglion neurons, we show that inhibition of M-current leads to depolarization of nociceptive neurons and generation of repetitive firing. To assess to what extent the M-current, acting at the nociceptive terminals, is able to stabilize terminals' membrane potential, thus preventing their ectopic activation, in normal and pathological conditions, we built a multi-compartment computational model of a pseudo-unipolar unmyelinated nociceptive neuron with a realistic terminal tree. The modeled terminal tree was based on the in vivo structure of nociceptive peripheral terminal, which we assessed by in vivo multiphoton imaging of GFP-expressing nociceptive neuronal terminals innervating mice hind paw. By modifying the conductance of the KV7/M channels at the modeled terminal tree (terminal gKV7/M) we have found that 40% of the terminal gKV7/M conductance is sufficient to prevent spontaneous firing, while ~75% of terminal gKV7/M is sufficient to inhibit stimulus induced activation of nociceptive neurons. Moreover, we showed that terminal M-current reduces susceptibility of nociceptive neurons to a small fluctuations of membrane potentials. Furthermore, we simulated how the interaction between terminal persistent sodium current and M-current affects the excitability of the neurons. We demonstrated that terminal M-current in nociceptive neurons impeded spontaneous firing even when terminal Na(V)1.9 channels conductance was substantially increased. On the other hand, when terminal gKV7/M was decreased, nociceptive neurons fire spontaneously after slight increase in terminal Na(V)1.9 conductance. Our results emphasize the pivotal role of M-current in stabilizing membrane potential and hereby in controlling nociceptive spontaneous firing, in normal and pathological conditions.
Mongillo, G, Rumpel S, Loewenstein Y.  2017.  Intrinsic volatility of synaptic connections — a challenge to the synaptic trace theory of memory. Current Opinion in Neurobiology. 46:7-13. Abstractpdf
According to the synaptic trace theory of memory, activity-induced changes in the pattern of synaptic connections underlie the storage of information for long periods. In this framework, the stability of memory critically depends on the stability of the underlying synaptic connections. Surprisingly however, synaptic connections in the living brain are highly volatile, which poses a fundamental challenge to the synaptic trace theory. Here we review recent experimental evidence that link the initial formation of a memory with changes in the pattern of connectivity, but also evidence that synaptic connections are considerably volatile even in the absence of learning. Then we consider different theoretical models that have been put forward to explain how memory can be maintained with such volatile building blocks.
Gal, E, London M, Globerson A, Ramaswamy S, Reimann MW, Muller E, Markram H, Segev I.  2017.  Rich cell-type-specific network topology in neocortical microcircuitry. Nature Neuroscience. 20(7) Abstract
Uncovering structural regularities and architectural topologies of cortical circuitry is vital for understanding neural computations. Recently, an experimentally constrained algorithm generated a dense network reconstruction of a ~0.3-mm 3 volume from juvenile rat somatosensory neocortex, comprising ~31,000 cells and ~36 million synapses. Using this reconstruction, we found a small-world topology with an average of 2.5 synapses separating any two cells and multiple cell-type-specific wiring features. Amounts of excitatory and inhibitory innervations varied across cells, yet pyramidal neurons maintained relatively constant excitation/inhibition ratios. The circuit contained highly connected hub neurons belonging to a small subset of cell types and forming an interconnected cell-type-specific rich club. Certain three-neuron motifs were overrepresented, matching recent experimental results. Cell-type-specific network properties were even more striking when synaptic strength and sign were considered in generating a functional topology. Our systematic approach enables interpretation of microconnectomics ‘big data’ and provides several experimentally testable predictions.
Mosheiff, N, Agmon H, Moriel A, Burak Y.  2017.  An efficient coding theory for a dynamic trajectory predicts non-uniform allocation of entorhinal grid cells to modules. PLoS Computational Biology. 13(6):e1005597.
Yarden-Rabinowitz, Y, Yarom Y.  2017.  In vivo analysis of synaptic activity in cerebellar nucleineurons unravels the efficacy of excitatory inputs. Journal of Physiology. 595(17) Abstract
It is commonly agreed that the main function of the cerebellar system is to providewell-timed signals used for the execution of motor commands or prediction of sensory inputs.This function is manifested as a temporal sequence of spiking that should be expressed in thecerebellar nuclei (CN) projection neurons. Whether spiking activity is generated by excitationor release from inhibition is still a hotly debated issue. In an attempt to resolve this debate,we recorded intracellularly from CN neurons in anaesthetized mice and performed an analysisof synaptic activity that yielded a number of important observations. First, we demonstratethat CN neurons can be classified into four groups. Second, shape-index plots of the excitatoryevents suggest that they are distributed over the entire dendritic tree. Third, the rise time ofexcitatory events is linearly related to amplitude, suggesting that all excitatory events contributeequally to the generation of action potentials (APs). Fourth, we identified a temporal patternof spontaneous excitatory events that represent climbing fibre inputs and confirm the resultsby direct stimulation and analysis on harmaline-evoked activity. Finally, we demonstrate thatthe probability of excitatory inputs generating an AP is 0.1 yet half of the APs are generated byexcitatory events. Moreover, the probability of a presumably spontaneous climbing fibre inputgenerating an AP is higher, reaching a mean population value of 0.15. In view of these results, themode of synaptic integration at the level of the CN should be re-considered.
Mongillo, G, Loewenstein Y.  2017.  Neuroscience: Formation of a Percept in the Rat Cortex. Current Biology. 27(11):1585-1596.e6. Abstractpdf
It has long been known that we subjectively experience longer stimuli as being more intense. A recent study sheds light on the neural mechanisms underlying this bias by tracking the formation of a percept of intensity in the rat brain.
Murakami, M, Shteingart H, Loewenstein Y, Mainen ZF.  2017.  Distinct Sources of Deterministic and Stochastic Components of Action Timing Decisions in Rodent Frontal Cortex. Neuron. 94(4):908–919. Abstractmmc2.pdf
The selection and timing of actions are subject to determinate influences such as sensory cues and internal state as well as to effectively stochastic variability. Although stochastic choice mechanisms are assumed by many theoretical models, their origin and mechanisms remain poorly understood. Here we investigated this issue by studying how neural circuits in the frontal cortex determine action timing in rats performing a waiting task. Electrophysiological recordings from two regions necessary for this behavior, medial prefrontal cortex (mPFC) and secondary motor cortex (M2), revealed an unexpected functional dissociation. Both areas encoded deterministic biases in action timing, but only M2 neurons reflected stochastic trial-by-trial fluctuations. This differential coding was reflected in distinct timescales of neural dynamics in the two frontal cortical areas. These results suggest a two-stage model in which stochastic components of action timing decisions are injected by circuits downstream of those carrying deterministic bias signals.
Shaham, N, Burak Y.  2017.  Slow Diffusive Dynamics in a Chaotic Balanced Neural Network. PLoS Computational Biology. 13(5):e1005505.2017_shaham_burak.pdf
Dan, O, Hochner-Celnikier D, Solnica A RN, Loewenstein Y.  2017.  Association of Catastrophic Neonatal Outcomes With Increased Rate of Subsequent Cesarean Deliveries. Obstetrics & Gynecology. 129(4):671-675. Abstractpdf Supplemental Digital Content
OBJECTIVE: To evaluate whether full-term deliveries resulting in neonates diagnosed with hypoxic–ischemic encephalopathy are associated with a significant increase in the rate of subsequent unscheduled cesarean deliveries. METHODS: We conducted a retrospective chart review study and examined all deliveries in the Department of Obstetrics and Gynecology at Hadassah University Hospital, Mt. Scopus campus, Jerusalem, Israel, during 2009–2014. We reviewed all cases of hypoxic–ischemic encephalopathy in singleton, term, liveborn neonates and identified seven such cases, three of which were attributed to obstetric mismanagement and four that were not. We measured the rate of unscheduled cesarean deliveries before and after the events and their respective hazard ratio. RESULTS: Before a mismanaged delivery resulting in hypoxic–ischemic encephalopathy, the baseline rate of unscheduled cesarean deliveries was approximately 80 unscheduled cesarean deliveries for every 1,000 deliveries. In the first 4 weeks immediately after each of the three identified cases, there was a significant increase in the rate of unscheduled cesarean deliveries by an additional 48 unscheduled cesarean deliveries per 1,000 deliveries (95% confidence interval [CI] 27–70/1,000). This increase was transient and lasted approximately 4 weeks. We estimated that each case was associated with approximately 17 additional unscheduled cesarean deliveries (95% CI 8–27). There was no increase in the rate of unscheduled cesarean deliveries in cases of hypoxic–ischemic encephalopathy that were not associated with mismanagement. CONCLUSION: The increase in the rate of unscheduled cesarean deliveries after a catastrophic neonatal outcome may result in short-term changes in obstetricians' risk evaluation.
Berman, S, West, K, Does, MD, Yeatman, JD, Mezer, AA.  2017.  Evaluating g-ratio weighted changes in the corpus callosum as a function of age and sex.. Abstract
Recent years have seen a growing interest in relating MRI measurements to the structural-biophysical properties of white matter fibers. The fiber g-ratio, defined as the ratio between the inner and outer radii of the axon myelin sheath, is an important structural property of white matter, affecting signal conduction. Recently proposed modeling methods that use a combination of quantitative-MRI signals, enable a measurement of the fiber g-ratio in vivo. Here we use an MRI-based g-ratio estimation to observe the variance of the g-ratio within the corpus callosum, and evaluate sex and age related differences. To estimate the g-ratio we used a model (Stikov, 2012; Duval et al., 2016) based on two different WM microstructure parameters: the relative amounts of myelin (myelin volume fraction, MVF) and fibers (fiber volume fraction, FVF) in a voxel. We derived the FVF from the fractional anisotropy (FA), and estimated the MVF by using the lipid and macromolecular tissue volume (MTV), calculated from the proton density (Mezer et al., 2013). In comparison to other methods of estimating the MVF, MTV represents a stable parameter with a straightforward route of acquisition. To establish our model, we first compared histological MVF measurements (West et al., 2016) with the MRI derived MTV. We then implemented our model on a large database of 92 subjects (44 males), aged 7 to 81, in order to evaluate age and sex related changes within the corpus callosum. Our results show that the MTV provides a good estimation of MVF for calculating g-ratio, and produced values from the corpus callosum that correspond to those found in animals ex vivo and are close to the theoretical optimum, as well as to published in vivo data. Our results demonstrate that the MTV derived g-ratio provides a simple and reliable in vivo g-ratio-weighted (GR*) measurement in humans. In agreement with theoretical predictions, and unlike other tissue parameters measured with MRI, the g-ratio estimations were found to be relatively stable with age, and we found no support for a significant sexual dimorphism with age.
Gomez, J, Barnett MA, Natu V, Mezer A, Palomero-Gallagher N, Weiner KS, Amunts K, Zilles K, Grill-Spector K.  2017.  Microstructural proliferation in human cortex is coupled with the development of face processing. Science. Abstract
How does cortical tissue change as brain function and behavior improve from childhood to adulthood? By combining quantitative and functional magnetic resonance imaging in children and adults, we find differential development of high-level visual areas that are involved in face and place recognition. Development of face-selective regions, but not place-selective regions, is dominated by microstructural proliferation. This tissue development is correlated with specific increases in functional selectivity to faces, as well as improvements in face recognition, and ultimately leads to differentiated tissue properties between face- and place-selective regions in adulthood, which we validate with postmortem cytoarchitectonic measurements. These data suggest a new model by which emergent brain function and behavior result from cortical tissue proliferation rather than from pruning exclusively.
Jaffe-Dax, S, Frenkel O, Ahissar M.  2017.  Shorter neural adaptation to sounds accounts for dyslexics' abnormal perceptual and reading dynamics. eLife. 6glocal_tones_block1.txtglocal_tones_block2.txtglocal_tones_block3.txtglocal_tones_block4.txtcorrelationmartices.pngresulttable.txt
Maoz, R, Garfinkel BP, Soreq H.  2017.  Alzheimer's Disease and ncRNAs. Adv Exp Med Biol. 978:337-361. Abstract
Alzheimer's disease is a devastating neurodegenerative disorder affecting a significant portion of the world's rapidly growing aging population. In spite of its prevalence, the etiology of the disease is still poorly understood, and effective therapy is all but unavailable. Over the past decade, noncoding RNA, including microRNA (miRNA), has emerged as a major class of regulatory molecules involved in virtually all physiological and disease states. The specificity provided by miRNA sequence complementarity, together with the ability of these molecules to regulate complex networks of genes, has made them exciting novel targets for therapeutic agents. In this chapter, we review recent progress on understanding the role of noncoding RNA in Alzheimer's disease (AD). The majority of available work has focused on miRNA, and we review the many studies implicating specific miRNAs in the development of the disease. More recently, several studies have tied other RNA classes to the disorder, including long noncoding RNA, circular RNA, and Y RNAs, and we review this fascinating field as well. Finally, we explore the potential promise of these findings for future therapeutic applications.