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Lebovich, L, Darshan R, Lavi Y, Hansel D, Loewenstein Y.  Submitted.  Idiosyncratic choice bias in decision tasks naturally emerges from neuronal network dynamics. Abstract
Idiosyncratic tendency to choose one alternative over others in the absence of an identified reason, is a common observation in two-alternative forced-choice experiments. It is tempting to account for it as resulting from the (unknown) participant-specific history and thus treat it as a measurement noise. Indeed, idiosyncratic choice biases are typically considered as nuisance. Care is taken to account for them by adding an ad-hoc bias parameter or by counterbalancing the choices to average them out. Here we quantify idiosyncratic choice biases in a perceptual discrimination task and a motor task. We report substantial and significant biases in both cases. Then, we present theoretical evidence that even in idealized experiments, in which the settings are symmetric, idiosyncratic choice bias is expected to emerge from the dynamics of competing neuronal networks. We thus argue that idiosyncratic choice bias reflects the microscopic dynamics of choice and therefore is virtually inevitable in any comparison or decision task.
2018
Maor, I, Elyada Y, Mizrahi A.  2018.  The Educage: an automated platform for studying auditory perceptual learning in mice. bioRxiv. Abstract
Perceptual learning (PL) is a form of implicit learning that requires lengthy training in order to improve perceptual abilities. Without reliable automation, this can require arduous manual labor which can impede experimental progress. We developed an automated platform, the Educage, that enables PL of groups of mice training simultaneously in a home-cage environment. The system is low-cost, runs automatically for long durations, and allows a large degree of flexibility in experimental design. We used the Educage to train mice on a go/no-go auditory discrimination task. Mice were trained to discriminate between pure tone sequences or frequency modulated vocalizations. We found that gradually increasing cognitive load by manipulating task difficulty was necessary to improve learning outcomes. Task difficulty was also associated with increased decision times and decreased discrimination performances of individual animals. The Educage is a new tool for studying, among others, perceptual learning in mice.
Heffley, W, Song E Y, Xu Z, Taylor BN, Hughes M A, McKinney A, Joshua M, Hull C.  2018.  Coordinated cerebellar climbing fiber activity signals learned sensorimotor predictions.. Nature neuroscience. 21(10):1431-1441. Abstract
The prevailing model of cerebellar learning states that climbing fibers (CFs) are both driven by, and serve to correct, erroneous motor output. However, this model is grounded largely in studies of behaviors that utilize hardwired neural pathways to link sensory input to motor output. To test whether this model applies to more flexible learning regimes that require arbitrary sensorimotor associations, we developed a cerebellar-dependent motor learning task that is compatible with both mesoscale and single-dendrite-resolution calcium imaging in mice. We found that CFs were preferentially driven by and more time-locked to correctly executed movements and other task parameters that predict reward outcome, exhibiting widespread correlated activity in parasagittal processing zones that was governed by these predictions. Together, our data suggest that such CF activity patterns are well-suited to drive learning by providing predictive instructional input that is consistent with an unsigned reinforcement learning signal but does not rely exclusively on motor errors.
de Hoz, L, Gierej D, Lioudyno V, Jaworski J, Blazejczyk M, Cruces-Solís H, Beroun A, Lebitko T, Nikolaev T, Knapska E et al..  2018.  Blocking c-Fos Expression Reveals the Role of Auditory Cortex Plasticity in Sound Frequency Discrimination Learning.. Cerebral cortex (New York, N.Y. : 1991). 28(5):1645-1655. Abstract
The behavioral changes that comprise operant learning are associated with plasticity in early sensory cortices as well as with modulation of gene expression, but the connection between the behavioral, electrophysiological, and molecular changes is only partially understood. We specifically manipulated c-Fos expression, a hallmark of learning-induced synaptic plasticity, in auditory cortex of adult mice using a novel approach based on RNA interference. Locally blocking c-Fos expression caused a specific behavioral deficit in a sound discrimination task, in parallel with decreased cortical experience-dependent plasticity, without affecting baseline excitability or basic auditory processing. Thus, c-Fos-dependent experience-dependent cortical plasticity is necessary for frequency discrimination in an operant behavioral task. Our results connect behavioral, molecular and physiological changes and demonstrate a role of c-Fos in experience-dependent plasticity and learning.
Lixenberg, A, Joshua M.  2018.  Encoding of Reward and Decoding Movement from the Frontal Eye Field during Smooth Pursuit Eye Movements.. The Journal of neuroscience : the official journal of the Society for Neuroscience. 38(49):10515-10524. Abstract
Expectation of reward potentiates sensorimotor transformations to drive vigorous movements. One of the main challenges in studying reward is to determine how representations of reward interact with the computations that drive behavior. We recorded activity in smooth pursuit neurons in the frontal eye field (FEF) of two male rhesus monkeys while controlling the eye speed by manipulating either reward size or target speed. The neurons encoded the different reward conditions more strongly than the different target speed conditions. This pattern could not be explained by differences in the eye speed, since the eye speed sensitivity of the neurons was also larger for the reward conditions. Pooling the responses by the preferred direction of the neurons attenuated the reward modulation and led to a tighter association between neural activity and behavior. Therefore, a plausible decoder such as the population vector could explain how the FEF both drives behavior and encodes reward beyond behavior. Motor areas combine sensory and reward information to drive movement. To disambiguate these sources, we manipulated the speed of smooth pursuit eye movements by controlling either the size of the reward or the speed of the visual motion signals. We found that the relationship between activity in frontal eye field and eye kinematics varied: the eye speed sensitivity was larger for the different reward conditions than for the different target speed conditions. Decoders that pooled signals by the preferred direction of the neurons attenuated the reward modulations. These decoders may indicate how reward can be both encoded beyond eye kinematics at the single neuron level and drive movement at the population level.
Polterovich, A, Jankowski MM, Nelken I.  2018.  Deviance sensitivity in the auditory cortex of freely moving rats.. PloS one. 13(6):e0197678. Abstract
Deviance sensitivity is the specific response to a surprising stimulus, one that violates expectations set by the past stimulation stream. In audition, deviance sensitivity is often conflated with stimulus-specific adaptation (SSA), the decrease in responses to a common stimulus that only partially generalizes to other, rare stimuli. SSA is usually measured using oddball sequences, where a common (standard) tone and a rare (deviant) tone are randomly intermixed. However, the larger responses to a tone when deviant does not necessarily represent deviance sensitivity. Deviance sensitivity is commonly tested using a control sequence in which many different tones serve as the standard, eliminating the expectations set by the standard ('deviant among many standards'). When the response to a tone when deviant (against a single standard) is larger than the responses to the same tone in the control sequence, it is concluded that true deviance sensitivity occurs. In primary auditory cortex of anesthetized rats, responses to deviants and to the same tones in the control condition are comparable in size. We recorded local field potentials and multiunit activity from the auditory cortex of awake, freely moving rats, implanted with 32-channel drivable microelectrode arrays and using telemetry. We observed highly significant SSA 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. These results establish the presence of true deviance sensitivity in primary auditory cortex in awake rats.
Tasaka, G-ichi, Guenthner CJ, Shalev A, Gilday O, Luo L, Mizrahi A.  2018.  Genetic tagging of active neurons in auditory cortex reveals maternal plasticity of coding ultrasonic vocalizations. Nat Commun. 9(1):871. Abstract
Cortical neurons are often functionally heterogeneous even for molecularly defined subtypes. In sensory cortices, physiological responses to natural stimuli can be sparse and vary widely even for neighboring neurons. It is thus difficult to parse out circuits that encode specific stimuli for further experimentation. Here, we report the development of a Cre-reporter mouse that allows recombination for cellular labeling and genetic manipulation, and use it with an activity-dependent Fos-CreERT2 driver to identify functionally active circuits in the auditory cortex. In vivo targeted patch recordings validate our method for neurons responding to physiologically relevant natural sounds such as pup wriggling calls and ultrasonic vocalizations (USVs). Using this system to investigate cortical responses in postpartum mothers, we find a transient recruitment of neurons highly responsive to USVs. This subpopulation of neurons has distinct physiological properties that improve the coding efficiency for pup USV calls, implicating it as a unique signature in parental plasticity.
Mizrahi, A.  2018.  The Hard and Soft Wired Nature of the Olfactory Map. Trends in NeurosciencesTrends in Neurosciences. 41(12):872-874.
Botschko, Y, Yarkoni M, Joshua M.  2018.  Smooth Pursuit Eye Movement of Monkeys Naive to Laboratory Setups With Pictures and Artificial Stimuli.. Frontiers in systems neuroscience. 12:15. Abstract
When animal behavior is studied in a laboratory environment, the animals are often extensively trained to shape their behavior. A crucial question is whether the behavior observed after training is part of the natural repertoire of the animal or represents an outlier in the animal's natural capabilities. This can be investigated by assessing the extent to which the target behavior is manifested during the initial stages of training and the time course of learning. We explored this issue by examining smooth pursuit eye movements in monkeys naïve to smooth pursuit tasks. We recorded the eye movements of monkeys from the 1st days of training on a step-ramp paradigm. We used bright spots, monkey pictures and scrambled versions of the pictures as moving targets. We found that during the initial stages of training, the pursuit initiation was largest for the monkey pictures and in some direction conditions close to target velocity. When the pursuit initiation was large, the monkeys mostly continued to track the target with smooth pursuit movements while correcting for displacement errors with small saccades. Two weeks of training increased the pursuit eye velocity in all stimulus conditions, whereas further extensive training enhanced pursuit slightly more. The training decreased the coefficient of variation of the eye velocity. Anisotropies that grade pursuit across directions were observed from the 1st day of training and mostly persisted across training. Thus, smooth pursuit in the step-ramp paradigm appears to be part of the natural repertoire of monkeys' behavior and training adjusts monkeys' natural predisposed behavior.
Mongillo, G, Rumpel S, Loewenstein Y.  2018.  Inhibitory connectivity defines the realm of excitatory plasticity. Nature Neuroscience. 21:1463–1470. AbstractPDF
Recent experiments demonstrate substantial volatility of excitatory connectivity in the absence of any learning. This challenges the hypothesis that stable synaptic connections are necessary for long-term maintenance of acquired information. Here we measure ongoing synaptic volatility and use theoretical modeling to study its consequences on cortical dynamics. We show that in the balanced cortex, patterns of neural activity are primarily determined by inhibitory connectivity, despite the fact that most synapses and neurons are excitatory. Similarly, we show that the inhibitory network is more effective in storing memory patterns than the excitatory one. As a result, network activity is robust to ongoing volatility of excitatory synapses, as long as this volatility does not disrupt the balance between excitation and inhibition. We thus hypothesize that inhibitory connectivity, rather than excitatory, controls the maintenance and loss of information over long periods of time in the volatile cortex.
Elber-Dorozko, L, Loewenstein Y.  2018.  Striatal action-value neurons reconsidered. eLife. 7:e34248. Abstract PDF
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.
Fox, L, Choshen L, Loewenstein Y.  2018.  DORA The Explorer: Directed Outreaching Reinforcement Action-Selection. ICLR. 2018 AbstractPDF
Exploration is a fundamental aspect of Reinforcement Learning, typically implemented using stochastic action-selection. Exploration, however, can be more efficient if directed toward gaining new world knowledge. Visit-counters have been proven useful both in practice and in theory for directed exploration. However, a major limitation of counters is their locality. While there are a few model-based solutions to this shortcoming, a model-free approach is still missing. We propose $E$-values, a generalization of counters that can be used to evaluate the propagating exploratory value over state-action trajectories. We compare our approach to commonly used RL techniques, and show that using $E$-values improves learning and performance over traditional counters. We also show how our method can be implemented with function approximation to efficiently learn continuous MDPs. We demonstrate this by showing that our approach surpasses state of the art performance in the Freeway Atari 2600 game.
Lottem, E, Banerjee D, Vertechi P, Sarra D, oude Lohuis M, Mainen ZF.  2018.  Activation of serotonin neurons promotes active exploitation in a probabilistic foraging task. nature communications. Abstract
The neuromodulator serotonin (5-HT) has been implicated in a variety of functions that involve patience or impulse control. Many of these effects are consistent with a long-standing theory that 5-HT promotes behavioral inhibition, a motivational bias favoring passive over active behaviors. To further test this idea, we studied the impact of 5-HT in a probabilistic foraging task, in which mice must learn the statistics of the environment and infer when to leave a depleted foraging site for the next. Critically, mice were required to actively nose-poke in order to exploit a given site. We show that optogenetic activation of 5-HT neurons in the dorsal raphe nucleus increases the willingness of mice to actively attempt to exploit a reward site before giving up. These results indicate that behavioral inhibition is not an adequate description of 5-HT function and suggest that a unified account must be based on a higher-order function.
Mezer, AA, Filo S.  2018.  PD: Proton Density of Tissue Water. Quantitative MRI of the Brain Abstract
https://www.taylorfrancis.com/books/e/9781315363561/chapters/10.1201%2Fb21837-4
Segev, I, Moldwin T.  2018.  Perceptron learning and classification in a modeled cortical pyramidal cell. Abstract
The perceptron learning algorithm and its multiple-layer extension, the backpropagation algorithm, are the foundations of the present-day machine learning revolution. However, these algorithms utilize a highly simplified mathematical abstraction of a neuron; it is not clear to what extent real biophysical neurons with morphologically-extended nonlinear dendritic trees and conductance-based synapses could realize perceptron-like learning. Here we implemented the perceptron learning algorithm in a realistic biophysical model of a layer 5 cortical pyramidal cell. We tested this biophysical perceptron (BP) on a memorization task, where it needs to correctly binarily classify 1000 patterns, and a generalization task, where it should discriminate between 'noisy' patterns drawn from one of two probability distributions. We show that, for most cases, the BP performs these tasks with an accuracy comparable to that of the original perceptron. We concluded that cortical pyramidal neurons can act as powerful classification devices.
Yaara, L, Amsalem O, Segev I, Yarom Y.  2018.  Using subthreshold events to characterize the functional architecture of electrically coupled networks. bioRxiv. Abstract
The electrical connectivity in the inferior olive (IO) nucleus plays an important role in generating well-timed spiking activity. Here we combined electrophysiological and computational approaches to assess the functional organization of mice IO nucleus. Spontaneous fast and slow subthreshold events were commonly encountered during in vitro recordings. We show that the fast events represent a regenerative response in unique excitable spine-like structures in the axon hillock, whereas the slow events reflect the electrical connectivity between neurons (‘spikelets’). Recordings from cell pairs revealed the synchronized occurrence of distinct groups of spikelets; their rate and distribution enabled an accurate estimation of the number of connected cells and is suggestive of a clustered organization. This study thus provides a new perspective on the functional and structural organization of the olivary nucleus, insights into two different subthreshold non-synaptic events, and a novel experimental and theoretical approach to the study of electrically-coupled networks.
Atlan, G, Terem A, Peretz-Rivlin N, Sehrawat K, Gonzales B J, Pozner G, Tasaka G-ichi, Goll Y, Refaeli R, Zviran O et al..  2018.  The Claustrum Supports Resilience to Distraction. Current Biology. 28:2752-2762.e7. Abstract
Summary A barrage of information constantly assaults our senses, of which only a fraction is relevant at any given point in time. However, the neural circuitry supporting the suppression of irrelevant sensory distractors is not completely understood. The claustrum, a circuit hub with vast cortical connectivity, is an intriguing brain structure, whose restrictive anatomy, thin and elongated, has precluded functional investigation. Here, we describe the use of Egr2-CRE mice to access genetically defined claustral neurons. Utilizing conditional viruses for anterograde axonal labeling and retrograde trans-synaptic tracing, we validated this transgenic model for accessing the claustrum and extended the known repertoire of claustral input/output connectivity. Addressing the function of the claustrum, we inactivated CLEgr2+ neurons, chronically as well as acutely, in mice performing an automated two-alternative forced-choice behavioral task. Strikingly, inhibition of CLEgr2+ neurons did not significantly impact task performance under varying delay times and cue durations, but revealed a selective role for the claustrum in supporting performance in the presence of an irrelevant auditory distractor. Further investigation of behavior, in the naturalistic maternal pup-retrieval task, replicated the result of sensitization to an auditory distractor following inhibition of CLEgr2+ neurons. Initiating investigation into the underlying mechanism, we found that activation of CLEgr2+ neurons modulated cortical sensory processing, suppressing tone representation in the auditory cortex. This functional study, utilizing selective genetic access, implicates the claustrum in supporting resilience to distraction, a fundamental aspect of attention.
Schurr, R, Duan Y, Norcia AM, Ogawa S, Yeatman JD, Mezer AA.  2018.  Tractography optimization using quantitative T1 mapping in the human optic radiation. NeuroImage. 181:645-658.
2017
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.