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Neuron
Journal Prestige (SJR): 10.654
Citation Impact (citeScore): 11
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ISSN (Print) 0896-6273 - ISSN (Online) 1097-4199
Published by Elsevier Homepage  [3183 journals]
  • Neural Correlates of Optimal Multisensory Decision Making under
           Time-Varying Reliabilities with an Invariant Linear Probabilistic
           Population Code
    • Abstract: Publication date: Available online 10 October 2019Source: NeuronAuthor(s): Han Hou, Qihao Zheng, Yuchen Zhao, Alexandre Pouget, Yong GuSummaryPerceptual decisions are often based on multiple sensory inputs whose reliabilities rapidly vary over time, yet little is known about how the brain integrates these inputs to optimize behavior. The optimal solution requires that neurons simply add their sensory inputs across time and modalities, as long as these inputs are encoded with an invariant linear probabilistic population code (ilPPC). While this theoretical possibility has been raised before, it has never been tested experimentally. Here, we report that neural activities in the lateral intraparietal area (LIP) of macaques performing a vestibular-visual multisensory decision-making task are indeed consistent with the ilPPC theory. More specifically, we found that LIP accumulates momentary evidence proportional to the visual speed and the absolute value of vestibular acceleration, two variables that are encoded with close approximations to ilPPCs in sensory areas. Together, these results provide a remarkably simple and biologically plausible solution to near-optimal multisensory decision making.
       
  • Jacqueline Crawley
    • Abstract: Publication date: 9 October 2019Source: Neuron, Volume 104, Issue 1Author(s): Dr. Jacqueline Crawley aims to understand the genetic causes of autism spectrum disorder and discover effective medical therapeutics for the core diagnostic symptoms of autism using rodent models. In an interview with Neuron, she shares her career milestones, aspirations and guiding principles inspiring her ongoing work.
       
  • Bayesian Decision Models: A Primer
    • Abstract: Publication date: 9 October 2019Source: Neuron, Volume 104, Issue 1Author(s): Wei Ji MaTo understand decision-making behavior in simple, controlled environments, Bayesian models are often useful. First, optimal behavior is always Bayesian. Second, even when behavior deviates from optimality, the Bayesian approach offers candidate models to account for suboptimalities. Third, a realist interpretation of Bayesian models opens the door to studying the neural representation of uncertainty. In this tutorial, we review the principles of Bayesian models of decision making and then focus on five case studies with exercises. We conclude with reflections and future directions.
       
  • Chemistry of the Adaptive Mind: Lessons from Dopamine
    • Abstract: Publication date: 9 October 2019Source: Neuron, Volume 104, Issue 1Author(s): Roshan CoolsThe brain faces various computational tradeoffs, such as the stability-flexibility dilemma. The major ascending neuromodulatory systems are well suited to dynamically regulate these tradeoffs depending on changing task demands. This follows from various general principles of chemical neuromodulation, which are illustrated with evidence from pharmacological neuroimaging studies on striatal dopamine’s role in output gating and cost-benefit choice of cognitive tasks. The work raises open questions, including those regarding the top-down cortical control of the midbrain dopamine system, and begins to elucidate the mechanisms underlying the variability in catecholaminergic drug effects. Such drug effects depend on the baseline state of distinct target brain regions, reflecting, in part, the systems’ self-regulatory capacity to maintain equilibrium. It is hypothesized that the basal tone of different dopaminergic projection systems reflects the perceived statistics of the environment computed in frontal cortex. By normalizing dopamine levels, dopaminergic drugs might counteract the bias elicited by the perceived environment.
       
  • Designing and Interpreting Psychophysical Investigations of Cognition
    • Abstract: Publication date: 9 October 2019Source: Neuron, Volume 104, Issue 1Author(s): Michael L. Waskom, Gouki Okazawa, Roozbeh KianiScientific experimentation depends on the artificial control of natural phenomena. The inaccessibility of cognitive processes to direct manipulation can make such control difficult to realize. Here, we discuss approaches for overcoming this challenge. We advocate the incorporation of experimental techniques from sensory psychophysics into the study of cognitive processes such as decision making and executive control. These techniques include the use of simple parameterized stimuli to precisely manipulate available information and computational models to jointly quantify behavior and neural responses. We illustrate the potential for such techniques to drive theoretical development, and we examine important practical details of how to conduct controlled experiments when using them. Finally, we highlight principles guiding the use of computational models in studying the neural basis of cognition.
       
  • A Modular Approach to Vocal Learning: Disentangling the Diversity of a
           Complex Behavioral Trait
    • Abstract: Publication date: 9 October 2019Source: Neuron, Volume 104, Issue 1Author(s): Morgan Wirthlin, Edward F. Chang, Mirjam Knörnschild, Leah A. Krubitzer, Claudio V. Mello, Cory T. Miller, Andreas R. Pfenning, Sonja C. Vernes, Ofer Tchernichovski, Michael M. YartsevVocal learning is a behavioral trait in which the social and acoustic environment shapes the vocal repertoire of individuals. Over the past century, the study of vocal learning has progressed at the intersection of ecology, physiology, neuroscience, molecular biology, genomics, and evolution. Yet, despite the complexity of this trait, vocal learning is frequently described as a binary trait, with species being classified as either vocal learners or vocal non-learners. As a result, studies have largely focused on a handful of species for which strong evidence for vocal learning exists. Recent studies, however, suggest a continuum in vocal learning capacity across taxa. Here, we further suggest that vocal learning is a multi-component behavioral phenotype comprised of distinct yet interconnected modules. Discretizing the vocal learning phenotype into its constituent modules would facilitate integration of findings across a wider diversity of species, taking advantage of the ways in which each excels in a particular module, or in a specific combination of features. Such comparative studies can improve understanding of the mechanisms and evolutionary origins of vocal learning. We propose an initial set of vocal learning modules supported by behavioral and neurobiological data and highlight the need for diversifying the field in order to disentangle the complexity of the vocal learning phenotype.
       
  • Neural Basis of Observational Fear Learning: A Potential Model of
           Affective Empathy
    • Abstract: Publication date: 9 October 2019Source: Neuron, Volume 104, Issue 1Author(s): Sehoon Keum, Hee-Sup ShinObservational fear learning in rodents is a type of context-dependent fear conditioning in which an unconditioned stimulus (US) is provided vicariously by observing conspecific others receiving foot shocks. This suggests the involvement of affective empathy, with several recent studies showing many similarities between this behavior and human empathy. Neurobiologically, it is important to understand the neural mechanisms by which the vicarious US activates the fear circuit via the affective pain system, obviating the sensory pain pathway and eventually leading to fear memory formation. This paper reviews current studies on the neural mechanisms underlying observational fear learning and provides a perspective on future research on this subject.
       
  • Learning from Action: Reconsidering Movement Signaling in Midbrain
           Dopamine Neuron Activity
    • Abstract: Publication date: 9 October 2019Source: Neuron, Volume 104, Issue 1Author(s): Luke T. Coddington, Joshua T. DudmanAnimals infer when and where a reward is available from experience with informative sensory stimuli and their own actions. In vertebrates, this is thought to depend upon the release of dopamine from midbrain dopaminergic neurons. Studies of the role of dopamine have focused almost exclusively on their encoding of informative sensory stimuli; however, many dopaminergic neurons are active just prior to movement initiation, even in the absence of sensory stimuli. How should current frameworks for understanding the role of dopamine incorporate these observations' To address this question, we review recent anatomical and functional evidence for action-related dopamine signaling. We conclude by proposing a framework in which dopaminergic neurons encode subjective signals of action initiation to solve an internal credit assignment problem.
       
  • The Meaning of Behavior: Discriminating Reflex and Volition in the Brain
    • Abstract: Publication date: 9 October 2019Source: Neuron, Volume 104, Issue 1Author(s): Bernard W. BalleineThe ability to establish behaviorally what psychological capacity an animal is deploying—to discern accurately what an animal is doing—is key to functional analyses of the brain. Our current understanding of these capacities suggests, however, that this task is complex; there is evidence that multiple capacities are engaged simultaneously and contribute independently to the control of behavior. As such, establishing the contribution of a cell, circuit, or neural system to any one function requires careful dissection of that role from its influence on other functions and, therefore, the careful selection and design of behavioral tasks fit for that purpose. Here I describe recent research that has sought to utilize behavioral tools to investigate the neural bases of instrumental conditioning, particularly the circuits and systems supporting the capacity for goal-directed action, as opposed to conditioned reflexes and habits, and how these sources of action control interact to generate adaptive behavior.
       
  • Progressive Circuit Changes during Learning and Disease
    • Abstract: Publication date: 9 October 2019Source: Neuron, Volume 104, Issue 1Author(s): Alison L. Barth, Ajit RayA critical step toward understanding cognition, learning, and brain dysfunction will be identification of the underlying cellular computations that occur in and across discrete brain areas, as well as how they are progressively altered by experience or disease. These computations will be revealed by targeted analyses of the neurons that perform these calculations, defined not only by their firing properties but also by their molecular identity and how they are wired within the local and broad-scale network of the brain. New studies that take advantage of sophisticated genetic tools for cell-type-specific identification and control are revealing how learning and neurological disorders initiate and successively change the properties of defined neural circuits. Understanding the temporal sequence of adaptive or pathological synaptic changes across multiple synapses within a network will shed light into how small-scale neural circuits contribute to higher cognitive functions during learning and disease.
       
  • The Life of Behavior
    • Abstract: Publication date: 9 October 2019Source: Neuron, Volume 104, Issue 1Author(s): Alex Gomez-Marin, Asif A. GhazanfarNeuroscience needs behavior. However, it is daunting to render the behavior of organisms intelligible without suppressing most, if not all, references to life. When animals are treated as passive stimulus-response, disembodied and identical machines, the life of behavior perishes. Here, we distill three biological principles (materiality, agency, and historicity), spell out their consequences for the study of animal behavior, and illustrate them with various examples from the literature. We propose to put behavior back into context, with the brain in a species-typical body and with the animal’s body situated in the world; stamp Newtonian time with nested ontogenetic and phylogenetic processes that give rise to individuals with their own histories; and supplement linear cause-and-effect chains and information processing with circular loops of purpose and meaning. We believe that conceiving behavior in these ways is imperative for neuroscience.
       
  • Computational Neuroethology: A Call to Action
    • Abstract: Publication date: 9 October 2019Source: Neuron, Volume 104, Issue 1Author(s): Sandeep Robert Datta, David J. Anderson, Kristin Branson, Pietro Perona, Andrew LeiferThe brain is worthy of study because it is in charge of behavior. A flurry of recent technical advances in measuring and quantifying naturalistic behaviors provide an important opportunity for advancing brain science. However, the problem of understanding unrestrained behavior in the context of neural recordings and manipulations remains unsolved, and developing approaches to addressing this challenge is critical. Here we discuss considerations in computational neuroethology—the science of quantifying naturalistic behaviors for understanding the brain—and propose strategies to evaluate progress. We point to open questions that require resolution and call upon the broader systems neuroscience community to further develop and leverage measures of naturalistic, unrestrained behavior, which will enable us to more effectively probe the richness and complexity of the brain.
       
  • Angela Roberts
    • Abstract: Publication date: 9 October 2019Source: Neuron, Volume 104, Issue 1Author(s): Angela Roberts is interested in emotion regulation. In an interview with Neuron, she talks about her work in primates, the importance of a deep understanding of behavior and comparative neuroanatomy, and the potential for concerted collaborative efforts to translate insights from animal studies into the clinic.
       
  • John Krakauer
    • Abstract: Publication date: 9 October 2019Source: Neuron, Volume 104, Issue 1Author(s): In an interview with Neuron, Dr. John Krakauer talks about his lab’s current work on motor learning and neurorehabilitation and shares his views on promoting “the slow and deep over the fast and shallow” and on the crucial need for diversity in academia.
       
  • Premembering Experience: A Hierarchy of Time-Scales for Proactive
           Attention
    • Abstract: Publication date: 9 October 2019Source: Neuron, Volume 104, Issue 1Author(s): Anna C. Nobre, Mark G. StokesMemories are about the past, but they serve the future. Memory research often emphasizes the former aspect: focusing on the functions that re-constitute (re-member) experience and elucidating the various types of memories and their interrelations, timescales, and neural bases. Here we highlight the prospective nature of memory in guiding selective attention, focusing on functions that use previous experience to anticipate the relevant events about to unfold—to “premember” experience. Memories of various types and timescales play a fundamental role in guiding perception and performance adaptively, proactively, and dynamically. Consonant with this perspective, memories are often recorded according to expected future demands. Using working memory as an example, we consider how mnemonic content is selected and represented for future use. This perspective moves away from the traditional representational account of memory toward a functional account in which forward-looking memory traces are informationally and computationally tuned for interacting with incoming sensory signals to guide adaptive behavior.
       
  • Behavior Matters
    • Abstract: Publication date: 9 October 2019Source: Neuron, Volume 104, Issue 1Author(s): Benedicte M. Babayan, Christina S. Konen
       
  • Enhancing Attentional Control: Lessons from Action Video Games
    • Abstract: Publication date: 9 October 2019Source: Neuron, Volume 104, Issue 1Author(s): Daphne Bavelier, C. Shawn GreenThe possibility of leveraging video games for enhancing behavior and brain function has led to an emerging new field situated at the crossroads of cognitive neuroscience, health science, educational interventions, and game design. Here we review the impact of video game play, in particular action video game play, on attentional control. We also examine the underlying neural bases of these effects and the game design features hypothesized to drive the plastic changes. We argue that not all games have the same impact, with both differences in the characteristics of the games themselves as well as individual differences in player style determining the final outcome. These facts, mixed with changes in the game industry, (e.g., greater mixing of genre characteristics; greater freedom of player experience) calls for a paradigm shift relative to the approach taken in the field to-date, including iteratively alternating between targeted game design and efficacy evaluation.
       
  • Recapitulation and Reversal of Schizophrenia-Related Phenotypes in
           Setd1a-Deficient Mice
    • Abstract: Publication date: Available online 9 October 2019Source: NeuronAuthor(s): Jun Mukai, Enrico Cannavò, Gregg W. Crabtree, Ziyi Sun, Anastasia Diamantopoulou, Pratibha Thakur, Chia-Yuan Chang, Yifei Cai, Stavros Lomvardas, Atsushi Takata, Bin Xu, Joseph A. GogosSummarySETD1A, a lysine-methyltransferase, is a key schizophrenia susceptibility gene. Mice carrying a heterozygous loss-of-function mutation of the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics accompanied by working memory deficits. We show that Setd1a binds both promoters and enhancers with a striking overlap between Setd1a and Mef2 on enhancers. Setd1a targets are highly expressed in pyramidal neurons and display a complex pattern of transcriptional up- and downregulations shaped by presumed opposing functions of Setd1a on promoters and Mef2-bound enhancers. Notably, evolutionarily conserved Setd1a targets are associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues cognitive deficits. Finally, we identify LSD1 as a major counteracting demethylase for Setd1a and show that its pharmacological antagonism results in a full rescue of the behavioral and morphological deficits in Setd1a-deficient mice. Our findings advance understanding of how SETD1A mutations predispose to schizophrenia (SCZ) and point to novel therapeutic interventions.
       
  • Pum2 Shapes the Transcriptome in Developing Axons through Retention of
           Target mRNAs in the Cell Body
    • Abstract: Publication date: Available online 9 October 2019Source: NeuronAuthor(s): José C. Martínez, Lisa K. Randolph, Daniel Maxim Iascone, Helena F. Pernice, Franck Polleux, Ulrich HengstSummaryLocalized protein synthesis is fundamental for neuronal development, maintenance, and function. Transcriptomes in axons and soma are distinct, but the mechanisms governing the composition of axonal transcriptomes and their developmental regulation are only partially understood. We found that the binding motif for the RNA-binding proteins Pumilio 1 and 2 (Pum1 and Pum2) is underrepresented in transcriptomes of developing axons. Introduction of Pumilio-binding elements (PBEs) into mRNAs containing a β-actin zipcode prevented axonal localization and translation. Pum2 is restricted to the soma of developing neurons, and Pum2 knockdown or blocking its binding to mRNA caused the appearance and translation of PBE-containing mRNAs in axons. Pum2-deficient neurons exhibited axonal growth and branching defects in vivo and impaired axon regeneration in vitro. These results reveal that Pum2 shapes axonal transcriptomes by preventing the transport of PBE-containing mRNAs into axons, and they identify somatic mRNAs retention as a mechanism for the temporal control of intra-axonal protein synthesis.Graphical Graphical abstract for this article
       
  • An ER Assembly Line of AMPA-Receptors Controls Excitatory
           Neurotransmission and Its Plasticity
    • Abstract: Publication date: Available online 8 October 2019Source: NeuronAuthor(s): Jochen Schwenk, Sami Boudkkazi, Maciej K. Kocylowski, Aline Brechet, Gerd Zolles, Thorsten Bus, Kaue Costa, Astrid Kollewe, Johannes Jordan, Julia Bank, Wolfgang Bildl, Rolf Sprengel, Akos Kulik, Jochen Roeper, Uwe Schulte, Bernd FaklerSummaryExcitatory neurotransmission and its activity-dependent plasticity are largely determined by AMPA-receptors (AMPARs), ion channel complexes whose cell physiology is encoded by their interactome. Here, we delineate the assembly of AMPARs in the endoplasmic reticulum (ER) of native neurons as multi-state production line controlled by distinct interactome constituents: ABHD6 together with porcupine stabilizes pore-forming GluA monomers, and the intellectual-disability-related FRRS1l-CPT1c complexes promote GluA oligomerization and co-assembly of GluA tetramers with cornichon and transmembrane AMPA-regulatory proteins (TARP) to render receptor channels ready for ER exit. Disruption of the assembly line by FRRS1l deletion largely reduces AMPARs in the plasma membrane, impairs synapse formation, and abolishes activity-dependent synaptic plasticity, while FRRS1l overexpression has the opposite effect. As a consequence, FRSS1l knockout mice display severe deficits in learning tasks and behavior. Our results provide mechanistic insight into the stepwise biogenesis of AMPARs in native ER membranes and establish FRRS1l as a powerful regulator of synaptic signaling and plasticity.Graphical Graphical abstract for this article
       
  • Cortical Circuit Dynamics Are Homeostatically Tuned to Criticality
           In Vivo
    • Abstract: Publication date: Available online 7 October 2019Source: NeuronAuthor(s): Zhengyu Ma, Gina G. Turrigiano, Ralf Wessel, Keith B. HengenSummaryHomeostatic mechanisms stabilize neuronal activity in vivo, but whether this process gives rise to balanced network dynamics is unknown. Here, we continuously monitored the statistics of network spiking in visual cortical circuits in freely behaving rats for 9 days. Under control conditions in light and dark, networks were robustly organized around criticality, a regime that maximizes information capacity and transmission. When input was perturbed by visual deprivation, network criticality was severely disrupted and subsequently restored to criticality over 48 h. Unexpectedly, the recovery of excitatory dynamics preceded homeostatic plasticity of firing rates by>30 h. We utilized model investigations to manipulate firing rate homeostasis in a cell-type-specific manner at the onset of visual deprivation. Our results suggest that criticality in excitatory networks is established by inhibitory plasticity and architecture. These data establish that criticality is consistent with a homeostatic set point for visual cortical dynamics and suggest a key role for homeostatic regulation of inhibition.
       
  • CRISPR-Cas9 Screens Identify the RNA Helicase DDX3X as a Repressor of
           C9ORF72 (GGGGCC)n Repeat-Associated Non-AUG Translation
    • Abstract: Publication date: Available online 3 October 2019Source: NeuronAuthor(s): Weiwei Cheng, Shaopeng Wang, Zhe Zhang, David W. Morgens, Lindsey R. Hayes, Soojin Lee, Bede Portz, Yongzhi Xie, Baotram V. Nguyen, Michael S. Haney, Shirui Yan, Daoyuan Dong, Alyssa N. Coyne, Junhua Yang, Fengfan Xian, Don W. Cleveland, Zhaozhu Qiu, Jeffrey D. Rothstein, James Shorter, Fen-Biao GaoSummaryHexanucleotide GGGGCC repeat expansion in C9ORF72 is the most prevalent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One pathogenic mechanism is the aberrant accumulation of dipeptide repeat (DPR) proteins produced by the unconventional translation of expanded RNA repeats. Here, we performed genome-wide CRISPR-Cas9 screens for modifiers of DPR protein production in human cells. We found that DDX3X, an RNA helicase, suppresses the repeat-associated non-AUG translation of GGGGCC repeats. DDX3X directly binds to (GGGGCC)n RNAs but not antisense (CCCCGG)n RNAs. Its helicase activity is essential for the translation repression. Reduction of DDX3X increases DPR levels in C9ORF72-ALS/FTD patient cells and enhances (GGGGCC)n-mediated toxicity in Drosophila. Elevating DDX3X expression is sufficient to decrease DPR levels, rescue nucleocytoplasmic transport abnormalities, and improve survival of patient iPSC-differentiated neurons. This work identifies genetic modifiers of DPR protein production and provides potential therapeutic targets for C9ORF72-ALS/FTD.Graphical Graphical abstract for this article
       
  • Orofacial Movements Involve Parallel Corticobulbar Projections from Motor
           Cortex to Trigeminal Premotor Nuclei
    • Abstract: Publication date: Available online 3 October 2019Source: NeuronAuthor(s): Nicole Mercer Lindsay, Per M. Knutsen, Adrian F. Lozada, Daniel Gibbs, Harvey J. Karten, David KleinfeldSummaryHow do neurons in orofacial motor cortex (MCtx) orchestrate behaviors' We show that focal activation of MCtx corticobulbar neurons evokes behaviorally relevant concurrent movements of the forelimb, jaw, nose, and vibrissae. The projections from different locations in MCtx form gradients of boutons across premotor nuclei spinal trigeminal pars oralis (SpVO) and interpolaris rostralis (SpVIr). Furthermore, retrograde viral tracing from muscles that control orofacial actions shows that these premotor nuclei segregate their outputs. In the most dramatic case, both SpVO and SpVIr are premotor to forelimb and vibrissa muscles, while only SpVO is premotor to jaw muscles. Functional confirmation of the superimposed control by MCtx was obtained through selective optogenetic activation of corticobulbar neurons on the basis of their preferential projections to SpVO versus SpVIr. We conclude that neighboring projection neurons in orofacial MCtx form parallel pathways to distinct pools of trigeminal premotor neurons that coordinate motor actions into a behavior.
       
  • Identification of Spinal Neurons Contributing to the Dorsal Column
           Projection Mediating Fine Touch and Corrective Motor Movements
    • Abstract: Publication date: Available online 2 October 2019Source: NeuronAuthor(s): Sónia Paixão, Laura Loschek, Louise Gaitanos, Pilar Alcalà Morales, Martyn Goulding, Rüdiger KleinSummaryTactile stimuli are integrated and processed by neuronal circuits in the deep dorsal horn of the spinal cord. Several spinal interneuron populations have been implicated in tactile information processing. However, dorsal horn projection neurons that contribute to the postsynaptic dorsal column (PSDC) pathway transmitting tactile information to the brain are poorly characterized. Here, we show that spinal neurons marked by the expression of Zic2creER mediate light touch sensitivity and textural discrimination. A subset of Zic2creER neurons are PSDC neurons that project to brainstem dorsal column nuclei, and chemogenetic activation of Zic2 PSDC neurons increases sensitivity to light touch stimuli. Zic2 neurons receive direct input from the cortex and brainstem motor nuclei and are required for corrective motor movements. These results suggest that Zic2 neurons integrate sensory input from cutaneous afferents with descending signals from the brain to promote corrective movements and transmit processed touch information back to the brain.Graphical Graphical abstract for this article
       
  • Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral
           and Neurophysiological Abnormalities by Activating the Immune Response
    • Abstract: Publication date: Available online 1 October 2019Source: NeuronAuthor(s): Jennifer L. Johnson, Loredana Stoica, Yuwei Liu, Ping Jun Zhu, Abhisek Bhattacharya, Shelly Buffington, Redwan Huq, N. Tony Eissa, Ola Larsson, Bo T. Porse, Deepti Domingo, Urwah Nawaz, Renee Carroll, Lachlan Jolly, Tom S. Scerri, Hyung-Goo Kim, Amanda Brignell, Matthew J. Coleman, Ruth Braden, Usha KiniSummaryIn humans, disruption of nonsense-mediated decay (NMD) has been associated with neurodevelopmental disorders (NDDs) such as autism spectrum disorder and intellectual disability. However, the mechanism by which deficient NMD leads to neurodevelopmental dysfunction remains unknown, preventing development of targeted therapies. Here we identified novel protein-coding UPF2 (UP-Frameshift 2) variants in humans with NDD, including speech and language deficits. In parallel, we found that mice lacking Upf2 in the forebrain (Upf2 fb-KO mice) show impaired NMD, memory deficits, abnormal long-term potentiation (LTP), and social and communication deficits. Surprisingly, Upf2 fb-KO mice exhibit elevated expression of immune genes and brain inflammation. More importantly, treatment with two FDA-approved anti-inflammatory drugs reduced brain inflammation, restored LTP and long-term memory, and reversed social and communication deficits. Collectively, our findings indicate that impaired UPF2-dependent NMD leads to neurodevelopmental dysfunction and suggest that anti-inflammatory agents may prove effective for treatment of disorders with impaired NMD.Graphical Graphical abstract for this article
       
  • Control of Non-REM Sleep by Midbrain Neurotensinergic Neurons
    • Abstract: Publication date: Available online 30 September 2019Source: NeuronAuthor(s): Peng Zhong, Zhe Zhang, Zeke Barger, Chenyan Ma, Danqian Liu, Xinlu Ding, Yang DanSummaryThe periaqueductal gray (PAG) in the midbrain is known to coordinate behavioral and autonomic responses to threat and injury through its descending projections to the brainstem. Here, we show that neurotensin (NTS)-expressing glutamatergic neurons in the ventrolateral PAG (vlPAG) powerfully promote non-rapid eye movement (NREM) sleep partly through their projection to the caudal medulla. Optogenetic and chemogenetic activation of vlPAG NTS neurons strongly enhanced NREM sleep, whereas their inactivation increased wakefulness. Calcium imaging and optrode recording showed that they are preferentially active during NREM sleep. The NREM-promoting effect of vlPAG NTS neurons is partly mediated by their projection to the caudal ventromedial medulla, where they excite GABAergic neurons. Bidirectional optogenetic and chemogenetic manipulations showed that the medullary GABAergic neurons also promote NREM sleep, and they innervate multiple monoaminergic populations. Together, these findings reveal a novel pathway for NREM sleep generation, in which glutamatergic neurons drive broad GABAergic inhibition of wake-promoting neuronal populations.
       
  • Task-Dependent Changes in the Large-Scale Dynamics and Necessity of
           Cortical Regions
    • Abstract: Publication date: Available online 26 September 2019Source: NeuronAuthor(s): Lucas Pinto, Kanaka Rajan, Brian DePasquale, Stephan Y. Thiberge, David W. Tank, Carlos D. BrodySummaryNeural activity throughout the cortex is correlated with perceptual decisions, but inactivation studies suggest that only a small number of areas are necessary for these behaviors. Here we show that the number of required cortical areas and their dynamics vary across related tasks with different cognitive computations. In a visually guided virtual T-maze task, bilateral inactivation of only a few dorsal cortical regions impaired performance. In contrast, in tasks requiring evidence accumulation and/or post-stimulus memory, performance was impaired by inactivation of widespread cortical areas with diverse patterns of behavioral deficits across areas and tasks. Wide-field imaging revealed widespread ramps of Ca2+ activity during the accumulation and visually guided tasks. Additionally, during accumulation, different regions had more diverse activity profiles, leading to reduced inter-area correlations. Using a modular recurrent neural network model trained to perform analogous tasks, we argue that differences in computational strategies alone could explain these findings.
       
  • Semaphorin 2b Regulates Sleep-Circuit Formation in the Drosophila
           Central Brain
    • Abstract: Publication date: Available online 26 September 2019Source: NeuronAuthor(s): Xiaojun Xie, Masashi Tabuchi, Abel Corver, Grace Duan, Mark N. Wu, Alex L. KolodkinSummaryThe fan-shaped body (FB) neuropil in the Drosophila brain central complex (CX) controls a variety of adult behaviors, including navigation and sleep. How neuronal processes are organized into precise layers and columns in the FB and how alterations in FB neural-circuit wiring affect animal behaviors are unknown. We report here that secreted semaphorin 2b (Sema-2b) acts through its transmembrane receptor Plexin B (PlexB) to locally attract neural processes to specific FB laminae. Aberrant Sema-2b/PlexB signaling leads to select disruptions in neural lamination, and these disruptions result in the formation of ectopic inhibitory connections between subsets of FB neurons. These structural alternations and connectivity defects are associated with changes in fly sleep and arousal, emphasizing the importance of lamination-mediated neural wiring in a central brain region critical for normal sleep behavior.
       
  • Are You There, Cortex' It’s Me, Acetylcholine
    • Abstract: Publication date: 25 September 2019Source: Neuron, Volume 103, Issue 6Author(s): Kevin J. Monk, Marshall G. Hussain ShulerIt is not well understood how associations between two temporally removed stimuli form. In this issue of Neuron, Guo et al. (2019) implicate basal forebrain cholinergic neurons as providing a link between auditory cues and the aversive outcomes they predict.
       
  • Development and Arealization of the Cerebral Cortex
    • Abstract: Publication date: 25 September 2019Source: Neuron, Volume 103, Issue 6Author(s): Cathryn R. Cadwell, Aparna Bhaduri, Mohammed A. Mostajo-Radji, Matthew G. Keefe, Tomasz J. NowakowskiAdult cortical areas consist of specialized cell types and circuits that support unique higher-order cognitive functions. How this regional diversity develops from an initially uniform neuroepithelium has been the subject of decades of seminal research, and emerging technologies, including single-cell transcriptomics, provide a new perspective on area-specific molecular diversity. Here, we review the early developmental processes that underlie cortical arealization, including both cortex intrinsic and extrinsic mechanisms as embodied by the protomap and protocortex hypotheses, respectively. We propose an integrated model of serial homology whereby intrinsic genetic programs and local factors establish early transcriptomic differences between excitatory neurons destined to give rise to broad “proto-regions,” and activity-dependent mechanisms lead to progressive refinement and formation of sharp boundaries between functional areas. Finally, we explore the potential of these basic developmental processes to inform our understanding of the emergence of functional neural networks and circuit abnormalities in neurodevelopmental disorders.
       
  • Engineering a Less Artificial Intelligence
    • Abstract: Publication date: 25 September 2019Source: Neuron, Volume 103, Issue 6Author(s): Fabian H. Sinz, Xaq Pitkow, Jacob Reimer, Matthias Bethge, Andreas S. ToliasDespite enormous progress in machine learning, artificial neural networks still lag behind brains in their ability to generalize to new situations. Given identical training data, differences in generalization are caused by many defining features of a learning algorithm, such as network architecture and learning rule. Their joint effect, called “inductive bias,” determines how well any learning algorithm—or brain—generalizes: robust generalization needs good inductive biases. Artificial networks use rather nonspecific biases and often latch onto patterns that are only informative about the statistics of the training data but may not generalize to different scenarios. Brains, on the other hand, generalize across comparatively drastic changes in the sensory input all the time. We highlight some shortcomings of state-of-the-art learning algorithms compared to biological brains and discuss several ideas about how neuroscience can guide the quest for better inductive biases by providing useful constraints on representations and network architecture.
       
  • Networking: Translating Neuroscience to Public Policy
    • Abstract: Publication date: 25 September 2019Source: Neuron, Volume 103, Issue 6Author(s): Keith HumphreysNeuroscientific findings are rarely translated into public policies that improve the health and well-being of people experiencing serious disorders. I advocate here for investment in policymaker-scientist networks dedicated to such translation for a range of diseases.
       
  • Becoming a Principal Investigator: Designing and Navigating Your Academic
           Adventure
    • Abstract: Publication date: 25 September 2019Source: Neuron, Volume 103, Issue 6Author(s): Paul L. Greer, Melanie A. SamuelStarting your own academic lab is a wonderful opportunity to impact science through research and trainee mentoring. In this article, we share some thoughts and resources for this undertaking in the hope that they may enhance the experience of others.
       
  • Why Are Sequence Representations in Primary Motor Cortex So Elusive'
    • Abstract: Publication date: 25 September 2019Source: Neuron, Volume 103, Issue 6Author(s): Aaron L. Wong, John W. KrakauerIn this issue of Neuron, Yokoi and Diedrichsen (2019) use a finger keyboard task to show that sequences are widely represented across cortex but that only single elements are represented in primary motor cortex. These results suggest that sequence tasks primarily probe the ability to order discreet actions rather than to execute a skilled continuous sequential action.
       
  • Scratching after Stroking and Poking: A Spinal Circuit Underlying
           Mechanical Itch
    • Abstract: Publication date: 25 September 2019Source: Neuron, Volume 103, Issue 6Author(s): Zilong Wang, Christopher R. Donnelly, Ru-Rong JiMechanical itch is a desire to scratch due to light mechanical stimuli. In this issue of Neuron, Pan et al. (2019) identify a feedforward inhibition circuit in the spinal cord dorsal horn that processes mechanical itch as well as spontaneous itch.
       
  • Simplicity, Flexibility, and Interpretability in a Model of Dendritic
           Protein Distributions
    • Abstract: Publication date: 25 September 2019Source: Neuron, Volume 103, Issue 6Author(s): Cian O’DonnellIn this issue of Neuron, Fonkeu et al. (2019) present a mathematical model of mRNA and protein synthesis, degradation, diffusion, and trafficking in neuronal dendrites. The model can predict the spatial distribution and temporal dynamics of proteins along dendrites. The authors use the model to account for in situ imaging data of CaMKII⍺ mRNA and protein in hippocampal neurons.
       
  • Enhanced Actin Dynamics: A Therapeutic Strategy for Axonal
           Regeneration'
    • Abstract: Publication date: 25 September 2019Source: Neuron, Volume 103, Issue 6Author(s): Hauke B. Werner, Klaus-Armin NaveSpinal cord injury causes permanent paralysis due to the inability of neurons in the central nervous system to regenerate transected axons. In this issue of Neuron, Tedeschi et al. (2019) report that axonal regrowth can be stimulated by actin-depolymerizing proteins, at least in mice.
       
  • Input-Specific Metaplasticity in the Visual Cortex Requires
           Homer1a-Mediated mGluR5 Signaling
    • Abstract: Publication date: Available online 25 September 2019Source: NeuronAuthor(s): Varun Chokshi, Ming Gao, Bryce D. Grier, Ashley Owens, Hui Wang, Paul F. Worley, Hey-Kyoung LeeSummaryEffective sensory processing depends on sensory experience-dependent metaplasticity, which allows homeostatic maintenance of neural network activity and preserves feature selectivity. Following a strong increase in sensory drive, plasticity mechanisms that decrease the strength of excitatory synapses are preferentially engaged to maintain stability in neural networks. Such adaptation has been demonstrated in various model systems, including mouse primary visual cortex (V1), where excitatory synapses on layer 2/3 (L2/3) neurons undergo rapid reduction in strength when visually deprived mice are reexposed to light. Here, we report that this form of plasticity is specific to intracortical inputs to V1 L2/3 neurons and depends on the activity of NMDA receptors (NMDARs) and group I metabotropic glutamate receptor 5 (mGluR5). Furthermore, we found that expression of the immediate early gene (IEG) Homer1a (H1a) and its subsequent interaction with mGluR5s are necessary for this input-specific metaplasticity.Graphical Graphical abstract for this article
       
  • Visual Cortex Gains Independence from Peripheral Drive before Eye Opening
    • Abstract: Publication date: Available online 24 September 2019Source: NeuronAuthor(s): Alexandra Gribizis, Xinxin Ge, Tanya L. Daigle, James B. Ackman, Hongkui Zeng, Daeyeol Lee, Michael C. CrairSummaryVisual spatial perception in the mammalian brain occurs through two parallel pathways: one reaches the primary visual cortex (V1) through the thalamus and another the superior colliculus (SC) via direct projections from the retina. The origin, development, and relative function of these two evolutionarily distinct pathways remain obscure. We examined the early functional development of both pathways by simultaneously imaging pre- and post-synaptic spontaneous neuronal activity. We observed that the quality of retinal activity transfer to the thalamus and superior colliculus does not change across the first two postnatal weeks. However, beginning in the second postnatal week, retinal activity does not drive V1 as strongly as earlier wave activity, suggesting that intrinsic cortical activity competes with signals from the sensory periphery as the cortex matures. Together, these findings bring new insight into the function of the SC and V1 and the role of peripheral activity in driving both circuits across development.
       
  • Distinct Nanoscale Calcium Channel and Synaptic Vesicle Topographies
           Contribute to the Diversity of Synaptic Function
    • Abstract: Publication date: Available online 23 September 2019Source: NeuronAuthor(s): Nelson Rebola, Maria Reva, Tekla Kirizs, Miklos Szoboszlay, Andrea Lőrincz, Gael Moneron, Zoltan Nusser, David A. DiGregorioSummaryThe nanoscale topographical arrangement of voltage-gated calcium channels (VGCC) and synaptic vesicles (SVs) determines synaptic strength and plasticity, but whether distinct spatial distributions underpin diversity of synaptic function is unknown. We performed single bouton Ca2+ imaging, Ca2+ chelator competition, immunogold electron microscopic (EM) localization of VGCCs and the active zone (AZ) protein Munc13-1, at two cerebellar synapses. Unexpectedly, we found that weak synapses exhibited 3-fold more VGCCs than strong synapses, while the coupling distance was 5-fold longer. Reaction-diffusion modeling could explain both functional and structural data with two strikingly different nanotopographical motifs: strong synapses are composed of SVs that are tightly coupled (∼10 nm) to VGCC clusters, whereas at weak synapses VGCCs were excluded from the vicinity (∼50 nm) of docked vesicles. The distinct VGCC-SV topographical motifs also confer differential sensitivity to neuromodulation. Thus, VGCC-SV arrangements are not canonical, and their diversity could underlie functional heterogeneity across CNS synapses.
       
  • Structural and Functional Remodeling of Amygdala GABAergic Synapses in
           Associative Fear Learning
    • Abstract: Publication date: Available online 19 September 2019Source: NeuronAuthor(s): Yu Kasugai, Elisabeth Vogel, Heide Hörtnagl, Sabine Schönherr, Enrica Paradiso, Markus Hauschild, Georg Göbel, Ivan Milenkovic, Yvan Peterschmitt, Ramon Tasan, Günther Sperk, Ryuichi Shigemoto, Werner Sieghart, Nicolas Singewald, Andreas Lüthi, Francesco FerragutiSummaryAssociative learning is thought to involve different forms of activity-dependent synaptic plasticity. Although previous studies have mostly focused on learning-related changes occurring at excitatory glutamatergic synapses, we found that associative learning, such as fear conditioning, also entails long-lasting functional and structural plasticity of GABAergic synapses onto pyramidal neurons of the murine basal amygdala. Fear conditioning-mediated structural remodeling of GABAergic synapses was associated with a change in mIPSC kinetics and an increase in the fraction of synaptic benzodiazepine-sensitive (BZD) GABAA receptors containing the α2 subunit without altering the intrasynaptic distribution and overall amount of BZD-GABAA receptors. These structural and functional synaptic changes were partly reversed by extinction training. These findings provide evidence that associative learning, such as Pavlovian fear conditioning and extinction, sculpts inhibitory synapses to regulate inhibition of active neuronal networks, a process that may tune amygdala circuit responses to threats.Graphical Graphical abstract for this article
       
  • Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability
           Homeostasis
    • Abstract: Publication date: Available online 18 September 2019Source: NeuronAuthor(s): Peter Dongmin Sohn, Cindy Tzu-Ling Huang, Rui Yan, Li Fan, Tara E. Tracy, Carolina M. Camargo, Kelly M. Montgomery, Taylor Arhar, Sue-Ann Mok, Rebecca Freilich, Justin Baik, Manni He, Shiaoching Gong, Erik D. Roberson, Celeste M. Karch, Jason E. Gestwicki, Ke Xu, Kenneth S. Kosik, Li GanSummaryDysregulation of neuronal excitability underlies the pathogenesis of tauopathies, including frontotemporal dementia (FTD) with tau inclusions. A majority of FTD-causing tau mutations are located in the microtubule-binding domain, but how these mutations alter neuronal excitability is largely unknown. Here, using CRISPR/Cas9-based gene editing in human pluripotent stem cell (iPSC)-derived neurons and isogenic controls, we show that the FTD-causing V337M tau mutation impairs activity-dependent plasticity of the cytoskeleton in the axon initial segment (AIS). Extracellular recordings by multi-electrode arrays (MEAs) revealed that the V337M tau mutation in human neurons leads to an abnormal increase in neuronal activity in response to chronic depolarization. Stochastic optical reconstruction microscopy of human neurons with this mutation showed that AIS plasticity is impaired by the abnormal accumulation of end-binding protein 3 (EB3) in the AIS submembrane region. These findings expand our understanding of how FTD-causing tau mutations dysregulate components of the neuronal cytoskeleton, leading to network dysfunction.Graphical Graphical abstract for this article
       
  • A Modality-Independent Network Underlies the Retrieval of Large-Scale
           Spatial Environments in the Human Brain
    • Abstract: Publication date: Available online 17 September 2019Source: NeuronAuthor(s): Derek J. Huffman, Arne D. EkstromSummaryIn humans, the extent to which body-based cues, such as vestibular, somatosensory, and motoric cues, are necessary for normal expression of spatial representations remains unclear. Recent breakthroughs in immersive virtual reality technology allowed us to test how body-based cues influence spatial representations of large-scale environments in humans. Specifically, we manipulated the availability of body-based cues during navigation using an omnidirectional treadmill and a head-mounted display, investigating brain differences in levels of activation (i.e., univariate analysis), patterns of activity (i.e., multivariate pattern analysis), and putative network interactions between spatial retrieval tasks using fMRI. Our behavioral and neuroimaging results support the idea that there is a core, modality-independent network supporting spatial memory retrieval in the human brain. Thus, for well-learned spatial environments, at least in humans, primarily visual input may be sufficient for expression of complex representations of spatial environments.Video
       
  • The Neuropeptide Galanin Is Required for Homeostatic Rebound Sleep
           following Increased Neuronal Activity
    • Abstract: Publication date: Available online 16 September 2019Source: NeuronAuthor(s): Sabine Reichert, Oriol Pavón Arocas, Jason RihelSummarySleep pressure increases during wake and dissipates during sleep, but the molecules and neurons that measure homeostatic sleep pressure remain poorly understood. We present a pharmacological assay in larval zebrafish that generates short-term increases in wakefulness followed by sustained rebound sleep after washout. The intensity of global neuronal activity during drug-induced wakefulness predicted the amount of subsequent rebound sleep. Whole-brain mapping with the neuronal activity marker phosphorylated extracellular signal-regulated kinase (pERK) identified preoptic Galanin (Galn)-expressing neurons as selectively active during rebound sleep, and the relative induction of galn transcripts was predictive of total rebound sleep time. Galn is required for sleep homeostasis, as galn mutants almost completely lacked rebound sleep following both pharmacologically induced neuronal activity and physical sleep deprivation. These results suggest that Galn plays a key role in responding to sleep pressure signals derived from neuronal activity and functions as an output arm of the vertebrate sleep homeostat.
       
  • The eIF2α Kinase GCN2 Modulates Period and Rhythmicity of the Circadian
           Clock by Translational Control of Atf4
    • Abstract: Publication date: Available online 12 September 2019Source: NeuronAuthor(s): Salil Saurav Pathak, Dong Liu, Tianbao Li, Nuria de Zavalia, Lei Zhu, Jin Li, Ramanujam Karthikeyan, Tommy Alain, Andrew C. Liu, Kai-Florian Storch, Randal J. Kaufman, Victor X. Jin, Shimon Amir, Nahum Sonenberg, Ruifeng CaoSummaryThe integrated stress response (ISR) is activated in response to diverse stress stimuli to maintain homeostasis in neurons. Central to this process is the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). Here, we report a critical role for ISR in regulating the mammalian circadian clock. The eIF2α kinase GCN2 rhythmically phosphorylates eIF2α in the suprachiasmatic circadian clock. Increased eIF2α phosphorylation shortens the circadian period in both fibroblasts and mice, whereas reduced eIF2α phosphorylation lengthens the circadian period and impairs circadian rhythmicity in animals. Mechanistically, phosphorylation of eIF2α promotes mRNA translation of Atf4. ATF4 binding motifs are identified in multiple clock genes, including Per2, Per3, Cry1, Cry2, and Clock. ATF4 binds to the TTGCAGCA motif in the Per2 promoter and activates its transcription. Together, these results demonstrate a significant role for ISR in circadian physiology and provide a potential link between dysregulated ISR and circadian dysfunction in brain diseases.Graphical Graphical abstract for this article
       
  • Hippocampal-Prefrontal Theta Transmission Regulates Avoidance Behavior
    • Abstract: Publication date: Available online 11 September 2019Source: NeuronAuthor(s): Nancy Padilla-Coreano, Sarah Canetta, Rachel M. Mikofsky, Emily Alway, Johannes Passecker, Maxym V. Myroshnychenko, Alvaro L. Garcia-Garcia, Richard Warren, Eric Teboul, Dakota R. Blackman, Mitchell P. Morton, Sofiya Hupalo, Kay M. Tye, Christoph Kellendonk, David A. Kupferschmidt, Joshua A. GordonSummaryLong-range synchronization of neural oscillations correlates with distinct behaviors, yet its causal role remains unproven. In mice, tests of avoidance behavior evoke increases in theta-frequency (∼8 Hz) oscillatory synchrony between the ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC). To test the causal role of this synchrony, we dynamically modulated vHPC-mPFC terminal activity using optogenetic stimulation. Oscillatory stimulation at 8 Hz maximally increased avoidance behavior compared to 2, 4, and 20 Hz. Moreover, avoidance behavior was selectively increased when 8-Hz stimulation was delivered in an oscillatory, but not pulsatile, manner. Furthermore, 8-Hz oscillatory stimulation enhanced vHPC-mPFC neurotransmission and entrained neural activity in the vHPC-mPFC network, resulting in increased synchrony between vHPC theta activity and mPFC spiking. These data suggest a privileged role for vHPC-mPFC theta-frequency communication in generating avoidance behavior and provide direct evidence that synchronized oscillations play a role in facilitating neural transmission and behavior.
       
  • Paradoxical Rules of Spike Train Decoding Revealed at the Sensitivity
           Limit of Vision
    • Abstract: Publication date: Available online 10 September 2019Source: NeuronAuthor(s): Lina Smeds, Daisuke Takeshita, Tuomas Turunen, Jussi Tiihonen, Johan Westö, Nataliia Martyniuk, Aarni Seppänen, Petri Ala-LaurilaSummaryAll sensory information is encoded in neural spike trains. It is unknown how the brain utilizes this neural code to drive behavior. Here, we unravel the decoding rules of the brain at the most elementary level by linking behavioral decisions to retinal output signals in a single-photon detection task. A transgenic mouse line allowed us to separate the two primary retinal outputs, ON and OFF pathways, carrying information about photon absorptions as increases and decreases in spiking, respectively. We measured the sensitivity limit of rods and the most sensitive ON and OFF ganglion cells and correlated these results with visually guided behavior using markerless head and eye tracking. We show that behavior relies only on the ON pathway even when the OFF pathway would allow higher sensitivity. Paradoxically, behavior does not rely on the spike code with maximal information but instead relies on a decoding strategy based on increases in spiking.Graphical Graphical abstract for this article
       
  • SETD5 Regulates Chromatin Methylation State and Preserves Global
           Transcriptional Fidelity during Brain Development and Neuronal Wiring
    • Abstract: Publication date: Available online 9 September 2019Source: NeuronAuthor(s): Alessandro Sessa, Luca Fagnocchi, Giuseppina Mastrototaro, Luca Massimino, Mattia Zaghi, Marzia Indrigo, Stefano Cattaneo, Davide Martini, Chiara Gabellini, Cecilia Pucci, Alessandra Fasciani, Romina Belli, Stefano Taverna, Massimiliano Andreazzoli, Alessio Zippo, Vania BroccoliSummaryMutations in one SETD5 allele are genetic causes of intellectual disability and autistic spectrum disorders. However, the mechanisms by which SETD5 regulates brain development and function remain largely elusive. Herein, we found that Setd5 haploinsufficiency impairs the proliferative dynamics of neural progenitors and synaptic wiring of neurons, ultimately resulting in behavioral deficits in mice. Mechanistically, Setd5 inactivation in neural stem cells, zebrafish, and mice equally affects genome-wide levels of H3K36me3 on active gene bodies. Notably, we demonstrated that SETD5 directly deposits H3K36me3, which is essential to allow on-time RNA elongation dynamics. Hence, Setd5 gene loss leads to abnormal transcription, with impaired RNA maturation causing detrimental effects on gene integrity and splicing. These findings identify SETD5 as a fundamental epigenetic enzyme controlling the transcriptional landscape in neural progenitors and their derivatives and illuminate the molecular events that connect epigenetic defects with neuronal dysfunctions at the basis of related human diseases.Graphical Graphical abstract for this article
       
  • Can One Concurrently Record Electrical Spikes from Every Neuron in a
           Mammalian Brain'
    • Abstract: Publication date: Available online 5 September 2019Source: NeuronAuthor(s): David Kleinfeld, Lan Luan, Partha P. Mitra, Jacob T. Robinson, Rahul Sarpeshkar, Kenneth Shepard, Chong Xie, Timothy D. HarrisSummaryThe classic approach to measure the spiking response of neurons involves the use of metal electrodes to record extracellular potentials. Starting over 60 years ago with a single recording site, this technology now extends to ever larger numbers and densities of sites. We argue, based on the mechanical and electrical properties of existing materials, estimates of signal-to-noise ratios, assumptions regarding extracellular space in the brain, and estimates of heat generation by the electronic interface, that it should be possible to fabricate rigid electrodes to concurrently record from essentially every neuron in the cortical mantle. This will involve fabrication with existing yet nontraditional materials and procedures. We further emphasize the need to advance materials for improved flexible electrodes as an essential advance to record from neurons in brainstem and spinal cord in moving animals.
       
  • Functional Logic of Layer 2/3 Inhibitory Connectivity in the Ferret Visual
           Cortex
    • Abstract: Publication date: Available online 5 September 2019Source: NeuronAuthor(s): Benjamin Scholl, Daniel E. Wilson, Juliane Jaepel, David FitzpatrickSummaryUnderstanding how cortical inhibition shapes circuit function requires identifying the connectivity rules relating the response properties of inhibitory interneurons and their postsynaptic targets. Here we explore the orientation tuning of layer 2/3 inhibitory inputs in the ferret visual cortex using a combination of in vivo axon imaging, functional input mapping, and physiology. Inhibitory boutons exhibit robust orientation-tuned responses with preferences that can differ significantly from the cortical column in which they reside. Inhibitory input fields measured with patterned optogenetic stimulation and intracellular recordings revealed that these inputs originate from a wide range of orientation domains, inconsistent with a model of co-tuned inhibition and excitation. Intracellular synaptic conductance measurements confirm that individual neurons can depart from a co-tuned regime. Our results argue against a simple rule for the arrangement of inhibitory inputs supplied by layer 2/3 circuits and suggest that heterogeneity in presynaptic inhibitory networks contributes to neural response properties.
       
  • Nucleome Dynamics during Retinal Development
    • Abstract: Publication date: Available online 4 September 2019Source: NeuronAuthor(s): Jackie L. Norrie, Marybeth S. Lupo, Beisi Xu, Issam Al Diri, Marc Valentine, Daniel Putnam, Lyra Griffiths, Jiakun Zhang, Dianna Johnson, John Easton, Ying Shao, Victoria Honnell, Sharon Frase, Shondra Miller, Valerie Stewart, Xin Zhou, Xiang Chen, Michael A. DyerSummaryMore than 8,000 genes are turned on or off as progenitor cells produce the 7 classes of retinal cell types during development. Thousands of enhancers are also active in the developing retinae, many having features of cell- and developmental stage-specific activity. We studied dynamic changes in the 3D chromatin landscape important for precisely orchestrated changes in gene expression during retinal development by ultra-deep in situ Hi-C analysis on murine retinae. We identified developmental-stage-specific changes in chromatin compartments and enhancer-promoter interactions. We developed a machine learning-based algorithm to map euchromatin and heterochromatin domains genome-wide and overlaid it with chromatin compartments identified by Hi-C. Single-cell ATAC-seq and RNA-seq were integrated with our Hi-C and previous ChIP-seq data to identify cell- and developmental-stage-specific super-enhancers (SEs). We identified a bipolar neuron-specific core regulatory circuit SE upstream of Vsx2, whose deletion in mice led to the loss of bipolar neurons.Graphical Graphical abstract for this article
       
  • Phase Separation-Mediated TARP/MAGUK Complex Condensation and AMPA
           Receptor Synaptic Transmission
    • Abstract: Publication date: Available online 3 September 2019Source: NeuronAuthor(s): Menglong Zeng, Javier Díaz-Alonso, Fei Ye, Xudong Chen, Jia Xu, Zeyang Ji, Roger A. Nicoll, Mingjie ZhangSummaryTransmembrane AMPA receptor (AMPAR) regulatory proteins (TARPs) modulate AMPAR synaptic trafficking and transmission via disc-large (DLG) subfamily of membrane-associated guanylate kinases (MAGUKs). Despite extensive studies, the molecular mechanism governing specific TARP/MAGUK interaction remains elusive. Using stargazin and PSD-95 as the representatives, we discover that the entire tail of stargazin (Stg_CT) is required for binding to PSD-95. The PDZ binding motif (PBM) and an Arg-rich motif upstream of PBM conserved in TARPs bind to multiple sites on PSD-95, thus resulting in a highly specific and multivalent stargazin/PSD-95 complex. Stargazin in complex with PSD-95 or PSD-95-assembled postsynaptic complexes form highly concentrated and dynamic condensates via phase separation, reminiscent of stargazin/PSD-95-mediated AMPAR synaptic clustering and trapping. Importantly, charge neutralization mutations in TARP_CT Arg-rich motif weakened TARP’s condensation with PSD-95 and impaired TARP-mediated AMPAR synaptic transmission in mice hippocampal neurons. The TARP_CT/PSD-95 interaction mode may have implications for understanding clustering of other synaptic transmembrane proteins.Graphical Graphical abstract for this article
       
  • Inducing Different Neuronal Subtypes from Astrocytes in the Injured Mouse
           Cerebral Cortex
    • Abstract: Publication date: Available online 2 September 2019Source: NeuronAuthor(s): Nicola Mattugini, Riccardo Bocchi, Volker Scheuss, Gianluca Luigi Russo, Olof Torper, Chu Lan Lao, Magdalena GötzSummaryAstrocytes are particularly promising candidates for reprogramming into neurons, as they maintain some of the original patterning information from their radial glial ancestors. However, to which extent the position of astrocytes influences the fate of reprogrammed neurons remains unknown. To elucidate this, we performed stab wound injury covering an entire neocortical column, including the gray matter (GM) and white matter (WM), and targeted local reactive astrocytes via injecting FLEx switch (Cre-On) adeno-associated viral (AAV) vectors into mGFAP-Cre mice. Single proneural factors were not sufficient for adequate reprogramming, although their combination with the nuclear receptor-related 1 protein (Nurr1) improved reprogramming efficiency. Nurr1 and Neurogenin 2 (Ngn2) resulted in high-efficiency reprogramming of targeted astrocytes into neurons that develop lamina-specific hallmarks, including the appropriate long-distance axonal projections. Surprisingly, in the WM, we did not observe any reprogrammed neurons, thereby unveiling a crucial role of region- and layer-specific differences in astrocyte reprogramming.Graphical Graphical abstract for this article
       
  • Agonist Selectivity and Ion Permeation in the α3β4 Ganglionic
           Nicotinic Receptor
    • Abstract: Publication date: Available online 2 September 2019Source: NeuronAuthor(s): Anant Gharpure, Jinfeng Teng, Yuxuan Zhuang, Colleen M. Noviello, Richard M. Walsh, Rico Cabuco, Rebecca J. Howard, Nurulain T. Zaveri, Erik Lindahl, Ryan E. HibbsSummaryNicotinic acetylcholine receptors are pentameric ion channels that mediate fast chemical neurotransmission. The α3β4 nicotinic receptor subtype forms the principal relay between the central and peripheral nervous systems in the autonomic ganglia. This receptor is also expressed focally in brain areas that affect reward circuits and addiction. Here, we present structures of the α3β4 nicotinic receptor in lipidic and detergent environments, using functional reconstitution to define lipids appropriate for structural analysis. The structures of the receptor in complex with nicotine, as well as the α3β4-selective ligand AT-1001, complemented by molecular dynamics, suggest principles of agonist selectivity. The structures further reveal much of the architecture of the intracellular domain, where mutagenesis experiments and simulations define residues governing ion conductance.
       
  • Feedback-Driven Assembly of the Axon Initial Segment
    • Abstract: Publication date: Available online 29 August 2019Source: NeuronAuthor(s): Amélie Fréal, Dipti Rai, Roderick P. Tas, Xingxiu Pan, Eugene A. Katrukha, Dieudonnée van de Willige, Riccardo Stucchi, Amol Aher, Chao Yang, A.F. Maarten Altelaar, Karin Vocking, Jan Andries Post, Martin Harterink, Lukas C. Kapitein, Anna Akhmanova, Casper C. HoogenraadSummaryThe axon initial segment (AIS) is a unique neuronal compartment that plays a crucial role in the generation of action potential and neuronal polarity. The assembly of the AIS requires membrane, scaffolding, and cytoskeletal proteins, including Ankyrin-G and TRIM46. How these components cooperate in AIS formation is currently poorly understood. Here, we show that Ankyrin-G acts as a scaffold interacting with End-Binding (EB) proteins and membrane proteins such as Neurofascin-186 to recruit TRIM46-positive microtubules to the plasma membrane. Using in vitro reconstitution and cellular assays, we demonstrate that TRIM46 forms parallel microtubule bundles and stabilizes them by acting as a rescue factor. TRIM46-labeled microtubules drive retrograde transport of Neurofascin-186 to the proximal axon, where Ankyrin-G prevents its endocytosis, resulting in stable accumulation of Neurofascin-186 at the AIS. Neurofascin-186 enrichment in turn reinforces membrane anchoring of Ankyrin-G and subsequent recruitment of TRIM46-decorated microtubules. Our study reveals feedback-based mechanisms driving AIS assembly.
       
  • A Rare Mutation of β1-Adrenergic Receptor Affects
           Sleep/Wake Behaviors
    • Abstract: Publication date: Available online 28 August 2019Source: NeuronAuthor(s): Guangsen Shi, Lijuan Xing, David Wu, Bula J. Bhattacharyya, Christopher R. Jones, Thomas McMahon, S.Y. Christin Chong, Jason A. Chen, Giovanni Coppola, Daniel Geschwind, Andrew Krystal, Louis J. Ptáček, Ying-Hui FuSummarySleep is crucial for our survival, and many diseases are linked to long-term poor sleep quality. Before we can use sleep to enhance our health and performance and alleviate diseases associated with poor sleep, a greater understanding of sleep regulation is necessary. We have identified a mutation in the β1-adrenergic receptor gene in humans who require fewer hours of sleep than most. In vitro, this mutation leads to decreased protein stability and dampened signaling in response to agonist treatment. In vivo, the mice carrying the same mutation demonstrated short sleep behavior. We found that this receptor is highly expressed in the dorsal pons and that these ADRB1+ neurons are active during rapid eye movement (REM) sleep and wakefulness. Activating these neurons can lead to wakefulness, and the activity of these neurons is affected by the mutation. These results highlight the important role of β1-adrenergic receptors in sleep/wake regulation.
       
  • A Neural Circuit Arbitrates between Persistence and Withdrawal in Hungry
           Drosophila
    • Abstract: Publication date: Available online 27 August 2019Source: NeuronAuthor(s): Sercan Sayin, Jean-Francois De Backer, K.P. Siju, Marina E. Wosniack, Laurence P. Lewis, Lisa-Marie Frisch, Benedikt Gansen, Philipp Schlegel, Amelia Edmondson-Stait, Nadiya Sharifi, Corey B. Fisher, Steven A. Calle-Schuler, J. Scott Lauritzen, Davi D. Bock, Marta Costa, Gregory S.X.E. Jefferis, Julijana Gjorgjieva, Ilona C. Grunwald KadowSummaryIn pursuit of food, hungry animals mobilize significant energy resources and overcome exhaustion and fear. How need and motivation control the decision to continue or change behavior is not understood. Using a single fly treadmill, we show that hungry flies persistently track a food odor and increase their effort over repeated trials in the absence of reward suggesting that need dominates negative experience. We further show that odor tracking is regulated by two mushroom body output neurons (MBONs) connecting the MB to the lateral horn. These MBONs, together with dopaminergic neurons and Dop1R2 signaling, control behavioral persistence. Conversely, an octopaminergic neuron, VPM4, which directly innervates one of the MBONs, acts as a brake on odor tracking by connecting feeding and olfaction. Together, our data suggest a function for the MB in internal state-dependent expression of behavior that can be suppressed by external inputs conveying a competing behavioral drive.Graphical Graphical abstract for this article
       
  • Recruitment of GABAergic Interneurons in the Barrel Cortex during Active
           Tactile Behavior
    • Abstract: Publication date: Available online 26 August 2019Source: NeuronAuthor(s): Jianing Yu, Hang Hu, Ariel Agmon, Karel SvobodaSummaryNeural computation involves diverse types of GABAergic inhibitory interneurons that are integrated with excitatory (E) neurons into precisely structured circuits. To understand how each neuron type shapes sensory representations, we measured firing patterns of defined types of neurons in the barrel cortex while mice performed an active, whisker-dependent object localization task. Touch excited fast-spiking (FS) interneurons at short latency, followed by activation of E neurons and somatostatin-expressing (SST) interneurons. Touch only weakly modulated vasoactive intestinal polypeptide-expressing (VIP) interneurons. Voluntary whisker movement activated FS neurons in the ventral posteromedial nucleus (VPM) target layers, a subset of SST neurons and a majority of VIP neurons. Together, FS neurons track thalamic input, mediating feedforward inhibition. SST neurons monitor local excitation, providing feedback inhibition. VIP neurons are activated by non-sensory inputs, disinhibiting E and FS neurons. Our data reveal rules of recruitment for interneuron types during behavior, providing foundations for understanding computation in cortical microcircuits.Graphical Graphical abstract for this article
       
  • Discrete Evaluative and Premotor Circuits Enable Vocal Learning in
           Songbirds
    • Abstract: Publication date: Available online 22 August 2019Source: NeuronAuthor(s): Matthew Gene Kearney, Timothy L. Warren, Erin Hisey, Jiaxuan Qi, Richard MooneySummaryVirtuosic motor performance requires the ability to evaluate and modify individual gestures within a complex motor sequence. Where and how the evaluative and premotor circuits operate within the brain to enable such temporally precise learning is poorly understood. Songbirds can learn to modify individual syllables within their complex vocal sequences, providing a system for elucidating the underlying evaluative and premotor circuits. We combined behavioral and optogenetic methods to identify 2 afferents to the ventral tegmental area (VTA) that serve evaluative roles in syllable-specific learning and to establish that downstream cortico-basal ganglia circuits serve a learning role that is only premotor. Furthermore, song performance-contingent optogenetic stimulation of either VTA afferent was sufficient to drive syllable-specific learning, and these learning effects were of opposite valence. Finally, functional, anatomical, and molecular studies support the idea that these evaluative afferents bidirectionally modulate VTA dopamine neurons to enable temporally precise vocal learning.
       
  • Reliable Sequential Activation of Neural Assemblies by Single Pyramidal
           Cells in a Three-Layered Cortex
    • Abstract: Publication date: Available online 19 August 2019Source: NeuronAuthor(s): Mike Hemberger, Mark Shein-Idelson, Lorenz Pammer, Gilles LaurentSummaryRecent studies reveal the occasional impact of single neurons on surround firing statistics and even simple behaviors. Exploiting the advantages of a simple cortex, we examined the influence of single pyramidal neurons on surrounding cortical circuits. Brief activation of single neurons triggered reliable sequences of firing in tens of other excitatory and inhibitory cortical neurons, reflecting cascading activity through local networks, as indicated by delayed yet precisely timed polysynaptic subthreshold potentials. The evoked patterns were specific to the pyramidal cell of origin, extended over hundreds of micrometers from their source, and unfolded over up to 200 ms. Simultaneous activation of pyramidal cell pairs indicated balanced control of population activity, preventing paroxysmal amplification. Single cortical pyramidal neurons can thus trigger reliable postsynaptic activity that can propagate in a reliable fashion through cortex, generating rapidly evolving and non-random firing sequences reminiscent of those observed in mammalian hippocampus during “replay” and in avian song circuits.
       
  • CRISPR Interference-Based Platform for Multimodal Genetic Screens in Human
           iPSC-Derived Neurons
    • Abstract: Publication date: Available online 15 August 2019Source: NeuronAuthor(s): Ruilin Tian, Mariam A. Gachechiladze, Connor H. Ludwig, Matthew T. Laurie, Jason Y. Hong, Diane Nathaniel, Anika V. Prabhu, Michael S. Fernandopulle, Rajan Patel, Mehrnoosh Abshari, Michael E. Ward, Martin KampmannSummaryCRISPR/Cas9-based functional genomics have transformed our ability to elucidate mammalian cell biology. However, most previous CRISPR-based screens were conducted in cancer cell lines rather than healthy, differentiated cells. Here, we describe a CRISPR interference (CRISPRi)-based platform for genetic screens in human neurons derived from induced pluripotent stem cells (iPSCs). We demonstrate robust and durable knockdown of endogenous genes in such neurons and present results from three complementary genetic screens. First, a survival-based screen revealed neuron-specific essential genes and genes that improved neuronal survival upon knockdown. Second, a screen with a single-cell transcriptomic readout uncovered several examples of genes whose knockdown had strikingly cell-type-specific consequences. Third, a longitudinal imaging screen detected distinct consequences of gene knockdown on neuronal morphology. Our results highlight the power of unbiased genetic screens in iPSC-derived differentiated cell types and provide a platform for systematic interrogation of normal and disease states of neurons.Graphical Graphical abstract for this article
       
  • Enhanced mGlu5 Signaling in Excitatory Neurons Promotes Rapid
           Antidepressant Effects via AMPA Receptor Activation
    • Abstract: Publication date: Available online 13 August 2019Source: NeuronAuthor(s): Amrei Holz, Felix Mülsch, Martin K. Schwarz, Michael Hollmann, Mate D. Döbrössy, Volker A. Coenen, Marlene Bartos, Claus Normann, Knut Biber, Dietrich van Calker, Tsvetan SerchovSummaryConventional antidepressants have limited efficacy and many side effects, highlighting the need for fast-acting and specific medications. Induction of the synaptic protein Homer1a mediates the effects of different antidepressant treatments, including the rapid action of ketamine and sleep deprivation (SD). We show here that mimicking Homer1a upregulation via intravenous injection of cell-membrane-permeable TAT-Homer1a elicits rapid antidepressant effects in various tests. Similar to ketamine and SD, in vitro and in vivo application of TAT-Homer1a enhances mGlu5 signaling, resulting in increased mTOR pathway phosphorylation, and upregulates synaptic AMPA receptor expression and activity. The antidepressant action of SD and Homer1a induction depends on mGlu5 activation specifically in excitatory CaMK2a neurons and requires enhanced AMPA receptor activity, translation, and trafficking. Moreover, our data demonstrate a pronounced therapeutic potential of different TAT-fused peptides that directly modulate mGlu5 and AMPA receptor activity and thus might provide a novel strategy for rapid and effective antidepressant treatment.Graphical Graphical abstract for this article
       
  • A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals
           Shared Endosomal Abnormalities Mediated by APP β-CTFs, Not Aβ
    • Abstract: Publication date: Available online 12 August 2019Source: NeuronAuthor(s): Dylan Kwart, Andrew Gregg, Claudia Scheckel, Elisabeth Murphy, Dominik Paquet, Michael Duffield, John Fak, Olav Olsen, Robert Darnell, Marc Tessier-LavigneSummaryFamilial Alzheimer’s disease (fAD) results from mutations in the amyloid precursor protein (APP) and presenilin (PSEN1 and PSEN2) genes. Here we leveraged recent advances in induced pluripotent stem cell (iPSC) and CRISPR/Cas9 genome editing technologies to generate a panel of isogenic knockin human iPSC lines carrying APP and/or PSEN1 mutations. Global transcriptomic and translatomic profiling revealed that fAD mutations have overlapping effects on the expression of AD-related and endocytosis-associated genes. Mutant neurons also increased Rab5+ early endosome size. APP and PSEN1 mutations had discordant effects on Aβ production but similar effects on APP β C-terminal fragments (β-CTFs), which accumulate in all mutant neurons. Importantly, endosomal dysfunction correlated with accumulation of β-CTFs, not Aβ, and could be rescued by pharmacological modulation of β-secretase (BACE). These data display the utility of our mutant iPSCs in studying AD-related phenotypes in a non-overexpression human-based system and support mounting evidence that β-CTF may be critical in AD pathogenesis.
       
  • Distinct Contributions of Whisker Sensory Cortex and Tongue-Jaw Motor
           Cortex in a Goal-Directed Sensorimotor Transformation
    • Abstract: Publication date: Available online 8 August 2019Source: NeuronAuthor(s): Johannes M. Mayrhofer, Sami El-Boustani, Georgios Foustoukos, Matthieu Auffret, Keita Tamura, Carl C.H. PetersenSummaryThe neural circuits underlying goal-directed sensorimotor transformations in the mammalian brain are incompletely understood. Here, we compared the role of primary tongue-jaw motor cortex (tjM1) and primary whisker sensory cortex (wS1) in head-restrained mice trained to lick a reward spout in response to whisker deflection. Two-photon microscopy combined with microprisms allowed imaging of neuronal network activity across cortical layers in transgenic mice expressing a genetically encoded calcium indicator. Early-phase activity in wS1 encoded the whisker sensory stimulus and was necessary for detection of whisker stimuli. Activity in tjM1 encoded licking direction during task execution and was necessary for contralateral licking. Pre-stimulus activity in tjM1, but not wS1, was predictive of lick direction and contributed causally to small preparatory jaw movements. Our data reveal a shift in coding scheme from wS1 to tjM1, consistent with the hypothesis that these areas represent cortical start and end points for this goal-directed sensorimotor transformation.
       
  • ADF/Cofilin-Mediated Actin Turnover Promotes Axon Regeneration in the
           Adult CNS
    • Abstract: Publication date: Available online 7 August 2019Source: NeuronAuthor(s): Andrea Tedeschi, Sebastian Dupraz, Michele Curcio, Claudia J. Laskowski, Barbara Schaffran, Kevin C. Flynn, Telma E. Santos, Sina Stern, Brett J. Hilton, Molly J.E. Larson, Christine B. Gurniak, Walter Witke, Frank BradkeSummaryInjured axons fail to regenerate in the adult CNS, which contrasts with their vigorous growth during embryonic development. We explored the potential of re-initiating axon extension after injury by reactivating the molecular mechanisms that drive morphogenetic transformation of neurons during development. Genetic loss- and gain-of-function experiments followed by time-lapse microscopy, in vivo imaging, and whole-mount analysis show that axon regeneration is fueled by elevated actin turnover. Actin depolymerizing factor (ADF)/cofilin controls actin turnover to sustain axon regeneration after spinal cord injury through its actin-severing activity. This pinpoints ADF/cofilin as a key regulator of axon growth competence, irrespective of developmental stage. These findings reveal the central role of actin dynamics regulation in this process and elucidate a core mechanism underlying axon growth after CNS trauma. Thereby, neurons maintain the capacity to stimulate developmental programs during adult life, expanding their potential for plasticity. Thus, actin turnover is a key process for future regenerative interventions.Graphical Graphical abstract for this article
       
  • Synergistic Coding of Visual Information in Columnar Networks
    • Abstract: Publication date: Available online 6 August 2019Source: NeuronAuthor(s): Sunny Nigam, Sorin Pojoga, Valentin DragoiSummaryIncoming stimuli are encoded collectively by populations of cortical neurons, which transmit information by using a neural code thought to be predominantly redundant. Redundant coding is widely believed to reflect a design choice whereby neurons with overlapping receptive fields sample environmental stimuli to convey similar information. Here, we performed multi-electrode laminar recordings in awake monkey V1 to report significant synergistic interactions between nearby neurons within a cortical column. These interactions are clustered non-randomly across cortical layers to form synergy and redundancy hubs. Homogeneous sub-populations comprising synergy hubs decode stimulus information significantly better compared to redundancy hubs or heterogeneous sub-populations. Mechanistically, synergistic interactions emerge from the stimulus dependence of correlated activity between neurons. Our findings suggest a refinement of the prevailing ideas regarding coding schemes in sensory cortex: columnar populations can efficiently encode information due to synergistic interactions even when receptive fields overlap and shared noise between cells is high.
       
  • Unlimited Genetic Switches for Cell-Type-Specific Manipulation
    • Abstract: Publication date: Available online 5 August 2019Source: NeuronAuthor(s): Jorge Garcia-Marques, Ching-Po Yang, Isabel Espinosa-Medina, Kent Mok, Minoru Koyama, Tzumin LeeSummaryGaining independent genetic access to discrete cell types is critical to interrogate their biological functions as well as to deliver precise gene therapy. Transcriptomics has allowed us to profile cell populations with extraordinary precision, revealing that cell types are typically defined by a unique combination of genetic markers. Given the lack of adequate tools to target cell types based on multiple markers, most cell types remain inaccessible to genetic manipulation. Here we present CaSSA, a platform to create unlimited genetic switches based on CRISPR/Cas9 (Ca) and the DNA repair mechanism known as single-strand annealing (SSA). CaSSA allows engineering of independent genetic switches, each responding to a specific gRNA. Expressing multiple gRNAs in specific patterns enables multiplex cell-type-specific manipulations and combinatorial genetic targeting. CaSSA is a new genetic tool that conceptually works as an unlimited number of recombinases and will facilitate genetic access to cell types in diverse organisms.Graphical Graphical abstract for this article
       
  • Inhibition of Axon Regeneration by Liquid-like TIAR-2 Granules
    • Abstract: Publication date: Available online 1 August 2019Source: NeuronAuthor(s): Matthew G. Andrusiak, Panid Sharifnia, Xiaohui Lyu, Zhiping Wang, Andrea M. Dickey, Zilu Wu, Andrew D. Chisholm, Yishi JinSummaryPhase separation into liquid-like compartments is an emerging property of proteins containing prion-like domains (PrLDs), yet the in vivo roles of phase separation remain poorly understood. TIA proteins contain a C-terminal PrLD, and mutations in the PrLD are associated with several diseases. Here, we show that the C. elegans TIAR-2/TIA protein functions cell autonomously to inhibit axon regeneration. TIAR-2 undergoes liquid-liquid phase separation in vitro and forms granules with liquid-like properties in vivo. Axon injury induces a transient increase in TIAR-2 granule number. The PrLD is necessary and sufficient for granule formation and inhibiting regeneration. Tyrosine residues within the PrLD are important for granule formation and inhibition of regeneration. TIAR-2 is also serine phosphorylated in vivo. Non-phosphorylatable TIAR-2 variants do not form granules and are unable to inhibit axon regeneration. Our data demonstrate an in vivo function for phase-separated TIAR-2 and identify features critical for its function in axon regeneration.Graphical Graphical abstract for this article
       
  • Convergent Temperature Representations in Artificial and Biological Neural
           Networks
    • Abstract: Publication date: Available online 31 July 2019Source: NeuronAuthor(s): Martin Haesemeyer, Alexander F. Schier, Florian EngertSummaryDiscoveries in biological neural networks (BNNs) shaped artificial neural networks (ANNs) and computational parallels between ANNs and BNNs have recently been discovered. However, it is unclear to what extent discoveries in ANNs can give insight into BNN function. Here, we designed and trained an ANN to perform heat gradient navigation and found striking similarities in computation and heat representation to a known zebrafish BNN. This included shared ON- and OFF-type representations of absolute temperature and rates of change. Importantly, ANN function critically relied on zebrafish-like units. We furthermore used the accessibility of the ANN to discover a new temperature-responsive cell type in the zebrafish cerebellum. Finally, constraining the ANN by the C. elegans motor repertoire retuned sensory representations indicating that our approach generalizes. Together, these results emphasize convergence of ANNs and BNNs on stereotypical representations and that ANNs form a powerful tool to understand their biological counterparts.Graphical Graphical abstract for this article
       
  • Development of a Chimeric Model to Study and Manipulate Human Microglia
           In Vivo
    • Abstract: Publication date: Available online 30 July 2019Source: NeuronAuthor(s): Jonathan Hasselmann, Morgan A. Coburn, Whitney England, Dario X. Figueroa Velez, Sepideh Kiani Shabestari, Christina H. Tu, Amanda McQuade, Mahshad Kolahdouzan, Karla Echeverria, Christel Claes, Taylor Nakayama, Ricardo Azevedo, Nicole G. Coufal, Claudia Z. Han, Brian J. Cummings, Hayk Davtyan, Christopher K. Glass, Luke M. Healy, Sunil P. Gandhi, Robert C. SpitaleSummaryiPSC-derived microglia offer a powerful tool to study microglial homeostasis and disease-associated inflammatory responses. Yet, microglia are highly sensitive to their environment, exhibiting transcriptomic deficiencies when kept in isolation from the brain. Furthermore, species-specific genetic variations demonstrate that rodent microglia fail to fully recapitulate the human condition. To address this, we developed an approach to study human microglia within a surrogate brain environment. Transplantation of iPSC-derived hematopoietic-progenitors into the postnatal brain of humanized, immune-deficient mice results in context-dependent differentiation into microglia and other CNS macrophages, acquisition of an ex vivo human microglial gene signature, and responsiveness to both acute and chronic insults. Most notably, transplanted microglia exhibit robust transcriptional responses to Aβ-plaques that only partially overlap with that of murine microglia, revealing new, human-specific Aβ-responsive genes. We therefore have demonstrated that this chimeric model provides a powerful new system to examine the in vivo function of patient-derived and genetically modified microglia.Graphical Graphical abstract for this article
       
  • Precise Long-Range Microcircuit-to-Microcircuit Communication Connects the
           Frontal and Sensory Cortices in the Mammalian Brain
    • Abstract: Publication date: Available online 29 July 2019Source: NeuronAuthor(s): Si-Qiang Ren, Zhizhong Li, Susan Lin, Matteo Bergami, Song-Hai ShiSummaryThe frontal area of the cerebral cortex provides long-range inputs to sensory areas to modulate neuronal activity and information processing. These long-range circuits are crucial for accurate sensory perception and complex behavioral control; however, little is known about their precise circuit organization. Here we specifically identified the presynaptic input neurons to individual excitatory neuron clones as a unit that constitutes functional microcircuits in the mouse sensory cortex. Interestingly, the long-range input neurons in the frontal but not contralateral sensory area are spatially organized into discrete vertical clusters and preferentially form synapses with each other over nearby non-input neurons. Moreover, the assembly of distant presynaptic microcircuits in the frontal area depends on the selective synaptic communication of excitatory neuron clones in the sensory area that provide inputs to the frontal area. These findings suggest that highly precise long-range reciprocal microcircuit-to-microcircuit communication mediates frontal-sensory area interactions in the mammalian cortex.Graphical Graphical abstract for this article
       
  • Cortical Neurogenesis Requires Bcl6-Mediated Transcriptional Repression of
           Multiple Self-Renewal-Promoting Extrinsic Pathways
    • Abstract: Publication date: Available online 25 July 2019Source: NeuronAuthor(s): Jerome Bonnefont, Luca Tiberi, Jelle van den Ameele, Delphine Potier, Zachary B. Gaber, Xionghui Lin, Angéline Bilheu, Adèle Herpoel, Fausto D. Velez Bravo, François Guillemot, Stein Aerts, Pierre VanderhaeghenSummaryDuring neurogenesis, progenitors switch from self-renewal to differentiation through the interplay of intrinsic and extrinsic cues, but how these are integrated remains poorly understood. Here, we combine whole-genome transcriptional and epigenetic analyses with in vivo functional studies to demonstrate that Bcl6, a transcriptional repressor previously reported to promote cortical neurogenesis, acts as a driver of the neurogenic transition through direct silencing of a selective repertoire of genes belonging to multiple extrinsic pathways promoting self-renewal, most strikingly the Wnt pathway. At the molecular level, Bcl6 represses its targets through Sirt1 recruitment followed by histone deacetylation. Our data identify a molecular logic by which a single cell-intrinsic factor represses multiple extrinsic pathways that favor self-renewal, thereby ensuring robustness of neuronal fate transition.Graphical Graphical abstract for this article
       
  • The Cholinergic Basal Forebrain Links Auditory Stimuli with Delayed
           Reinforcement to Support Learning
    • Abstract: Publication date: Available online 24 July 2019Source: NeuronAuthor(s): Wei Guo, Blaise Robert, Daniel B. PolleySummaryAnimals learn to fear conditioned sound stimuli (CSs) that accompany aversive unconditioned stimuli (USs). Auditory cortex (ACx) circuits reorganize to support auditory fear learning when CS-evoked activity temporally overlaps with US-evoked acetylcholine release from the basal forebrain. Here we describe robust fear learning and acetylcholine-dependent ACx plasticity even when the US is delayed by several seconds following CS offset. A 5-s CS-US gap was not bridged by persistent CS-evoked spiking throughout the trace period. Instead, within minutes following the start of conditioning, optogenetically identified basal forebrain neurons that encode the aversive US scaled up responses to the CS and increased functional coupling with the ACx. Over several days of conditioning, bulk imaging of cholinergic basal forebrain neurons revealed sustained sound-evoked activity that filled in the 5-s silent gap preceding the US. These findings identify a plasticity in the basal forebrain that supports learned associations between sensory stimuli and delayed reinforcement.Graphical Graphical abstract for this article
       
  • How mRNA Localization and Protein Synthesis Sites Influence Dendritic
           Protein Distribution and Dynamics
    • Abstract: Publication date: Available online 23 July 2019Source: NeuronAuthor(s): Yombe Fonkeu, Nataliya Kraynyukova, Anne-Sophie Hafner, Lisa Kochen, Fabio Sartori, Erin M. Schuman, Tatjana TchumatchenkoSummaryProteins drive the function of neuronal synapses. The synapses are distributed throughout the dendritic arbor, often hundreds of micrometers away from the soma. It is still unclear how somatic and dendritic sources of proteins shape protein distribution and respectively contribute to local protein changes during synaptic plasticity. Here, we present a unique computational framework describing for a given protein species the dendritic distribution of the mRNA and the corresponding protein in a dendrite. Using CaMKIIα as a test case, our model reveals the key role active transport plays in the maintenance of dendritic mRNA and protein levels and predicts the short and long timescales of protein dynamics. Our model reveals the fundamental role of mRNA localization and dendritic mRNA translation in synaptic maintenance and plasticity in distal compartments. We developed a web application for neuroscientists to explore the dynamics of the mRNA or protein of interest.Graphical Graphical abstract for this article
       
  • Neural Organization of Hierarchical Motor Sequence Representations in the
           Human Neocortex
    • Abstract: Publication date: Available online 22 July 2019Source: NeuronAuthor(s): Atsushi Yokoi, Jörn DiedrichsenSummaryAlthough it is widely accepted that the brain represents movement sequences hierarchically, the neural implementation of this organization is still poorly understood. To address this issue, we experimentally manipulated how participants represented sequences of finger presses at the levels of individual movements, chunks, and entire sequences. Using representational fMRI analyses, we then examined how this hierarchical structure was reflected in the fine-grained brain activity patterns of the participants while they performed the 8 trained sequences. We found clear evidence of each level of the movement hierarchy at the representational level. However, anatomically, chunk and sequence representations substantially overlapped in the premotor and parietal cortices, whereas individual movements were uniquely represented in the primary motor cortex. The findings challenge the common hypothesis of an orderly anatomical separation of different levels of an action hierarchy and argue for a special status of the distinction between individual movements and sequential context.
       
  • Persistent Gamma Spiking in SI Nonsensory Fast Spiking Cells Predicts
           Perceptual Success
    • Abstract: Publication date: Available online 18 July 2019Source: NeuronAuthor(s): Hyeyoung Shin, Christopher I. MooreSummaryGamma oscillations (30–55 Hz) are hypothesized to temporally coordinate sensory encoding, enabling perception. However, fast spiking interneurons (FS), key gamma generators, can be highly sensory responsive, as is the gamma band local field potential (LFP). How can FS-mediated gamma act as an impartial temporal reference for sensory encoding, when the sensory drive itself presumably perturbs the pre-established rhythm? Combining tetrode recording in SI barrel cortex with controlled psychophysics, we found a unique FS subtype that was not sensory responsive and spiked regularly at gamma range intervals (gamma regular nonsensory FS [grnsFS]). Successful detection was predicted by a further increase in gamma regular spiking of grnsFS, persisting from before to after sensory onset. In contrast, broadband LFP power, including gamma, negatively predicted detection and did not cohere with gamma band spiking by grnsFS. These results suggest that a distinct FS subtype mediates perceptually relevant oscillations, independent of the LFP and sensory drive.Graphical Graphical abstract for this article
       
  • Dopamine Deficiency Reduces Striatal Cholinergic Interneuron Function in
           Models of Parkinson’s Disease
    • Abstract: Publication date: Available online 16 July 2019Source: NeuronAuthor(s): Jonathan W. McKinley, Ziqing Shi, Ivana Kawikova, Matthew Hur, Ian J. Bamford, Suma Priya Sudarsana Devi, Annie Vahedipour, Martin Darvas, Nigel S. BamfordSummaryMotor and cognitive functions depend on the coordinated interactions between dopamine (DA) and acetylcholine (ACh) at striatal synapses. Increased ACh availability was assumed to accompany DA deficiency based on the outcome of pharmacological treatments and measurements in animals that were critically depleted of DA. Using Slc6a3DTR/+ diphtheria-toxin-sensitive mice, we demonstrate that a progressive and L-dopa-responsive DA deficiency reduces ACh availability and the transcription of hyperpolarization-activated cation (HCN) channels that encode the spike timing of ACh-releasing tonically active striatal interneurons (ChIs). Although the production and release of ACh and DA are reduced, the preponderance of ACh over DA contributes to the motor deficit. The increase in striatal ACh relative to DA is heightened via D1-type DA receptors that activate ChIs in response to DA release from residual axons. These results suggest that stabilizing the expression of HCN channels may improve ACh-DA reciprocity and motor function in Parkinson’s disease (PD).Video Graphical Graphical abstract for this article
       
  • Identification of a Spinal Circuit for Mechanical and Persistent
           Spontaneous Itch
    • Abstract: Publication date: Available online 16 July 2019Source: NeuronAuthor(s): Haili Pan, Mahar Fatima, Alan Li, Hankyu Lee, Wei Cai, Lorraine Horwitz, Chia Chun Hor, Nizam Zaher, Mitchell Cin, Hannah Slade, Tianwen Huang, X.Z. Shawn Xu, Bo DuanSummaryLightly stroking the lips or gently poking some skin regions can evoke mechanical itch in healthy human subjects. Sensitization of mechanical itch and persistent spontaneous itch are intractable symptoms in chronic itch patients. However, the underlying neural circuits are not well defined. We identified a subpopulation of excitatory interneurons expressing Urocortin 3::Cre (Ucn3+) in the dorsal spinal cord as a central node in the pathway that transmits acute mechanical itch and mechanical itch sensitization as well as persistent spontaneous itch under chronic itch conditions. This population receives peripheral inputs from Toll-like receptor 5-positive (TLR5+) Aβ low-threshold mechanoreceptors and is directly innervated by inhibitory interneurons expressing neuropeptide Y::Cre (NPY+) in the dorsal spinal cord. Reduced synaptic inhibition and increased intrinsic excitability of Ucn3+ neurons lead to chronic itch sensitization. Our study sheds new light on the neural basis of chronic itch and unveils novel avenues for developing mechanism-specific therapeutic advancements.Graphical Graphical abstract for this article
       
 
 
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