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Journal Prestige (SJR): 10.654
Citation Impact (citeScore): 11
Number of Followers: 207  
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ISSN (Print) 0896-6273 - ISSN (Online) 1097-4199
Published by Elsevier Homepage  [3162 journals]
  • Entrainment of Circadian Rhythms Depends on Firing Rates and Neuropeptide
           Release of VIP SCN Neurons
    • Abstract: Publication date: Available online 12 July 2018Source: NeuronAuthor(s): Cristina Mazuski, John H. Abel, Samantha P. Chen, Tracey O. Hermanstyne, Jeff R. Jones, Tatiana Simon, Francis J. Doyle, Erik D. HerzogSummaryThe mammalian suprachiasmatic nucleus (SCN) functions as a master circadian pacemaker, integrating environmental input to align physiological and behavioral rhythms to local time cues. Approximately 10% of SCN neurons express vasoactive intestinal polypeptide (VIP); however, it is unknown how firing activity of VIP neurons releases VIP to entrain circadian rhythms. To identify physiologically relevant firing patterns, we optically tagged VIP neurons and characterized spontaneous firing over 3 days. VIP neurons had circadian rhythms in firing rate and exhibited two classes of instantaneous firing activity. We next tested whether physiologically relevant firing affected circadian rhythms through VIP release. We found that VIP neuron stimulation with high, but not low, frequencies shifted gene expression rhythms in vitro through VIP signaling. In vivo, high-frequency VIP neuron activation rapidly entrained circadian locomotor rhythms. Thus, increases in VIP neuronal firing frequency release VIP and entrain molecular and behavioral circadian rhythms.
  • Radial Glial Lineage Progression and Differential Intermediate Progenitor
           Amplification Underlie Striatal Compartments and Circuit Organization
    • Abstract: Publication date: Available online 12 July 2018Source: NeuronAuthor(s): Sean M. Kelly, Ricardo Raudales, Miao He, Jannifer H. Lee, Yongsoo Kim, Leif G. Gibb, Priscilla Wu, Katherine Matho, Pavel Osten, Ann M. Graybiel, Z. Josh HuangSummaryThe circuitry of the striatum is characterized by two organizational plans: the division into striosome and matrix compartments, thought to mediate evaluation and action, and the direct and indirect pathways, thought to promote or suppress behavior. The developmental origins of these organizations and their developmental relationships are unknown, leaving a conceptual gap in understanding the cortico-basal ganglia system. Through genetic fate mapping, we demonstrate that striosome-matrix compartmentalization arises from a lineage program embedded in lateral ganglionic eminence radial glial progenitors mediating neurogenesis through two distinct types of intermediate progenitors (IPs). The early phase of this program produces striosomal spiny projection neurons (SPNs) through fate-restricted apical IPs (aIPSs) with limited capacity; the late phase produces matrix SPNs through fate-restricted basal IPs (bIPMs) with expanded capacity. Notably, direct and indirect pathway SPNs arise within both aIPS and bIPM pools, suggesting that striosome-matrix architecture is the fundamental organizational plan of basal ganglia circuitry.
  • Melanopsin Phototransduction Is Repurposed by ipRGC Subtypes to Shape the
           Function of Distinct Visual Circuits
    • Abstract: Publication date: Available online 12 July 2018Source: NeuronAuthor(s): Takuma Sonoda, Seul Ki Lee, Lutz Birnbaumer, Tiffany M. SchmidtSummaryMelanopsin is expressed in distinct types of intrinsically photosensitive retinal ganglion cells (ipRGCs), which drive behaviors from circadian photoentrainment to contrast detection. A major unanswered question is how the same photopigment, melanopsin, influences such vastly different functions. Here we show that melanopsin’s role in contrast detection begins in the retina, via direct effects on M4 ipRGC (ON alpha RGC) signaling. This influence persists across an unexpectedly wide range of environmental light levels ranging from starlight to sunlight, which considerably expands the functional reach of melanopsin on visual processing. Moreover, melanopsin increases the excitability of M4 ipRGCs via closure of potassium leak channels, a previously unidentified target of the melanopsin phototransduction cascade. Strikingly, this mechanism is selective for image-forming circuits, as M1 ipRGCs (involved in non-image forming behaviors), exhibit a melanopsin-mediated decrease in excitability. Thus, melanopsin signaling is repurposed by ipRGC subtypes to shape distinct visual behaviors.Graphical Graphical abstract for this article
  • Functional Networks for Social Communication in the Macaque Monkey
    • Abstract: Publication date: Available online 12 July 2018Source: NeuronAuthor(s): Stephen V. Shepherd, Winrich A. FreiwaldSummaryAll primates communicate. To dissect the neural circuits of social communication, we used fMRI to map non-human primate brain regions for social perception, second-person (interactive) social cognition, and orofacial movement generation. Face perception, second-person cognition, and face motor networks were largely non-overlapping and acted as distinct functional units rather than an integrated feedforward-processing pipeline. Whereas second-person context selectively engaged a region of medial prefrontal cortex, production of orofacial movements recruited distributed subcortical and cortical areas in medial and lateral frontal and insular cortex. These areas exhibited some specialization, but not dissociation, of function along the medio-lateral axis. Production of lipsmack movements recruited areas including putative homologs of Broca’s area. These findings provide a new view of the neural architecture for social communication and suggest expressive orofacial movements generated by lateral premotor cortex as a putative evolutionary precursor to human speech.Graphical Graphical abstract for this article
  • Sensorimotor Integration and Amplification of Reflexive Whisking by
           Well-Timed Spiking in the Cerebellar Corticonuclear Circuit
    • Abstract: Publication date: Available online 12 July 2018Source: NeuronAuthor(s): Spencer T. Brown, Indira M. RamanSummaryTo test how cerebellar crus I/II Purkinje cells and their targets in the lateral cerebellar nuclei (CbN) integrate sensory and motor-related inputs and contribute to reflexive movements, we recorded extracellularly in awake, head-fixed mice during non-contact whisking. Ipsilateral or contralateral air puffs elicited changes in population Purkinje simple spike rates that matched whisking kinematics (∼1 Hz/1° protraction). Responses remained relatively unaffected when ipsilateral sensory feedback was removed by lidocaine but were reduced by optogenetically inhibiting the reticular nuclei. Optogenetically silencing cerebellar output suppressed movements. During puff-evoked whisks, both Purkinje and CbN cells generated well-timed spikes in sequential 2- to 4-ms windows at response onset, such that they alternately elevated their firing rates just before protraction. With spontaneous whisks, which were smaller than puff-evoked whisks, well-timed spikes were absent and CbN cells were inhibited. Thus, sensory input can facilitate millisecond-scale, well-timed spiking in Purkinje and CbN cells and amplify reflexive whisker movements.
  • Are We There Yet' Identification of Reward-Selective Cells in the
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Marielena Sosa, Loren M. FrankNavigation to a previously visited reward site requires a reliable and accurate spatial memory. In this issue of Neuron, Gauthier and Tank (2018) use two-photon calcium imaging to uncover a discrete hippocampal subpopulation specialized for encoding reward location.
  • The BDNF Val66Met Prodomain Disassembles Dendritic Spines Altering Fear
           Extinction Circuitry and Behavior
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Joanna I. Giza, Jihye Kim, Heidi C. Meyer, Agustin Anastasia, Iva Dincheva, Crystal I. Zheng, Katherine Lopez, Henrietta Bains, Jianmin Yang, Clay Bracken, Conor Liston, Deqiang Jing, Barbara L. Hempstead, Francis S. LeeSummaryA human variant in the BDNF gene (Val66Met; rs6265) is associated with impaired fear extinction. Using super-resolution imaging, we demonstrate that the BDNF Met prodomain disassembles dendritic spines and eliminates synapses in hippocampal neurons. In vivo, ventral CA1 (vCA1) hippocampal neurons undergo similar morphological changes dependent on their transient co-expression of a SorCS2/p75NTR receptor complex during peri-adolescence. BDNF Met prodomain infusion into the vCA1 during this developmental time frame reduces dendritic spine density and prelimbic (PL) projections, impairing cued fear extinction. Adolescent BdnfMet/Met mice display similar spine and PL innervation deficits. Using fiber photometry, we found that, in wild-type mice, vCA1 neurons projecting to the PL encode extinction by enhancing neural activity in threat anticipation and rapidly subsiding their response. This adaptation is absent in BDNFMet/Met mice. We conclude that the BDNF Met prodomain renders vCA1-PL projection neurons underdeveloped, preventing their capacity for subsequent circuit modulation necessary for fear extinction.Video
  • Persistent Sodium Current Mediates the Steep Voltage Dependence of Spatial
           Coding in Hippocampal Pyramidal Neurons
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Ching-Lung Hsu, Xinyu Zhao, Aaron D. Milstein, Nelson SprustonSummaryThe mammalian hippocampus forms a cognitive map using neurons that fire according to an animal’s position (“place cells”) and many other behavioral and cognitive variables. The responses of these neurons are shaped by their presynaptic inputs and the nature of their postsynaptic integration. In CA1 pyramidal neurons, spatial responses in vivo exhibit a strikingly supralinear dependence on baseline membrane potential. The biophysical mechanisms underlying this nonlinear cellular computation are unknown. Here, through a combination of in vitro, in vivo, and in silico approaches, we show that persistent sodium current mediates the strong membrane potential dependence of place cell activity. This current operates at membrane potentials below the action potential threshold and over seconds-long timescales, mediating a powerful and rapidly reversible amplification of synaptic responses, which drives place cell firing. Thus, we identify a biophysical mechanism that shapes the coding properties of neurons composing the hippocampal cognitive map.Graphical Graphical abstract for this article
  • Internally Generated Predictions Enhance Neural and Behavioral Detection
           of Sensory Stimuli in an Electric Fish
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Armen G. Enikolopov, L.F. Abbott, Nathaniel B. SawtellSummaryStudies of cerebellum-like circuits in fish have demonstrated that synaptic plasticity shapes the motor corollary discharge responses of granule cells into highly-specific predictions of self-generated sensory input. However, the functional significance of such predictions, known as negative images, has not been directly tested. Here we provide evidence for improvements in neural coding and behavioral detection of prey-like stimuli due to negative images. In addition, we find that manipulating synaptic plasticity leads to specific changes in circuit output that disrupt neural coding and detection of prey-like stimuli. These results link synaptic plasticity, neural coding, and behavior and also provide a circuit-level account of how combining external sensory input with internally generated predictions enhances sensory processing.
  • How Diverse Retinal Functions Arise from Feedback at the First Visual
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Antonia Drinnenberg, Felix Franke, Rei K. Morikawa, Josephine Jüttner, Daniel Hillier, Peter Hantz, Andreas Hierlemann, Rava Azeredo da Silveira, Botond RoskaSummaryMany brain regions contain local interneurons of distinct types. How does an interneuron type contribute to the input-output transformations of a given brain region' We addressed this question in the mouse retina by chemogenetically perturbing horizontal cells, an interneuron type providing feedback at the first visual synapse, while monitoring the light-driven spiking activity in thousands of ganglion cells, the retinal output neurons. We uncovered six reversible perturbation-induced effects in the response dynamics and response range of ganglion cells. The effects were enhancing or suppressive, occurred in different response epochs, and depended on the ganglion cell type. A computational model of the retinal circuitry reproduced all perturbation-induced effects and led us to assign specific functions to horizontal cells with respect to different ganglion cell types. Our combined experimental and theoretical work reveals how a single interneuron type can differentially shape the dynamical properties of distinct output channels of a brain region.
  • Layer I Interneurons Sharpen Sensory Maps during Neonatal Development
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Alicia Che, Rachel Babij, Andrew F. Iannone, Robert N. Fetcho, Monica Ferrer, Conor Liston, Gord Fishell, Natalia V. De Marco GarcíaSummaryThe neonatal mammal faces an array of sensory stimuli when diverse neuronal types have yet to form sensory maps. How these inputs interact with intrinsic neuronal activity to facilitate circuit assembly is not well understood. By using longitudinal calcium imaging in unanesthetized mouse pups, we show that layer I (LI) interneurons, delineated by co-expression of the 5HT3a serotonin receptor (5HT3aR) and reelin (Re), display spontaneous calcium transients with the highest degree of synchrony among cell types present in the superficial barrel cortex at postnatal day 6 (P6). 5HT3aR Re interneurons are activated by whisker stimulation during this period, and sensory deprivation induces decorrelation of their activity. Moreover, attenuation of thalamic inputs through knockdown of NMDA receptors (NMDARs) in these interneurons results in expansion of whisker responses, aberrant barrel map formation, and deficits in whisker-dependent behavior. These results indicate that recruitment of specific interneuron types during development is critical for adult somatosensory function.Video Graphical Graphical abstract for this article
  • Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to
           Focal Cortical Dyslamination
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Sang Min Park, Jae Seok Lim, Suresh Ramakrishina, Se Hoon Kim, Woo Kyeong Kim, Junehawk Lee, Hoon-Chul Kang, Jeremy F. Reiter, Dong Seok Kim, Hyongbum (Henry) Kim, Jeong Ho LeeSummaryFocal malformations of cortical development (FMCDs), including focal cortical dysplasia (FCD) and hemimegalencephaly (HME), are major etiologies of pediatric intractable epilepsies exhibiting cortical dyslamination. Brain somatic mutations in MTOR have recently been identified as a major genetic cause of FMCDs. However, the molecular mechanism by which these mutations lead to cortical dyslamination remains poorly understood. Here, using patient tissue, genome-edited cells, and mouse models with brain somatic mutations in MTOR, we discovered that disruption of neuronal ciliogenesis by the mutations underlies cortical dyslamination in FMCDs. We found that abnormal accumulation of OFD1 at centriolar satellites due to perturbed autophagy was responsible for the defective neuronal ciliogenesis. Additionally, we found that disrupted neuronal ciliogenesis accounted for cortical dyslamination in FMCDs by compromising Wnt signals essential for neuronal polarization. Altogether, this study describes a molecular mechanism by which brain somatic mutations in MTOR contribute to the pathogenesis of cortical dyslamination in FMCDs.
  • Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption
           of Molecular, Genetic, and Clinical Networks by Human Herpesvirus
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Ben Readhead, Jean-Vianney Haure-Mirande, Cory C. Funk, Matthew A. Richards, Paul Shannon, Vahram Haroutunian, Mary Sano, Winnie S. Liang, Noam D. Beckmann, Nathan D. Price, Eric M. Reiman, Eric E. Schadt, Michelle E. Ehrlich, Sam Gandy, Joel T. DudleySummaryInvestigators have long suspected that pathogenic microbes might contribute to the onset and progression of Alzheimer’s disease (AD) although definitive evidence has not been presented. Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration, is also difficult to resolve. We constructed multiscale networks of the late-onset AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathological data across four brain regions from human post-mortem tissue. We observed increased human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. We observed regulatory relationships linking viral abundance and modulators of APP metabolism, including induction of APBB2, APPBP2, BIN1, BACE1, CLU, PICALM, and PSEN1 by HHV-6A. This study elucidates networks linking molecular, clinical, and neuropathological features with viral activity and is consistent with viral activity constituting a general feature of AD.
  • Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by
           Herpesviridae to Protect against Brain Infection
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): William A. Eimer, Deepak Kumar Vijaya Kumar, Nanda Kumar Navalpur Shanmugam, Alex S. Rodriguez, Teryn Mitchell, Kevin J. Washicosky, Bence György, Xandra O. Breakefield, Rudolph E. Tanzi, Robert D. MoirSummaryAmyloid-β peptide (Aβ) fibrilization and deposition as β-amyloid are hallmarks of Alzheimer’s disease (AD) pathology. We recently reported Aβ is an innate immune protein that protects against fungal and bacterial infections. Fibrilization pathways mediate Aβ antimicrobial activities. Thus, infection can seed and dramatically accelerate β-amyloid deposition. Here, we show Aβ oligomers bind herpesvirus surface glycoproteins, accelerating β-amyloid deposition and leading to protective viral entrapment activity in 5XFAD mouse and 3D human neural cell culture infection models against neurotropic herpes simplex virus 1 (HSV1) and human herpesvirus 6A and B. Herpesviridae are linked to AD, but it has been unclear how viruses may induce β-amyloidosis in brain. These data support the notion that Aβ might play a protective role in CNS innate immunity, and suggest an AD etiological mechanism in which herpesviridae infection may directly promote Aβ amyloidosis.
  • A Visual-Cue-Dependent Memory Circuit for Place Navigation
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Han Qin, Ling Fu, Bo Hu, Xiang Liao, Jian Lu, Wenjing He, Shanshan Liang, Kuan Zhang, Ruijie Li, Jiwei Yao, Junan Yan, Hao Chen, Hongbo Jia, Benedikt Zott, Arthur Konnerth, Xiaowei ChenSummaryThe ability to remember and to navigate to safe places is necessary for survival. Place navigation is known to involve medial entorhinal cortex (MEC)-hippocampal connections. However, learning-dependent changes in neuronal activity in the distinct circuits remain unknown. Here, by using optic fiber photometry in freely behaving mice, we discovered the experience-dependent induction of a persistent-task-associated (PTA) activity. This PTA activity critically depends on learned visual cues and builds up selectively in the MEC layer II-dentate gyrus, but not in the MEC layer III-CA1 pathway, and its optogenetic suppression disrupts navigation to the target location. The findings suggest that the visual system, the MEC layer II, and the dentate gyrus are essential hubs of a memory circuit for visually guided navigation.
  • Rapid Cue-Specific Remodeling of the Nascent Axonal Proteome
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Roberta Cagnetta, Christian K. Frese, Toshiaki Shigeoka, Jeroen Krijgsveld, Christine E. HoltSummaryAxonal protein synthesis and degradation are rapidly regulated by extrinsic signals during neural wiring, but the full landscape of proteomic changes remains unknown due to limitations in axon sampling and sensitivity. By combining pulsed stable isotope labeling of amino acids in cell culture with single-pot solid-phase-enhanced sample preparation, we characterized the nascent proteome of isolated retinal axons on an unparalleled rapid timescale (5 min). Our analysis detects 350 basally translated axonal proteins on average, including several linked to neurological disease. Axons stimulated by different cues (Netrin-1, BDNF, Sema3A) show distinct signatures with more than 100 different nascent protein species up- or downregulated within the first 5 min followed by further dynamic remodeling. Switching repulsion to attraction triggers opposite regulation of a subset of common nascent proteins. Our findings thus reveal the rapid remodeling of the axonal proteomic landscape by extrinsic cues and uncover a logic underlying attraction versus repulsion.Graphical Graphical abstract for this article
  • Dendritic Tau in Alzheimer’s Disease
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Arne Ittner, Lars M. IttnerThe microtubule-associated protein tau and amyloid-β (Aβ) are key players in Alzheimer’s disease (AD). Aβ and tau are linked in a molecular pathway at the post-synapse with tau-dependent synaptic dysfunction being a major pathomechanism in AD. Recent work on site-specific modification of dendritic and more specifically post-synaptic tau has revealed new endogenous functions of tau that limits synaptic Aβ toxicity. Thus, molecular studies opened a new perspective on tau, placing it at the center of neurotoxic and neuroprotective signaling at the post-synapse. Here, we review recent advances on tau in the dendritic compartments, with implications for understanding and treatment of AD and related neurological conditions.
  • Setting the Stage for the Next Generation of Neuroscience
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Neuroscientists share their vision—spanning from the nanoscale to complex social behavior—for what is needed to take on the big challenges of the field.
  • Attractor Dynamics in Networks with Learning Rules Inferred from
           In Vivo Data
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Ulises Pereira, Nicolas BrunelSummaryThe attractor neural network scenario is a popular scenario for memory storage in the association cortex, but there is still a large gap between models based on this scenario and experimental data. We study a recurrent network model in which both learning rules and distribution of stored patterns are inferred from distributions of visual responses for novel and familiar images in the inferior temporal cortex (ITC). Unlike classical attractor neural network models, our model exhibits graded activity in retrieval states, with distributions of firing rates that are close to lognormal. Inferred learning rules are close to maximizing the number of stored patterns within a family of unsupervised Hebbian learning rules, suggesting that learning rules in ITC are optimized to store a large number of attractor states. Finally, we show that there exist two types of retrieval states: one in which firing rates are constant in time and another in which firing rates fluctuate chaotically.
  • Parallel Processing of Negative Feedback: E Unum Pluribus
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Jen-Chun Hsiang, Daniel KerschensteinerHow do canonical computational elements interact to shape neural circuit function' In this issue of Neuron, Drinnenberg et al. (2018) show that parallel processing converts unitary negative feedback at the first synapse of the retina into diverse output signals to the brain.
  • mTOR’ing across the Cortex by Chopping the Cilia
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Alessia Di Nardo, Mustafa SahinSomatic mutation of the MTOR gene is a genetic etiology of focal malformations of cortical development. In this issue of Neuron, Park et al. (2018) identify defective autophagy-dependent ciliogenesis/Wnt signaling as an underlying mechanism affecting neuronal migration and cortical lamination.
  • Axon Guidance: Gained in Translation
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Frédéric CharronIn this issue of Neuron, Cagnetta et al. (2018) describe a novel method to identify, in an unbiased manner, newly synthesized axonal proteins in response to axon guidance cues. They find that axons stimulated by different guidance cues (Netrin-1, BDNF, and Sema3A) show distinct and common signatures.
  • Parvalbumin Interneurons Modulate Striatal Output and Enhance Performance
           during Associative Learning
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Kwang Lee, Sandra M. Holley, Justin L. Shobe, Natalie C. Chong, Carlos Cepeda, Michael S. Levine, Sotiris C. Masmanidis
  • The Epigenetic State of PRDM16-Regulated Enhancers in Radial Glia Controls
           Cortical Neuron Position
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): José-Manuel Baizabal, Meeta Mistry, Miguel Turrero García, Nicolás Gómez, Olubusola Olukoya, Diana Tran, Matthew B. Johnson, Christopher A. Walsh, Corey C. Harwell
  • Feature-Based Visual Short-Term Memory Is Widely Distributed and
           Hierarchically Organized
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Nicholas M. Dotson, Steven J. Hoffman, Baldwin Goodell, Charles M. GraySummaryFeature-based visual short-term memory is known to engage both sensory and association cortices. However, the extent of the participating circuit and the neural mechanisms underlying memory maintenance is still a matter of vigorous debate. To address these questions, we recorded neuronal activity from 42 cortical areas in monkeys performing a feature-based visual short-term memory task and an interleaved fixation task. We find that task-dependent differences in firing rates are widely distributed throughout the cortex, while stimulus-specific changes in firing rates are more restricted and hierarchically organized. We also show that microsaccades during the memory delay encode the stimuli held in memory and that units modulated by microsaccades are more likely to exhibit stimulus specificity, suggesting that eye movements contribute to visual short-term memory processes. These results support a framework in which most cortical areas, within a modality, contribute to mnemonic representations at timescales that increase along the cortical hierarchy.
  • Enhanced Neural Processing by Covert Attention only during Microsaccades
           Directed toward the Attended Stimulus
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Eric Lowet, Bruno Gomes, Karthik Srinivasan, Huihui Zhou, Robert John Schafer, Robert DesimoneSummaryAttention can be “covertly” directed without eye movements; yet, even during fixation, there are continuous microsaccades (MSs). In areas V4 and IT of macaques, we found that firing rates and stimulus representations were enhanced by attention but only following a MS toward the attended stimulus. The onset of neural attentional modulations was tightly coupled to the MS onset. The results reveal a major link between the effects of covert attention on cortical visual processing and the overt movement of the eyes.
  • A Dynamic Bayesian Observer Model Reveals Origins of Bias in Visual Path
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Kaushik J. Lakshminarasimhan, Marina Petsalis, Hyeshin Park, Gregory C. DeAngelis, Xaq Pitkow, Dora E. AngelakiSummaryPath integration is a strategy by which animals track their position by integrating their self-motion velocity. To identify the computational origins of bias in visual path integration, we asked human subjects to navigate in a virtual environment using optic flow and found that they generally traveled beyond the goal location. Such a behavior could stem from leaky integration of unbiased self-motion velocity estimates or from a prior expectation favoring slower speeds that causes velocity underestimation. Testing both alternatives using a probabilistic framework that maximizes expected reward, we found that subjects’ biases were better explained by a slow-speed prior than imperfect integration. When subjects integrate paths over long periods, this framework intriguingly predicts a distance-dependent bias reversal due to buildup of uncertainty, which we also confirmed experimentally. These results suggest that visual path integration in noisy environments is limited largely by biases in processing optic flow rather than by leaky integration.
  • A Dedicated Population for Reward Coding in the Hippocampus
    • Abstract: Publication date: 11 July 2018Source: Neuron, Volume 99, Issue 1Author(s): Jeffrey L. Gauthier, David W. TankSummaryThe hippocampus plays a critical role in goal-directed navigation. Across different environments, however, hippocampal maps are randomized, making it unclear how goal locations could be encoded consistently. To address this question, we developed a virtual reality task with shifting reward contingencies to distinguish place versus reward encoding. In mice performing the task, large-scale recordings in CA1 and subiculum revealed a small, specialized cell population that was only active near reward yet whose activity could not be explained by sensory cues or stereotyped reward anticipation behavior. Across different virtual environments, most cells remapped randomly, but reward encoding consistently arose from a single pool of cells, suggesting that they formed a dedicated channel for reward. These observations represent a significant departure from the current understanding of CA1 as a relatively homogeneous ensemble without fixed coding properties and provide a new candidate for the cellular basis of goal memory in the hippocampus.Graphical Graphical abstract for this article
  • Luminance Changes Drive Directional Startle through a Thalamic Pathway
    • Abstract: Publication date: Available online 5 July 2018Source: NeuronAuthor(s): Lucy A.L. Heap, Gilles Vanwalleghem, Andrew W. Thompson, Itia A. Favre-Bulle, Ethan K. ScottSummaryLooming visual stimuli result in escape responses that are conserved from insects to humans. Despite their importance for survival, the circuits mediating visual startle have only recently been explored in vertebrates. Here we show that the zebrafish thalamus is a luminance detector critical to visual escape. Thalamic projection neurons deliver dim-specific information to the optic tectum, and ablations of these projections disrupt normal tectal responses to looms. Without this information, larvae are less likely to escape from dark looming stimuli and lose the ability to escape away from the source of the loom. Remarkably, when paired with an isoluminant loom stimulus to the opposite eye, dimming is sufficient to increase startle probability and to reverse the direction of the escape so that it is toward the loom. We suggest that bilateral comparisons of luminance, relayed from the thalamus to the tectum, facilitate escape responses and are essential for their directionality.
  • A Modular Organization of LRR Protein-Mediated Synaptic Adhesion Defines
           Synapse Identity
    • Abstract: Publication date: Available online 5 July 2018Source: NeuronAuthor(s): Anna Schroeder, Jeroen Vanderlinden, Katlijn Vints, Luís F. Ribeiro, Kristel M. Vennekens, Natalia V. Gounko, Keimpe D. Wierda, Joris de WitSummaryPyramidal neurons express rich repertoires of leucine-rich repeat (LRR)-containing adhesion molecules with similar synaptogenic activity in culture. The in vivo relevance of this molecular diversity is unclear. We show that hippocampal CA1 pyramidal neurons express multiple synaptogenic LRR proteins that differentially distribute to the major excitatory inputs on their apical dendrites. At Schaffer collateral (SC) inputs, FLRT2, LRRTM1, and Slitrk1 are postsynaptically localized and differentially regulate synaptic structure and function. FLRT2 controls spine density, whereas LRRTM1 and Slitrk1 exert opposing effects on synaptic vesicle distribution at the active zone. All LRR proteins differentially affect synaptic transmission, and their combinatorial loss results in a cumulative phenotype. At temporoammonic (TA) inputs, LRRTM1 is absent; FLRT2 similarly controls functional synapse number, whereas Slitrk1 function diverges to regulate postsynaptic AMPA receptor density. Thus, LRR proteins differentially control synaptic architecture and function and act in input-specific combinations and a context-dependent manner to specify synaptic properties.Graphical Graphical abstract for this article
  • OLMα2 Cells Bidirectionally Modulate Learning
    • Abstract: Publication date: Available online 5 July 2018Source: NeuronAuthor(s): Samer Siwani, Arthur S.C. França, Sanja Mikulovic, Amilcar Reis, Markus M. Hilscher, Steven J. Edwards, Richardson N. Leão, Adriano B.L. Tort, Klas KullanderSummaryInhibitory interneurons participate in mnemonic processes. However, defined roles for identified interneuron populations are scarce. A subpopulation of oriens lacunosum-moleculare (OLM) interneurons genetically defined by the expression of the nicotinic receptor α2 subunit has been shown to gate information carried by either the temporoammonic pathway or Schaffer collaterals in vitro. Here we set out to determine whether selective modulation of OLMα2 cells in the intermediate CA1 affects learning and memory in vivo. Our data show that intermediate OLMα2 cells can either enhance (upon their inhibition) or impair (upon their activation) object memory encoding in freely moving mice, thus exerting bidirectional control. Moreover, we find that OLMα2 cell activation inhibits fear-related memories and that OLMα2 cells respond differently to nicotine in the dorsoventral axis. These results suggest that intermediate OLMα2 cells are an important component in the CA1 microcircuit regulating learning and memory processes.
  • Motivation, Perception, and Chance Converge to Make a Binary Decision
    • Abstract: Publication date: Available online 5 July 2018Source: NeuronAuthor(s): Stephen X. Zhang, Lauren E. Miner, Christine L. Boutros, Dragana Rogulja, Michael A. CrickmoreSummaryWe reveal a central role for chance neuronal events in the decision of a male fly to court, which can be modeled as a coin flip with odds set by motivational state. The decision is prompted by a tap of a female with the male’s pheromone-receptor-containing foreleg. Each tap evokes competing excitation and inhibition onto P1 courtship command neurons. A motivating dopamine signal desensitizes P1 to the inhibition, increasing the fraction of taps that successfully initiate courtship. Once courtship has begun, the same dopamine tone potentiates recurrent excitation of P1, maintaining the courtship of highly motivated males for minutes and buffering against termination. Receptor diversity within P1 creates separate channels for tuning the propensities to initiate and sustain courtship toward appropriate targets. These findings establish a powerful invertebrate system for cue-triggered binary decisions and demonstrate that noise can be exploited by motivational systems to make behaviors scalable and flexible.Graphical Graphical abstract for this article
  • A Distance-Dependent Distribution of Presynaptic Boutons Tunes
           Frequency-Dependent Dendritic Integration
    • Abstract: Publication date: Available online 5 July 2018Source: NeuronAuthor(s): Federico W. Grillo, Guilherme Neves, Alison Walker, Gema Vizcay-Barrena, Roland A. Fleck, Tiago Branco, Juan BurroneSummaryHow presynaptic inputs and neurotransmitter release dynamics are distributed along a dendritic tree is not well established. Here, we show that presynaptic boutons that form onto basal dendrites of CA1 pyramidal neurons display a decrease in active zone (AZ) size with distance from the soma, resulting in a distance-dependent increase in short-term facilitation. Our findings suggest that the spatial distribution of short-term facilitation serves to compensate for the electrotonic attenuation of subthreshold distal inputs during repeated stimulation and fine-tunes the preferred input frequency of dendritic domains.
  • De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human
           Congenital Hydrocephalus
    • Abstract: Publication date: Available online 5 July 2018Source: NeuronAuthor(s): Charuta Gavankar Furey, Jungmin Choi, Sheng Chih Jin, Xue Zeng, Andrew T. Timberlake, Carol Nelson-Williams, M. Shahid Mansuri, Qiongshi Lu, Daniel Duran, Shreyas Panchagnula, August Allocco, Jason K. Karimy, Arjun Khanna, Jonathan R. Gaillard, Tyrone DeSpenza, Prince Antwi, Erin Loring, William E. Butler, Edward R. Smith, Benjamin C. WarfSummaryCongenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10−7), SMARCC1 (p = 8.15 × 10−10), and PTCH1 (p = 1.06 × 10−6). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10−4). Together, these probands account for ∼10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.
  • Mettl14 Is Essential for Epitranscriptomic Regulation of Striatal
           Function and Learning
    • Abstract: Publication date: Available online 28 June 2018Source: NeuronAuthor(s): Jessica L. Koranda, Lou Dore, Hailing Shi, Meera J. Patel, Lee O. Vaasjo, Meghana N. Rao, Kai Chen, Zhike Lu, Yangtian Yi, Wanhao Chi, Chuan He, Xiaoxi ZhuangSummaryN6-methyladenosine (m6A) regulates mRNA metabolism and translation, serving as an important source of post-transcriptional regulation. To date, the functional consequences of m6A deficiency within the adult brain have not been determined. To achieve m6A deficiency, we deleted Mettl14, an essential component of the m6A methyltransferase complex, in two related yet discrete mouse neuronal populations: striatonigral and striatopallidal. Mettl14 deletion reduced striatal m6A levels without altering cell numbers or morphology. Transcriptome-wide profiling of m6A-modified mRNAs in Mettl14-deleted striatum revealed downregulation of similar striatal mRNAs encoding neuron- and synapse-specific proteins in both neuronal types, but striatonigral and striatopallidal identity genes were uniquely downregulated in each respective manipulation. Upregulated mRNA species encoded non-neuron-specific proteins. These changes increased neuronal excitability, reduced spike frequency adaptation, and profoundly impaired striatal-mediated behaviors. Using viral-mediated, neuron-specific striatal Mettl14 deletion in adult mice, we further confirmed the significance of m6A in maintaining normal striatal function in the adult mouse.
  • Triheteromeric GluN1/GluN2A/GluN2C NMDARs with Unique Single-Channel
           Properties Are the Dominant Receptor Population in Cerebellar Granule
    • Abstract: Publication date: Available online 28 June 2018Source: NeuronAuthor(s): Subhrajit Bhattacharya, Alpa Khatri, Sharon A. Swanger, John O. DiRaddo, Feng Yi, Kasper B. Hansen, Hongjie Yuan, Stephen F. TraynelisSummaryNMDA-type glutamate receptors (NMDARs) are ligand-gated ion channels that mediate excitatory neurotransmission in the CNS. Here we describe functional and single-channel properties of triheteromeric GluN1/GluN2A/GluN2C receptors, which contain two GluN1, one GluN2A, and one GluN2C subunits. This NMDAR has three conductance levels and opens in bursts similar to GluN1/GluN2A receptors but with a single-channel open time and open probability reminiscent of GluN1/GluN2C receptors. The deactivation time course of GluN1/GluN2A/GluN2C receptors is intermediate to GluN1/GluN2A and GluN1/GluN2C receptors and is not dominated by GluN2A or GluN2C. We show that triheteromeric GluN1/GluN2A/GluN2C receptors are the predominant NMDARs in cerebellar granule cells and propose that co-expression of GluN2A and GluN2C in cerebellar granule cells occludes cell surface expression of diheteromeric GluN1/GluN2C receptors. This new insight into neuronal GluN1/GluN2A/GluN2C receptors highlights the complexity of NMDAR signaling in the CNS.
  • The Temporal Dynamics of Arc Expression Regulate Cognitive Flexibility
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Mark J. Wall, Dawn R. Collins, Samantha L. Chery, Zachary D. Allen, Elissa D. Pastuzyn, Arlene J. George, Viktoriya D. Nikolova, Sheryl S. Moy, Benjamin D. Philpot, Jason D. Shepherd, Jürgen Müller, Michael D. Ehlers, Angela M. Mabb, Sonia A.L. CorrêaSummaryNeuronal activity regulates the transcription and translation of the immediate-early gene Arc/Arg3.1, a key mediator of synaptic plasticity. Proteasome-dependent degradation of Arc tightly limits its temporal expression, yet the significance of this regulation remains unknown. We disrupted the temporal control of Arc degradation by creating an Arc knockin mouse (ArcKR) where the predominant Arc ubiquitination sites were mutated. ArcKR mice had intact spatial learning but showed specific deficits in selecting an optimal strategy during reversal learning. This cognitive inflexibility was coupled to changes in Arc mRNA and protein expression resulting in a reduced threshold to induce mGluR-LTD and enhanced mGluR-LTD amplitude. These findings show that the abnormal persistence of Arc protein limits the dynamic range of Arc signaling pathways specifically during reversal learning. Our work illuminates how the precise temporal control of activity-dependent molecules, such as Arc, regulates synaptic plasticity and is crucial for cognition.Graphical Graphical abstract for this article
  • Biallelic Mutations in MYORG Cause Autosomal Recessive Primary
           Familial Brain Calcification
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Xiang-Ping Yao, Xuewen Cheng, Chong Wang, Miao Zhao, Xin-Xin Guo, Hui-Zhen Su, Lu-Lu Lai, Xiao-Huan Zou, Xue-Jiao Chen, Yuying Zhao, En-Lin Dong, Ying-Qian Lu, Shuang Wu, Xiaojuan Li, Gaofeng Fan, Hongjie Yu, Jianfeng Xu, Ning Wang, Zhi-Qi Xiong, Wan-Jin ChenSummaryPrimary familial brain calcification (PFBC) is a genetically heterogeneous disorder characterized by bilateral calcifications in the basal ganglia and other brain regions. The genetic basis of this disorder remains unknown in a significant portion of familial cases. Here, we reported a recessive causal gene, MYORG, for PFBC. Compound heterozygous or homozygous mutations of MYORG co-segregated completely with PFBC in six families, with logarithm of odds (LOD) score of 4.91 at the zero recombination fraction. In mice, Myorg mRNA was expressed specifically in S100β-positive astrocytes, and knockout of Myorg induced the formation of brain calcification at 9 months of age. Our findings provide strong evidence that loss-of-function mutations of MYORG cause brain calcification in humans and mice.
  • Unsupervised Discovery of Demixed, Low-Dimensional Neural Dynamics across
           Multiple Timescales through Tensor Component Analysis
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Alex H. Williams, Tony Hyun Kim, Forea Wang, Saurabh Vyas, Stephen I. Ryu, Krishna V. Shenoy, Mark Schnitzer, Tamara G. Kolda, Surya GanguliSummaryPerceptions, thoughts, and actions unfold over millisecond timescales, while learned behaviors can require many days to mature. While recent experimental advances enable large-scale and long-term neural recordings with high temporal fidelity, it remains a formidable challenge to extract unbiased and interpretable descriptions of how rapid single-trial circuit dynamics change slowly over many trials to mediate learning. We demonstrate a simple tensor component analysis (TCA) can meet this challenge by extracting three interconnected, low-dimensional descriptions of neural data: neuron factors, reflecting cell assemblies; temporal factors, reflecting rapid circuit dynamics mediating perceptions, thoughts, and actions within each trial; and trial factors, describing both long-term learning and trial-to-trial changes in cognitive state. We demonstrate the broad applicability of TCA by revealing insights into diverse datasets derived from artificial neural networks, large-scale calcium imaging of rodent prefrontal cortex during maze navigation, and multielectrode recordings of macaque motor cortex during brain machine interface learning.Graphical Graphical abstract for this article
  • Glutamatergic Signaling in the Central Nervous System: Ionotropic and
           Metabotropic Receptors in Concert
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Andreas Reiner, Joshua LevitzGlutamate serves as both the mammalian brain’s primary excitatory neurotransmitter and as a key neuromodulator to control synapse and circuit function over a wide range of spatial and temporal scales. This functional diversity is decoded by two receptor families: ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). The challenges posed by the complexity and physiological importance of each of these subtypes has limited our appreciation and understanding of how these receptors work in concert. In this review, by comparing both receptor families with a focus on their crosstalk, we argue for a more holistic understanding of neural glutamate signaling.
  • Investigating the Neural Encoding of Emotion with Music
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Stefan KoelschDoes our understanding of the human brain remain incomplete without a proper understanding of how the brain processes music' Here, the author makes a passionate plea for the use of music in the investigation of human emotion and its brain correlates, arguing that music can change activity in all brain structures associated with emotions, which has important implications on how we understand human emotions and their disorders and how we can make better use of beneficial effects of music in therapy.
  • Morgan Sheng
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Morgan Sheng leads research and drug discovery efforts for diseases of the nervous system at Genentech. In an interview with Neuron, Dr. Sheng shares a striking moment from his postdoc training, his guiding philosophy as a scientist, and his excitement for how recent technological advances will transform neuroscience research.
  • Magdalena Götz
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): In an interview with Neuron, Magdalena Götz highlights the responsibility of scientists to educate the public about the process of scientific discovery and how ideas evolve. She also describes how her current research on neuronal reprogramming is influenced by her earlier findings that radial glial cells give rise to neurons.
  • Zen and the Art of Making a Bayesian Espresso
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Lei Zhang, Saša Redžepović, Michael Rose, Jan GläscherIn this issue of Neuron, Konovalov and Krajbich (2018) argue that a Bayesian inference is employed when learning new sequences and identify distinct brain networks that track the uncertainty of both the current state and the underlying pattern structure.
  • Acetylcholine Receptor Stimulation for Cognitive Enhancement: Better the
           Devil You Know'
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Mark G. Baxter, Johanna L. CriminsDrug treatments to improve memory focus on enhancing acetylcholine. However, Vijayraghavan and colleagues (2018) show that direct stimulation of the M1 muscarinic acetylcholine receptor adversely affected neuronal activity in prefrontal cortex related to working memory for behavioral rules.
  • Shining a Light on Olfactory Circuits
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Christopher J. PotterHow is odor information organized in the brain' In this issue of Neuron, Jeanne et al. (2018) pair optogenetics with electrophysiology to map functional connections between two olfactory brain regions. They suggest that lateral horn neurons encode “odor scenes” to represent biologically relevant odor environments.
  • Parkinson’s Disease: Mitochondria Parked at the ER Hit the Snooze
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Nathaniel S. Woodling, Linda PartridgeParkinson’s disease patients report sleep disturbances well ahead of motor symptoms. In this issue of Neuron, Valadas et al. (2018) report that the disease genes pink1 and parkin exert novel, cell-type-specific effects to modulate ER-mitochondria contacts, neuropeptidergic transmission, and sleep patterns.
  • A Stable Neural Code for Birdsong
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Ruidong Chen, Tejapratap Bollu, Jesse H. GoldbergProteins, synapses, and neural connections are in constant flux, yet motor behaviors somehow remain stable. In this issue of Neuron, Katlowitz et al. (2018) show that temporally precise neural activity driving birdsong production is stable for weeks.
  • APOE4 Causes Widespread Molecular and Cellular Alterations Associated with
           Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Yuan-Ta Lin, Jinsoo Seo, Fan Gao, Heather M. Feldman, Hsin-Lan Wen, Jay Penney, Hugh P. Cam, Elizabeta Gjoneska, Waseem K. Raja, Jemmie Cheng, Richard Rueda, Oleg Kritskiy, Fatema Abdurrob, Zhuyu Peng, Blerta Milo, Chung Jong Yu, Sara Elmsaouri, Dilip Dey, Tak Ko, Bruce A. Yankner
  • Neurocomputational Dynamics of Sequence Learning
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Arkady Konovalov, Ian KrajbichSummaryThe brain is often able to learn complex structures of the environment using a very limited amount of evidence, which is crucial for model-based planning and sequential prediction. However, little is known about the neurocomputational mechanisms of deterministic sequential prediction, as prior work has primarily focused on stochastic transition structures. Here we find that human subjects’ beliefs about a sequence of states, captured by reaction times, are well explained by a Bayesian pattern-learning model that tracks beliefs about both the current state and the underlying structure of the environment, taking into account prior beliefs about possible patterns in the sequence. Using functional magnetic resonance imaging, we find distinct neural signatures of uncertainty computations on both levels. These results support the hypothesis that structure learning in the brain employs Bayesian inference.
  • Theta and Alpha Oscillations Are Traveling Waves in the Human Neocortex
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Honghui Zhang, Andrew J. Watrous, Ansh Patel, Joshua JacobsSummaryHuman cognition requires the coordination of neural activity across widespread brain networks. Here, we describe a new mechanism for large-scale coordination in the human brain: traveling waves of theta and alpha oscillations. Examining direct brain recordings from neurosurgical patients performing a memory task, we found contiguous clusters of cortex in individual patients with oscillations at specific frequencies within 2 to 15 Hz. These oscillatory clusters displayed spatial phase gradients, indicating that they formed traveling waves that propagated at ∼0.25–0.75 m/s. Traveling waves were relevant behaviorally because their propagation correlated with task events and was more consistent when subjects performed the task well. Human traveling theta and alpha waves can be modeled by a network of coupled oscillators because the direction of wave propagation correlated with the spatial orientation of local frequency gradients. Our findings suggest that oscillations support brain connectivity by organizing neural processes across space and time.
  • Muscarinic M1 Receptor Overstimulation Disrupts Working Memory Activity
           for Rules in Primate Prefrontal Cortex
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Susheel Vijayraghavan, Alex James Major, Stefan EverlingSummaryAcetylcholine release in the prefrontal cortex (PFC), acting through muscarinic receptors, has an essential role in regulating flexible behavior and working memory (WM). General muscarinic receptor blockade disrupts PFC WM representations, while selective stimulation of muscarinic receptor subtypes is of great interest for the treatment of cognitive dysfunction in Alzheimer’s disease. Here, we tested selective stimulation and blockade of muscarinic M1 receptors (M1Rs) in macaque PFC, during performance of a cognitive control task in which rules maintained in WM specified saccadic responses. We hypothesized that M1R blockade and stimulation would disrupt and enhance rule representation in WM, respectively. Unexpectedly, M1R blockade did not consistently affect PFC neuronal rule selectivity. Moreover, M1R stimulation suppressed PFC activity, and at higher doses, degraded rule representations. Our results suggest that, in primates, the deleterious effects of general muscarinic blockade on PFC WM activity are not mediated by M1Rs, while their overstimulation deteriorates PFC rule maintenance.
  • Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal
           Circuits: Implications for Activity-Dependent Disconnection in
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Jennifer L. Zick, Rachael K. Blackman, David A. Crowe, Bagrat Amirikian, Adele L. DeNicola, Theoden I. Netoff, Matthew V. ChafeeSummaryWe employed multi-electrode array recording to evaluate the influence of NMDA receptors (NMDAR) on spike-timing dynamics in prefrontal networks of monkeys as they performed a cognitive control task measuring specific deficits in schizophrenia. Systemic, periodic administration of an NMDAR antagonist (phencyclidine) reduced the prevalence and strength of synchronous (0-lag) spike correlation in simultaneously recorded neuron pairs. We employed transfer entropy analysis to measure effective connectivity between prefrontal neurons at lags consistent with monosynaptic interactions and found that effective connectivity was persistently reduced following exposure to the NMDAR antagonist. These results suggest that a disruption of spike timing and effective connectivity might be interrelated factors in pathogenesis, supporting an activity-dependent disconnection theory of schizophrenia. In this theory, disruption of NMDAR synaptic function leads to dysregulated timing of action potentials in prefrontal networks, accelerating synaptic disconnection through a spike-timing-dependent mechanism.
  • Transformation of a Spatial Map across the Hippocampal-Lateral Septal
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): David Tingley, György BuzsákiSummaryThe hippocampus constructs a map of the environment. How this “cognitive map” is utilized by other brain regions to guide behavior remains unexplored. To examine how neuronal firing patterns in the hippocampus are transmitted and transformed, we recorded neurons in its principal subcortical target, the lateral septum (LS). We observed that LS neurons carry reliable spatial information in the phase of action potentials, relative to hippocampal theta oscillations, while the firing rates of LS neurons remained uninformative. Furthermore, this spatial phase code had an anatomical microstructure within the LS and was bound to the hippocampal spatial code by synchronous gamma frequency cell assemblies. Using a data-driven model, we show that rate-independent spatial tuning arises through the dynamic weighting of CA1 and CA3 cell assemblies. Our findings demonstrate that transformation of the hippocampal spatial map depends on higher-order theta-dependent neuronal sequences.Video
  • Active Sampling State Dynamically Enhances Olfactory Bulb Odor
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Rebecca Jordan, Izumi Fukunaga, Mihaly Kollo, Andreas T. SchaeferSummaryThe olfactory bulb (OB) is the first site of synaptic odor information processing, yet a wealth of contextual and learned information has been described in its activity. To investigate the mechanistic basis of contextual modulation, we use whole-cell recordings to measure odor responses across rapid learning episodes in identified mitral/tufted cells (MTCs). Across these learning episodes, diverse response changes occur already during the first sniff cycle. Motivated mice develop active sniffing strategies across learning that robustly correspond to the odor response changes, resulting in enhanced odor representation. Evoking fast sniffing in different behavioral states demonstrates that response changes during active sampling exceed those predicted from feedforward input alone. Finally, response changes are highly correlated in tufted cells, but not mitral cells, indicating there are cell-type-specific effects on odor representation during active sampling. Altogether, we show that active sampling is strongly associated with enhanced OB responsiveness on rapid timescales.
  • The Organization of Projections from Olfactory Glomeruli onto Higher-Order
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): James M. Jeanne, Mehmet Fişek, Rachel I. WilsonSummaryEach odorant receptor corresponds to a unique glomerulus in the brain. Projections from different glomeruli then converge in higher brain regions, but we do not understand the logic governing which glomeruli converge and which do not. Here, we use two-photon optogenetics to map glomerular connections onto neurons in the lateral horn, the region of the Drosophila brain that receives the majority of olfactory projections. We identify 39 morphological types of lateral horn neurons (LHNs) and show that different types receive input from different combinations of glomeruli. We find that different LHN types do not have independent inputs; rather, certain combinations of glomeruli converge onto many of the same LHNs and so are over-represented. Notably, many over-represented combinations are composed of glomeruli that prefer chemically dissimilar ligands whose co-occurrence indicates a behaviorally relevant “odor scene.” The pattern of glomerulus-LHN connections thus represents a prediction of what ligand combinations will be most salient.
  • Synaptojanin and Endophilin Mediate Neck Formation during Ultrafast
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Shigeki Watanabe, Lauren Elizabeth Mamer, Sumana Raychaudhuri, Delgermaa Luvsanjav, Julia Eisen, Thorsten Trimbuch, Berit Söhl-Kielczynski, Pascal Fenske, Ira Milosevic, Christian Rosenmund, Erik M. JorgensenSummaryUltrafast endocytosis generates vesicles from the plasma membrane as quickly as 50 ms in hippocampal neurons following synaptic vesicle fusion. The molecular mechanism underlying the rapid maturation of these endocytic pits is not known. Here we demonstrate that synaptojanin-1, and its partner endophilin-A, function in ultrafast endocytosis. In the absence of synaptojanin or endophilin, the membrane is rapidly invaginated, but pits do not become constricted at the base. The 5-phosphatase activity of synaptojanin is involved in formation of the neck, but 4-phosphatase is not required. Nevertheless, these pits are eventually cleaved into vesicles; within a 30-s interval, synaptic endosomes form and are resolved by clathrin-mediated budding. Then synaptojanin and endophilin function at a second step to aid with the removal of clathrin coats from the regenerated vesicles. These data together suggest that synaptojanin and endophilin can mediate membrane remodeling on a millisecond timescale during ultrafast endocytosis.Graphical Graphical abstract for this article
  • A Combination of Ontogeny and CNS Environment Establishes Microglial
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): F. Chris Bennett, Mariko L. Bennett, Fazeela Yaqoob, Sara B. Mulinyawe, Gerald A. Grant, Melanie Hayden Gephart, Edward D. Plowey, Ben A. BarresSummaryMicroglia, the brain’s resident macrophages, are dynamic CNS custodians with surprising origins in the extra-embryonic yolk sac. The consequences of their distinct ontogeny are unknown but critical to understanding and treating brain diseases. We created a brain macrophage transplantation system to disentangle how environment and ontogeny specify microglial identity. We find that donor cells extensively engraft in the CNS of microglia-deficient mice, and even after exposure to a cell culture environment, microglia fully regain their identity when returned to the CNS. Though transplanted macrophages from multiple tissues can express microglial genes in the brain, only those of yolk-sac origin fully attain microglial identity. Transplanted macrophages of inappropriate origin, including primary human cells in a humanized host, express disease-associated genes and specific ontogeny markers. Through brain macrophage transplantation, we discover new principles of microglial identity that have broad applications to the study of disease and development of myeloid cell therapies.Graphical Graphical abstract for this article
  • ER Lipid Defects in Neuropeptidergic Neurons Impair Sleep Patterns in
           Parkinson’s Disease
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Jorge S. Valadas, Giovanni Esposito, Dirk Vandekerkhove, Katarzyna Miskiewicz, Liesbeth Deaulmerie, Susanna Raitano, Philip Seibler, Christine Klein, Patrik VerstrekenSummaryParkinson’s disease patients report disturbed sleep patterns long before motor dysfunction. Here, in parkin and pink1 models, we identify circadian rhythm and sleep pattern defects and map these to specific neuropeptidergic neurons in fly models and in hypothalamic neurons differentiated from patient induced pluripotent stem cells (iPSCs). Parkin and Pink1 control the clearance of mitochondria by protein ubiquitination. Although we do not observe major defects in mitochondria of mutant neuropeptidergic neurons, we do find an excess of endoplasmic reticulum-mitochondrial contacts. These excessive contact sites cause abnormal lipid trafficking that depletes phosphatidylserine from the endoplasmic reticulum (ER) and disrupts the production of neuropeptide-containing vesicles. Feeding mutant animals phosphatidylserine rescues neuropeptidergic vesicle production and acutely restores normal sleep patterns in mutant animals. Hence, sleep patterns and circadian disturbances in Parkinson’s disease models are explained by excessive ER-mitochondrial contacts, and blocking their formation or increasing phosphatidylserine levels rescues the defects in vivo.Graphical Graphical abstract for this article
  • APOE4 Causes Widespread Molecular and Cellular Alterations Associated with
           Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Yuan-Ta Lin, Jinsoo Seo, Fan Gao, Heather M. Feldman, Hsin-Lan Wen, Jay Penney, Hugh P. Cam, Elizabeta Gjoneska, Waseem K. Raja, Jemmie Cheng, Richard Rueda, Oleg Kritskiy, Fatema Abdurrob, Zhuyu Peng, Blerta Milo, Chung Jong Yu, Sara Elmsaouri, Dilip Dey, Tak Ko, Bruce A. YanknerSummaryThe apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer’s disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Aβ42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Aβ uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Aβ phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell-type-specific changes associated with the APOE4 variant.Video Graphical Graphical abstract for this article
  • Stable Sequential Activity Underlying the Maintenance of a Precisely
           Executed Skilled Behavior
    • Abstract: Publication date: 27 June 2018Source: Neuron, Volume 98, Issue 6Author(s): Kalman A. Katlowitz, Michel A. Picardo, Michael A. LongSummaryA vast array of motor skills can be maintained throughout life. Do these behaviors require stability of individual neuron tuning or can the output of a given circuit remain constant despite fluctuations in single cells' This question is difficult to address due to the variability inherent in most motor actions studied in the laboratory. A notable exception, however, is the courtship song of the adult zebra finch, which is a learned, highly precise motor act mediated by orderly dynamics within premotor neurons of the forebrain. By longitudinally tracking the activity of excitatory projection neurons during singing using two-photon calcium imaging, we find that both the number and the precise timing of song-related spiking events remain nearly identical over the span of several weeks to months. These findings demonstrate that learned, complex behaviors can be stabilized by maintaining precise and invariant tuning at the level of single neurons.
  • Vascular Compartmentalization of Functional Hyperemia from the Synapse to
           the Pia
    • Abstract: Publication date: Available online 21 June 2018Source: NeuronAuthor(s): Ravi L. Rungta, Emmanuelle Chaigneau, Bruno-Félix Osmanski, Serge CharpakSummaryFunctional hyperemia, a regional increase of blood flow triggered by local neural activation, is used to map brain activity in health and disease. However, the spatial-temporal dynamics of functional hyperemia remain unclear. Two-photon imaging of the entire vascular arbor in NG2-creERT2;GCaMP6f mice shows that local synaptic activation, measured via oligodendrocyte precursor cell (OPC) Ca2+ signaling, generates a synchronous Ca2+ drop in pericytes and smooth muscle cells (SMCs) enwrapping all upstream vessels feeding the activated synapses. Surprisingly, the onset timing, direction, and amplitude of vessel diameter and blood velocity changes vary dramatically from juxta-synaptic capillaries back to the pial arteriole. These results establish a precise spatial-temporal sequence of vascular changes triggered by neural activity and essential for the interpretation of blood-flow-based imaging techniques such as BOLD-fMRI.
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