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Journal Prestige (SJR): 10.654
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ISSN (Print) 0896-6273 - ISSN (Online) 1097-4199
Published by Elsevier Homepage  [3183 journals]
  • Discrete Evaluative and Premotor Circuits Enable Vocal Learning in
    • 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.
  • Of Pathways, Processes, and Orbitofrontal Cortex
    • Abstract: Publication date: 21 August 2019Source: Neuron, Volume 103, Issue 4Author(s): Vincent D. CostaOrbitofrontal cortex (OFC) predicts the consequences of our actions and updates our expectations based on experienced outcomes. In this issue of Neuron, Groman et al. (2019) precisely ablate pathways between the OFC, amygdala, and nucleus accumbens to reveal their separable contributions to reinforcement learning.
  • Neuromodulation of Spike-Timing-Dependent Plasticity: Past, Present, and
    • Abstract: Publication date: 21 August 2019Source: Neuron, Volume 103, Issue 4Author(s): Zuzanna Brzosko, Susanna B. Mierau, Ole PaulsenSpike-timing-dependent synaptic plasticity (STDP) is a leading cellular model for behavioral learning and memory with rich computational properties. However, the relationship between the millisecond-precision spike timing required for STDP and the much slower timescales of behavioral learning is not well understood. Neuromodulation offers an attractive mechanism to connect these different timescales, and there is now strong experimental evidence that STDP is under neuromodulatory control by acetylcholine, monoamines, and other signaling molecules. Here, we review neuromodulation of STDP, the underlying mechanisms, functional implications, and possible involvement in brain disorders.
  • A Societal Sleep Prescription
    • Abstract: Publication date: 21 August 2019Source: Neuron, Volume 103, Issue 4Author(s): Matthew P. WalkerWe are suffering a global sleep-loss epidemic. The health consequences within an individual are well characterized. But does society suffer just as much' Here, I discuss how insufficient sleep erodes our societal fabric as much as it does our biological fabric, and offer some prescriptive remedies.
  • Locus Coeruleus, Noradrenaline, and Behavior: Network Effect, Network
    • Abstract: Publication date: 21 August 2019Source: Neuron, Volume 103, Issue 4Author(s): Sebastien BouretHow does the noradrenergic nucleus locus coeruleus act on target networks to regulate behavior' In this issue of Neuron, Zerbi et al. (2019) combine functional neuroimaging and pharmacogenetics in mice to tackle that question, uncovering a network action underlying stress. And providing insight for cognition'
  • Loss of NaV1.2-Dependent Backpropagating Action Potentials in Dendrites
           Contributes to Autism and Intellectual Disability
    • Abstract: Publication date: 21 August 2019Source: Neuron, Volume 103, Issue 4Author(s): Leonard K. KaczmarekMutations in voltage-dependent sodium channels cause severe autism/intellectual disability. In this issue of Neuron, Spratt et al. (2019) show that lowering expression of Nav1.2 channels attenuates backpropagation of action potentials into dendrites of cortical neurons, preventing spike-timing-dependent synaptic plasticity.
  • Ganglion Cells in Primate Retina Use Fuzzy Logic to Encode Complex Visual
           Receptive Fields
    • Abstract: Publication date: 21 August 2019Source: Neuron, Volume 103, Issue 4Author(s): Jeffrey S. DiamondIn most neurons, all spikes look alike. However, in this issue of Neuron, Rhoades et al. (2019) describe a ganglion cell in primate retina that reports visual input to different regions of its receptive field with distinct action potential waveforms.
  • Exploring the Peripheral Initiation of Parkinson’s Disease in Animal
    • Abstract: Publication date: 21 August 2019Source: Neuron, Volume 103, Issue 4Author(s): Zachary A. Sorrentino, Benoit I. GiassonParkinson’s disease is a neurodegenerative movement disorder; however, peripheral symptoms can arise decades prior. In this issue of Neuron, Kim et al. (2019) provide evidence that progressive α-synuclein aggregation initiating in the gut could be a pathogenic epicenter anatomically rippling throughout the nervous system.
  • 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.
  • The Ministry of Fear: ‘The Conjuring’ of Fright in the
           Amygdala by the Raphe
    • Abstract: Publication date: 7 August 2019Source: Neuron, Volume 103, Issue 3Author(s): Praachi Tiwari, Sashaina E. Fanibunda, Vidita A. VaidyaIn this issue of Neuron, Sengupta and Holmes (2019) characterize a distinct serotonergic circuit from the dorsal raphe nucleus to the basal amygdala that facilitates fear conditioning and memory.
  • Bursting Enables GRP Neurons to Engage Spinal Itch Circuits
    • Abstract: Publication date: 7 August 2019Source: Neuron, Volume 103, Issue 3Author(s): Hugues Petitjean, Philippe Séguéla, Reza Sharif-Naeini
  • CaM Kinase: Still Inspiring at 40
    • Abstract: Publication date: 7 August 2019Source: Neuron, Volume 103, Issue 3Author(s): K. Ulrich Bayer, Howard SchulmanSummaryThe Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) was touted as a memory molecule, even before its involvement in long-term potentiation (LTP) was shown. The enzyme has not disappointed, with subsequent demonstrations of remarkable structural and regulatory properties. Its neuronal functions now extend to long-term depression (LTD), and last year saw the first direct evidence for memory storage by CaMKII. Although CaMKII may have taken the spotlight, it is a member of a large family of diverse and interesting CaM kinases. Our aim is to place CaMKII in context of the other CaM kinases and then review certain aspects of this kinase that are of current interest.
  • Cerebral Microvascular Injury: A Potentially Treatable Endophenotype of
           Traumatic Brain Injury-Induced Neurodegeneration
    • Abstract: Publication date: 7 August 2019Source: Neuron, Volume 103, Issue 3Author(s): Danielle K. Sandsmark, Asma Bashir, Cheryl L. Wellington, Ramon Diaz-ArrastiaTraumatic brain injury (TBI) is one the most common human afflictions, contributing to long-term disability in survivors. Emerging data indicate that functional improvement or deterioration can occur years after TBI. In this regard, TBI is recognized as risk factor for late-life neurodegenerative disorders. TBI encompasses a heterogeneous disease process in which diverse injury subtypes and multiple molecular mechanisms overlap. To develop precision medicine approaches where specific pathobiological processes are targeted by mechanistically appropriate therapies, techniques to identify and measure these subtypes are needed. Traumatic microvascular injury is a common but relatively understudied TBI endophenotype. In this review, we describe evidence of microvascular dysfunction in human and animal TBI, explore the role of vascular dysfunction in neurodegenerative disease, and discuss potential opportunities for vascular-directed therapies in ameliorating TBI-related neurodegeneration. We discuss the therapeutic potential of vascular-directed therapies in TBI and the use and limitations of preclinical models to explore these therapies.
  • Ring of Power: A Band of Peptidergic Midbrain Neurons that Binds
    • Abstract: Publication date: 7 August 2019Source: Neuron, Volume 103, Issue 3Author(s): Anne L. Collins, Amy R. Wolff, Benjamin T. SaundersA recent Cell paper identifies a novel population of neurons within the ventral tegmental area producing the endogenous opioid nociceptin that regulates dopamine neuron firing and acts uniquely to gate motivation in reward seeking. These results highlight neuropeptidergic signaling as a critical component of functional heterogeneity in the midbrain.
  • Re-exploring Mechanisms of Exploration
    • Abstract: Publication date: 7 August 2019Source: Neuron, Volume 103, Issue 3Author(s): Tamar Reitich-Stolero, Kristoffer C. Aberg, Rony PazDeciding when to exploit what is already known and when to explore new possibilities is crucial for adapting to novel and dynamic environments. Using reinforcement-based decision making, Costa et al. (2019) in this issue of Neuron find that neurons in the amygdala and ventral-striatum differentially signal the benefit from exploring new options and exploiting familiar ones.
  • Timing Rewarding Movements
    • Abstract: Publication date: 7 August 2019Source: Neuron, Volume 103, Issue 3Author(s): Rachael Stentiford, Nadia L. CerminaraPreparatory activity is found across the motor network. In this issue of Neuron, Chabrol et al. (2019) show that preparatory activity in the anterior lateral motor cortex (ALM) and cerebellum is related to the prediction of reward delivery and that the cerebellum provides a learned timing signal to the ALM.
  • The Basal Ganglia Sensory System Listens to Prefrontal Task Needs
    • Abstract: Publication date: 7 August 2019Source: Neuron, Volume 103, Issue 3Author(s): Mitsuko Watabe-UchidaThe prefrontal cortex modifies the sensory system to focus attention. In this issue of Neuron, Nakajima et al. (2019) fill the gap between the prefrontal cortex and the sensory system with an overlooked basal ganglia pathway.
  • Cholinergic Interneurons Provide a Link to Balance Excitation across
           Striatal Output Neurons
    • Abstract: Publication date: 7 August 2019Source: Neuron, Volume 103, Issue 3Author(s): Sheng Gong, Christopher P. FordD1-MSNs and D2-MSNs mediate output from the accumbens. How activity of one regulates the other is poorly understood. In this issue of Neuron, Francis et al. (2019) show that D1-MSN firing induces D2-MSN LTP via the recruitment of cholinergic interneurons.
  • 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
    • 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
  • Bayesian Computation through Cortical Latent Dynamics
    • Abstract: Publication date: Available online 15 July 2019Source: NeuronAuthor(s): Hansem Sohn, Devika Narain, Nicolas Meirhaeghe, Mehrdad JazayeriSummaryStatistical regularities in the environment create prior beliefs that we rely on to optimize our behavior when sensory information is uncertain. Bayesian theory formalizes how prior beliefs can be leveraged and has had a major impact on models of perception, sensorimotor function, and cognition. However, it is not known how recurrent interactions among neurons mediate Bayesian integration. By using a time-interval reproduction task in monkeys, we found that prior statistics warp neural representations in the frontal cortex, allowing the mapping of sensory inputs to motor outputs to incorporate prior statistics in accordance with Bayesian inference. Analysis of recurrent neural network models performing the task revealed that this warping was enabled by a low-dimensional curved manifold and allowed us to further probe the potential causal underpinnings of this computational strategy. These results uncover a simple and general principle whereby prior beliefs exert their influence on behavior by sculpting cortical latent dynamics.Graphical Graphical abstract for this article
  • A Single-Cell Transcriptomic Atlas of Human Neocortical Development during
    • Abstract: Publication date: Available online 11 July 2019Source: NeuronAuthor(s): Damon Polioudakis, Luis de la Torre-Ubieta, Justin Langerman, Andrew G. Elkins, Xu Shi, Jason L. Stein, Celine K. Vuong, Susanne Nichterwitz, Melinda Gevorgian, Carli K. Opland, Daning Lu, William Connell, Elizabeth K. Ruzzo, Jennifer K. Lowe, Tarik Hadzic, Flora I. Hinz, Shan Sabri, William E. Lowry, Mark B. Gerstein, Kathrin PlathSummaryWe performed RNA sequencing on 40,000 cells to create a high-resolution single-cell gene expression atlas of developing human cortex, providing the first single-cell characterization of previously uncharacterized cell types, including human subplate neurons, comparisons with bulk tissue, and systematic analyses of technical factors. These data permit deconvolution of regulatory networks connecting regulatory elements and transcriptional drivers to single-cell gene expression programs, significantly extending our understanding of human neurogenesis, cortical evolution, and the cellular basis of neuropsychiatric disease. We tie cell-cycle progression with early cell fate decisions during neurogenesis, demonstrating that differentiation occurs on a transcriptomic continuum; rather than only expressing a few transcription factors that drive cell fates, differentiating cells express broad, mixed cell-type transcriptomes before telophase. By mapping neuropsychiatric disease genes to cell types, we implicate dysregulation of specific cell types in ASD, ID, and epilepsy. We developed CoDEx, an online portal to facilitate data access and browsing.Graphical Graphical abstract for this article
  • TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in
           Alzheimer’s Disease
    • Abstract: Publication date: Available online 10 July 2019Source: NeuronAuthor(s): Ana Griciuc, Shaun Patel, Anthony N. Federico, Se Hoon Choi, Brendan J. Innes, Mary K. Oram, Gea Cereghetti, Danielle McGinty, Anthony Anselmo, Ruslan I. Sadreyev, Suzanne E. Hickman, Joseph El Khoury, Marco Colonna, Rudolph E. TanziSummaryThe microglial receptors CD33 and TREM2 have been associated with risk for Alzheimer’s disease (AD). Here, we investigated crosstalk between CD33 and TREM2. We showed that knockout of CD33 attenuated amyloid beta (Aβ) pathology and improved cognition in 5xFAD mice, both of which were abrogated by additional TREM2 knockout. Knocking out TREM2 in 5xFAD mice exacerbated Aβ pathology and neurodegeneration but reduced Iba1+ cell numbers, all of which could not be rescued by additional CD33 knockout. RNA-seq profiling of microglia revealed that genes related to phagocytosis and signaling (IL-6, IL-8, acute phase response) are upregulated in 5xFAD;CD33−/− and downregulated in 5xFAD;TREM2−/− mice. Differential gene expression in 5xFAD;CD33−/− microglia depended on the presence of TREM2, suggesting TREM2 acts downstream of CD33. Crosstalk between CD33 and TREM2 includes regulation of the IL-1β/IL-1RN axis and a gene set in the “receptor activity chemokine” cluster. Our results should facilitate AD therapeutics targeting these receptors.
  • Control of Synaptic Specificity by Establishing a Relative Preference for
           Synaptic Partners
    • Abstract: Publication date: Available online 9 July 2019Source: NeuronAuthor(s): Chundi Xu, Emma Theisen, Ryan Maloney, Jing Peng, Ivan Santiago, Clarence Yapp, Zachary Werkhoven, Elijah Rumbaut, Bryan Shum, Dorota Tarnogorska, Jolanta Borycz, Liming Tan, Maximilien Courgeon, Ian A. Meinertzhagen, Benjamin de Bivort, Jan Drugowitsch, Matthew Y. PecotSummaryThe ability of neurons to identify correct synaptic partners is fundamental to the proper assembly and function of neural circuits. Relative to other steps in circuit formation such as axon guidance, our knowledge of how synaptic partner selection is regulated is severely limited. Drosophila Dpr and DIP immunoglobulin superfamily (IgSF) cell-surface proteins bind heterophilically and are expressed in a complementary manner between synaptic partners in the visual system. Here, we show that in the lamina, DIP mis-expression is sufficient to promote synapse formation with Dpr-expressing neurons and that disrupting DIP function results in ectopic synapse formation. These findings indicate that DIP proteins promote synapses to form between specific cell types and that in their absence, neurons synapse with alternative partners. We propose that neurons have the capacity to synapse with a broad range of cell types and that synaptic specificity is achieved by establishing a preference for specific partners.
  • Sensory-to-Category Transformation via Dynamic Reorganization of Ensemble
           Structures in Mouse Auditory Cortex
    • Abstract: Publication date: Available online 8 July 2019Source: NeuronAuthor(s): Yu Xin, Lin Zhong, Yuan Zhang, Taotao Zhou, Jingwei Pan, Ning-long XuSummaryThe ability to group physical stimuli into behaviorally relevant categories is fundamental to perception and cognition. Despite a large body of work on stimulus categorization at the behavioral and cognitive levels, little is known about the underlying mechanisms at the neuronal level. Here, combining mouse auditory psychophysical behavior and in vivo two-photon imaging from the auditory cortex, we investigate how sensory-to-category transformation is implemented by cortical neurons during a stimulus categorization task. Distinct from responses during passive listening, many neurons exhibited emergent selectivity to stimuli near the category boundary during task performance, reshaping local tuning maps; other neurons became more selective to category membership of stimuli. At the population level, local cortical ensembles robustly encode category information and predict trial-by-trial decisions during task performance. Our data uncover a task-dependent dynamic reorganization of cortical response patterns serving as a neural mechanism for sensory-to-category transformation during perceptual decision-making.Graphical Graphical abstract for this article
  • Stable Representations of Decision Variables for Flexible Behavior
    • Abstract: Publication date: Available online 4 July 2019Source: NeuronAuthor(s): Bilal A. Bari, Cooper D. Grossman, Emily E. Lubin, Adithya E. Rajagopalan, Jianna I. Cressy, Jeremiah Y. CohenSummaryDecisions occur in dynamic environments. In the framework of reinforcement learning, the probability of performing an action is influenced by decision variables. Discrepancies between predicted and obtained rewards (reward prediction errors) update these variables, but they are otherwise stable between decisions. Although reward prediction errors have been mapped to midbrain dopamine neurons, it is unclear how the brain represents decision variables themselves. We trained mice on a dynamic foraging task in which they chose between alternatives that delivered reward with changing probabilities. Neurons in the medial prefrontal cortex, including projections to the dorsomedial striatum, maintained persistent firing rate changes over long timescales. These changes stably represented relative action values (to bias choices) and total action values (to bias response times) with slow decay. In contrast, decision variables were weakly represented in the anterolateral motor cortex, a region necessary for generating choices. Thus, we define a stable neural mechanism to drive flexible behavior.
  • Natural and Drug Rewards Engage Distinct Pathways that Converge on
           Coordinated Hypothalamic and Reward Circuits
    • Abstract: Publication date: Available online 2 July 2019Source: NeuronAuthor(s): Amber L. Alhadeff, Nitsan Goldstein, Onyoo Park, Michelle L. Klima, Alexandra Vargas, J. Nicholas BetleySummaryMotivated behavior is influenced by neural networks that integrate physiological needs. Here, we describe coordinated regulation of hypothalamic feeding and midbrain reward circuits in awake behaving mice. We find that alcohol and other non-nutritive drugs inhibit activity in hypothalamic feeding neurons. Interestingly, nutrients and drugs utilize different pathways for the inhibition of hypothalamic neuron activity, as alcohol signals hypothalamic neurons in a vagal-independent manner, while fat and satiation signals require the vagus nerve. Concomitantly, nutrients, alcohol, and drugs also increase midbrain dopamine signaling. We provide evidence that these changes are interdependent, as modulation of either hypothalamic neurons or midbrain dopamine signaling influences reward-evoked activity changes in the other population. Taken together, our results demonstrate that (1) food and drugs can engage at least two peripheral→central pathways to influence hypothalamic neuron activity, and (2) hypothalamic and dopamine circuits interact in response to rewards.Graphical Graphical abstract for this article
  • Memo1-Mediated Tiling of Radial Glial Cells Facilitates Cerebral Cortical
    • Abstract: Publication date: Available online 2 July 2019Source: NeuronAuthor(s): Naoki Nakagawa, Charlotte Plestant, Keiko Yabuno-Nakagawa, Jingjun Li, Janice Lee, Chu-Wei Huang, Amelia Lee, Oleh Krupa, Aditi Adhikari, Suriya Thompson, Tamille Rhynes, Victoria Arevalo, Jason L. Stein, Zoltán Molnár, Ali Badache, E.S. AntonSummaryPolarized, non-overlapping, regularly spaced, tiled organization of radial glial cells (RGCs) serves as a framework to generate and organize cortical neuronal columns, layers, and circuitry. Here, we show that mediator of cell motility 1 (Memo1) is a critical determinant of radial glial tiling during neocortical development. Memo1 deletion or knockdown leads to hyperbranching of RGC basal processes and disrupted RGC tiling, resulting in aberrant radial unit assembly and neuronal layering. Memo1 regulates microtubule (MT) stability necessary for RGC tiling. Memo1 deficiency leads to disrupted MT minus-end CAMSAP2 distribution, initiation of aberrant MT branching, and altered polarized trafficking of key basal domain proteins such as GPR56, and thus aberrant RGC tiling. These findings identify Memo1 as a mediator of RGC scaffold tiling, necessary to generate and organize neurons into functional ensembles in the developing cerebral cortex.Graphical Graphical abstract for this article
  • Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules
           Prevents Persistent TDP-43 Accumulation in ALS/FTD
    • Abstract: Publication date: Available online 1 July 2019Source: NeuronAuthor(s): Mark Y. Fang, Sebastian Markmiller, Anthony Q. Vu, Ashkan Javaherian, William E. Dowdle, Philippe Jolivet, Paul J. Bushway, Nicholas A. Castello, Ashmita Baral, Michelle Y. Chan, Jeremy W. Linsley, Drew Linsley, Mark Mercola, Steven Finkbeiner, Eric Lecuyer, Joseph W. Lewcock, Gene W. YeoSummaryStress granules (SGs) form during cellular stress and are implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). To yield insights into the role of SGs in pathophysiology, we performed a high-content screen to identify small molecules that alter SG properties in proliferative cells and human iPSC-derived motor neurons (iPS-MNs). One major class of active molecules contained extended planar aromatic moieties, suggesting a potential to intercalate in nucleic acids. Accordingly, we show that several hit compounds can prevent the RNA-dependent recruitment of the ALS-associated RNA-binding proteins (RBPs) TDP-43, FUS, and HNRNPA2B1 into SGs. We further demonstrate that transient SG formation contributes to persistent accumulation of TDP-43 into cytoplasmic puncta and that our hit compounds can reduce this accumulation in iPS-MNs from ALS patients. We propose that compounds with planar moieties represent a promising starting point to develop small-molecule therapeutics for treating ALS/FTD.Graphical Graphical abstract for this article
  • Plug-and-Play Protein Modification Using Homology-Independent Universal
           Genome Engineering
    • Abstract: Publication date: Available online 1 July 2019Source: NeuronAuthor(s): Yudong Gao, Erin Hisey, Tyler W.A. Bradshaw, Eda Erata, Walter E. Brown, Jamie L. Courtland, Akiyoshi Uezu, Yu Xiang, Yarui Diao, Scott H. SoderlingSummaryAnalysis of endogenous protein localization, function, and dynamics is fundamental to the study of all cells, including the diversity of cell types in the brain. However, current approaches are often low throughput and resource intensive. Here, we describe a CRISPR-Cas9-based homology-independent universal genome engineering (HiUGE) method for endogenous protein manipulation that is straightforward, scalable, and highly flexible in terms of genomic target and application. HiUGE employs adeno-associated virus (AAV) vectors of autonomous insertional sequences (payloads) encoding diverse functional modifications that can integrate into virtually any genomic target loci specified by easily assembled gene-specific guide-RNA (GS-gRNA) vectors. We demonstrate that universal HiUGE donors enable rapid alterations of proteins in vitro or in vivo for protein labeling and dynamic visualization, neural-circuit-specific protein modification, subcellular rerouting and sequestration, and truncation-based structure-function analysis. Thus, the “plug-and-play” nature of HiUGE enables high-throughput and modular analysis of mechanisms driving protein functions in cellular neurobiology.Graphical Graphical abstract for this article
  • Neurovascular Coupling in the Dentate Gyrus Regulates Adult Hippocampal
    • Abstract: Publication date: Available online 27 June 2019Source: NeuronAuthor(s): Jia Shen, Depeng Wang, Xinxing Wang, Shashank Gupta, Bhargav Ayloo, Song Wu, Paras Prasad, Qiaojie Xiong, Jun Xia, Shaoyu GeSummaryNewborn dentate granule cells (DGCs) are continuously generated in the adult brain. The mechanism underlying how the adult brain governs hippocampal neurogenesis remains poorly understood. In this study, we investigated how coupling of pre-existing neurons to the cerebrovascular system regulates hippocampal neurogenesis. Using a new in vivo imaging method in freely moving mice, we found that hippocampus-engaged behaviors, such as exploration in a novel environment, rapidly increased microvascular blood-flow velocity in the dentate gyrus. Importantly, blocking this exploration-elevated blood flow dampened experience-induced hippocampal neurogenesis. By imaging the neurovascular niche in combination with chemogenetic manipulation, we revealed that pre-existing DGCs actively regulated microvascular blood flow. This neurovascular coupling was linked by parvalbumin-expressing interneurons, primarily through nitric-oxide signaling. Further, we showed that insulin growth factor 1 signaling participated in functional hyperemia-induced neurogenesis. Together, our findings revealed a neurovascular coupling network that regulates experience-induced neurogenesis in the adult brain.
  • Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons
    • Abstract: Publication date: Available online 27 June 2019Source: NeuronAuthor(s): Samuele G. Marro, Soham Chanda, Nan Yang, Justyna A. Janas, Giulio Valperga, Justin Trotter, Bo Zhou, Sean Merrill, Issa Yousif, Hannah Shelby, Hannes Vogel, M. Yashar S. Kalani, Thomas C. Südhof, Marius WernigSummaryThe autism-associated synaptic-adhesion gene Neuroligin-4 (NLGN4) is poorly conserved evolutionarily, limiting conclusions from Nlgn4 mouse models for human cells. Here, we show that the cellular and subcellular expression of human and murine Neuroligin-4 differ, with human Neuroligin-4 primarily expressed in cerebral cortex and localized to excitatory synapses. Overexpression of NLGN4 in human embryonic stem cell-derived neurons resulted in an increase in excitatory synapse numbers but a remarkable decrease in synaptic strength. Human neurons carrying the syndromic autism mutation NLGN4-R704C also formed more excitatory synapses but with increased functional synaptic transmission due to a postsynaptic mechanism, while genetic loss of NLGN4 did not significantly affect synapses in the human neurons analyzed. Thus, the NLGN4-R704C mutation represents a change-of-function mutation. Our work reveals contrasting roles of NLGN4 in human and mouse neurons, suggesting that human evolution has impacted even fundamental cell biological processes generally assumed to be highly conserved.
  • Non-Canonical Wnt-Signaling through Ryk Regulates the Generation of
           Somatostatin- and Parvalbumin-Expressing Cortical Interneurons
    • Abstract: Publication date: Available online 27 June 2019Source: NeuronAuthor(s): Melissa G. McKenzie, Lucy V. Cobbs, Patrick D. Dummer, Timothy J. Petros, Michael M. Halford, Steven Stacker, Yimin Zou, Gord J. Fishell, Edmund AuSummaryGABAergic interneurons have many important functions in cortical circuitry, a reflection of their cell diversity. The developmental origins of this diversity are poorly understood. Here, we identify rostral-caudal regionality in Wnt exposure within the interneuron progenitor zone delineating the specification of the two main interneuron subclasses. Caudally situated medial ganglionic eminence (MGE) progenitors receive high levels of Wnt signaling and give rise to somatostatin (SST)-expressing cortical interneurons. By contrast, parvalbumin (PV)-expressing basket cells originate mostly from the rostral MGE, where Wnt signaling is attenuated. Interestingly, rather than canonical signaling through β-catenin, signaling via the non-canonical Wnt receptor Ryk regulates interneuron cell-fate specification in vivo and in vitro. Indeed, gain of function of Ryk intracellular domain signaling regulates SST and PV fate in a dose-dependent manner, suggesting that Ryk signaling acts in a graded fashion. These data reveal an important role for non-canonical Wnt-Ryk signaling in establishing the correct ratios of cortical interneuron subtypes.
  • Thrombospondin-1 Mediates Axon Regeneration in Retinal Ganglion Cells
    • Abstract: Publication date: Available online 26 June 2019Source: NeuronAuthor(s): Eric R. Bray, Benjamin J. Yungher, Konstantin Levay, Marcio Ribeiro, Gennady Dvoryanchikov, Ana C. Ayupe, Kinjal Thakor, Victoria Marks, Michael Randolph, Matt C. Danzi, Tiffany M. Schmidt, Nirupa Chaudhari, Vance P. Lemmon, Samer Hattar, Kevin K. ParkSummaryNeuronal subtypes show diverse injury responses, but the molecular underpinnings remain elusive. Using transgenic mice that allow reliable visualization of axonal fate, we demonstrate that intrinsically photosensitive retinal ganglion cells (ipRGCs) are both resilient to cell death and highly regenerative. Using RNA sequencing (RNA-seq), we show genes that are differentially expressed in ipRGCs and that associate with their survival and axon regeneration. Strikingly, thrombospondin-1 (Thbs1) ranked as the most differentially expressed gene, along with the well-documented injury-response genes Atf3 and Jun. THBS1 knockdown in RGCs eliminated axon regeneration. Conversely, RGC overexpression of THBS1 enhanced regeneration in both ipRGCs and non-ipRGCs, an effect that was dependent on syndecan-1, a known THBS1-binding protein. All structural domains of the THBS1 were not equally effective; the trimerization and C-terminal domains promoted regeneration, while the THBS type-1 repeats were dispensable. Our results identify cell-type-specific induction of Thbs1 as a novel gene conferring high regenerative capacity.
  • Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the
           Brain Models Parkinson’s Disease
    • Abstract: Publication date: Available online 26 June 2019Source: NeuronAuthor(s): Sangjune Kim, Seung-Hwan Kwon, Tae-In Kam, Nikhil Panicker, Senthilkumar S. Karuppagounder, Saebom Lee, Jun Hee Lee, Wonjoong Richard Kim, Minjee Kook, Catherine A. Foss, Chentian Shen, Hojae Lee, Subhash Kulkarni, Pankaj J. Pasricha, Gabsang Lee, Martin G. Pomper, Valina L. Dawson, Ted M. Dawson, Han Seok KoSummaryAnalysis of human pathology led Braak to postulate that α-synuclein (α-syn) pathology could spread from the gut to brain via the vagus nerve. Here, we test this postulate by assessing α-synucleinopathy in the brain in a novel gut-to-brain α-syn transmission mouse model, where pathological α-syn preformed fibrils were injected into the duodenal and pyloric muscularis layer. Spread of pathologic α-syn in brain, as assessed by phosphorylation of serine 129 of α-syn, was observed first in the dorsal motor nucleus, then in caudal portions of the hindbrain, including the locus coeruleus, and much later in basolateral amygdala, dorsal raphe nucleus, and the substantia nigra pars compacta. Moreover, loss of dopaminergic neurons and motor and non-motor symptoms were observed in a similar temporal manner. Truncal vagotomy and α-syn deficiency prevented the gut-to-brain spread of α-synucleinopathy and associated neurodegeneration and behavioral deficits. This study supports the Braak hypothesis in the etiology of idiopathic Parkinson’s disease (PD).Graphical Graphical abstract for this article
  • Strengthened Temporal Coordination within Pre-existing Sequential Cell
           Assemblies Supports Trajectory Replay
    • Abstract: Publication date: Available online 25 June 2019Source: NeuronAuthor(s): Usman Farooq, Jeremie Sibille, Kefei Liu, George DragoiSummaryA central goal in learning and memory research is to reveal the neural substrates underlying episodic memory formation. The hallmark of sequential spatial trajectory learning, a model of episodic memory, has remained equivocal, with proposals ranging from de novo creation of compressed sequential replay from blank slate networks to selection of pre-existing compressed preplay sequences. Here, we show that increased millisecond-timescale activation of cell assemblies expressed during de novo sequential experience and increased neuronal firing rate correlations can explain the difference between post-experience trajectory replay and robust preplay. This increased activation results from an improved neuronal tuning to specific cell assemblies, higher recruitment of experience-tuned neurons into pre-existing cell assemblies, and increased recruitment of cell assemblies in replay. In contrast, changes in overall neuronal and cell assembly temporal order within extended sequences do not account for sequential trajectory learning. We propose the coordinated strengthening of cell assemblies played sequentially on robust pre-existing temporal frameworks could support rapid formation of episodic-like memory.
  • Orbitofrontal Circuits Control Multiple Reinforcement-Learning Processes
    • Abstract: Publication date: Available online 25 June 2019Source: NeuronAuthor(s): Stephanie M. Groman, Colby Keistler, Alex J. Keip, Emma Hammarlund, Ralph J. DiLeone, Christopher Pittenger, Daeyeol Lee, Jane R. TaylorSummaryAdaptive decision making in dynamic environments requires multiple reinforcement-learning steps that may be implemented by dissociable neural circuits. Here, we used a novel directionally specific viral ablation approach to investigate the function of several anatomically defined orbitofrontal cortex (OFC) circuits during adaptive, flexible decision making in rats trained on a probabilistic reversal learning task. Ablation of OFC neurons projecting to the nucleus accumbens selectively disrupted performance following a reversal, by disrupting the use of negative outcomes to guide subsequent choices. Ablation of amygdala neurons projecting to the OFC also impaired reversal performance, but due to disruptions in the use of positive outcomes to guide subsequent choices. Ablation of OFC neurons projecting to the amygdala, by contrast, enhanced reversal performance by destabilizing action values. Our data are inconsistent with a unitary function of the OFC in decision making. Rather, distinct OFC-amygdala-striatal circuits mediate distinct components of the action-value updating and maintenance necessary for decision making.
  • Deep Sequencing of Somatosensory Neurons Reveals Molecular Determinants of
           Intrinsic Physiological Properties
    • Abstract: Publication date: Available online 24 June 2019Source: NeuronAuthor(s): Yang Zheng, Pin Liu, Ling Bai, James S. Trimmer, Bruce P. Bean, David D. GintySummaryDorsal root ganglion (DRG) sensory neuron subtypes defined by their in vivo properties display distinct intrinsic electrical properties. We used bulk RNA sequencing of genetically labeled neurons and electrophysiological analyses to define ion channel contributions to the intrinsic electrical properties of DRG neuron subtypes. The transcriptome profiles of eight DRG neuron subtypes revealed differentially expressed and functionally relevant genes, including voltage-gated ion channels. Guided by these data, electrophysiological analyses using pharmacological and genetic manipulations as well as computational modeling of DRG neuron subtypes were undertaken to assess the functions of select voltage-gated potassium channels (Kv1, Kv2, Kv3, and Kv4) in shaping action potential (AP) waveforms and firing patterns. Our findings show that the transcriptome profiles have predictive value for defining ion channel contributions to sensory neuron subtype-specific intrinsic physiological properties. The distinct ensembles of voltage-gated ion channels predicted to underlie the unique intrinsic physiological properties of eight DRG neuron subtypes are presented.
  • The Serotonergic Raphe Promote Sleep in Zebrafish and Mice
    • Abstract: Publication date: Available online 24 June 2019Source: NeuronAuthor(s): Grigorios Oikonomou, Michael Altermatt, Rong-wei Zhang, Gerard M. Coughlin, Christin Montz, Viviana Gradinaru, David A. ProberSummaryThe role of serotonin (5-HT) in sleep is controversial: early studies suggested a sleep-promoting role, but eventually the paradigm shifted toward a wake-promoting function for the serotonergic raphe. Here, we provide evidence from zebrafish and mice that the raphe are critical for the initiation and maintenance of sleep. In zebrafish, genetic ablation of 5-HT production by the raphe reduces sleep, sleep depth, and the homeostatic response to sleep deprivation. Pharmacological inhibition or ablation of the raphe reduces sleep, while optogenetic stimulation increases sleep. Similarly, in mice, ablation of the raphe increases wakefulness and impairs the homeostatic response to sleep deprivation, whereas tonic optogenetic stimulation at a rate similar to baseline activity induces sleep. Interestingly, burst optogenetic stimulation induces wakefulness in accordance with previously described burst activity of the raphe during arousing stimuli. These results indicate that the serotonergic system promotes sleep in both diurnal zebrafish and nocturnal rodents.
  • Transforming the Choice Outcome to an Action Plan in Monkey Lateral
           Prefrontal Cortex: A Neural Circuit Model
    • Abstract: Publication date: Available online 20 June 2019Source: NeuronAuthor(s): Man Yi Yim, Xinying Cai, Xiao-Jing WangSummaryIn economic decisions, we make a good-based choice first, then we transform the outcome into an action to obtain the good. To elucidate the network mechanisms for such transformation, we constructed a neural circuit model consisting of modules representing choice, integration of choice with target locations, and the final action plan. We examined three scenarios regarding how the final action plan could emerge in the neural circuit and compared their implications with experimental data. Our model with heterogeneous connectivity predicts the coexistence of three types of neurons with distinct functions, confirmed by analyzing the neural activity in the lateral prefrontal cortex (LPFC) of behaving monkeys. We obtained a much more distinct classification of functional neuron types in the ventral than the dorsal region of LPFC, suggesting that the action plan is initially generated in ventral LPFC. Our model offers a biologically plausible neural circuit architecture that implements good-to-action transformation during economic choice.
  • The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and
           Synaptic Function in the Prefrontal Cortex
    • Abstract: Publication date: Available online 20 June 2019Source: NeuronAuthor(s): Perry W.E. Spratt, Roy Ben-Shalom, Caroline M. Keeshen, Kenneth J. Burke, Rebecca L. Clarkson, Stephan J. Sanders, Kevin J. BenderSummaryAutism spectrum disorder (ASD) is strongly associated with de novo gene mutations. One of the most commonly affected genes is SCN2A. ASD-associated SCN2A mutations impair the encoded protein NaV1.2, a sodium channel important for action potential initiation and propagation in developing excitatory cortical neurons. The link between an axonal sodium channel and ASD, a disorder typically attributed to synaptic or transcriptional dysfunction, is unclear. Here we show that NaV1.2 is unexpectedly critical for dendritic excitability and synaptic function in mature pyramidal neurons in addition to regulating early developmental axonal excitability. NaV1.2 loss reduced action potential backpropagation into dendrites, impairing synaptic plasticity and synaptic strength, even when NaV1.2 expression was disrupted in a cell-autonomous fashion late in development. These results reveal a novel dendritic function for NaV1.2, providing insight into cellular mechanisms probably underlying circuit and behavioral dysfunction in ASD.Graphical Graphical abstract for this article
  • Unusual Physiological Properties of Smooth Monostratified Ganglion Cell
           Types in Primate Retina
    • Abstract: Publication date: Available online 18 June 2019Source: NeuronAuthor(s): Colleen E. Rhoades, Nishal P. Shah, Michael B. Manookin, Nora Brackbill, Alexandra Kling, Georges Goetz, Alexander Sher, Alan M. Litke, E.J. ChichilniskySummaryThe functions of the diverse retinal ganglion cell types in primates and the parallel visual pathways they initiate remain poorly understood. Here, unusual physiological and computational properties of the ON and OFF smooth monostratified ganglion cells are explored. Large-scale multi-electrode recordings from 48 macaque retinas revealed that these cells exhibit irregular receptive field structure composed of spatially segregated hotspots, quite different from the classic center-surround model of retinal receptive fields. Surprisingly, visual stimulation of different hotspots in the same cell produced spikes with subtly different spatiotemporal voltage signatures, consistent with a dendritic contribution to hotspot structure. Targeted visual stimulation and computational inference demonstrated strong nonlinear subunit properties associated with each hotspot, supporting a model in which the hotspots apply nonlinearities at a larger spatial scale than bipolar cells. These findings reveal a previously unreported nonlinear mechanism in the output of the primate retina that contributes to signaling spatial information.
  • Rapid Reconfiguration of the Functional Connectome after Chemogenetic
           Locus Coeruleus Activation
    • Abstract: Publication date: Available online 18 June 2019Source: NeuronAuthor(s): Valerio Zerbi, Amalia Floriou-Servou, Marija Markicevic, Yannick Vermeiren, Oliver Sturman, Mattia Privitera, Lukas von Ziegler, Kim David Ferrari, Bruno Weber, Peter Paul De Deyn, Nicole Wenderoth, Johannes BohacekSummaryThe locus coeruleus (LC) supplies norepinephrine (NE) to the entire forebrain and regulates many fundamental brain functions. Studies in humans have suggested that strong LC activation might shift network connectivity to favor salience processing. To causally test this hypothesis, we use a mouse model to study the effect of LC stimulation on large-scale functional connectivity by combining chemogenetic activation of the LC with resting-state fMRI, an approach we term “chemo-connectomics.” We show that LC activation rapidly interrupts ongoing behavior and strongly increases brain-wide connectivity, with the most profound effects in the salience and amygdala networks. Functional connectivity changes strongly correlate with transcript levels of alpha-1 and beta-1 adrenergic receptors across the brain, and functional network connectivity correlates with NE turnover within select brain regions. We propose that these changes in large-scale network connectivity are critical for optimizing neural processing in the context of increased vigilance and threat detection.Graphical Graphical abstract for this article
  • High-Frequency Activation of Nucleus Accumbens D1-MSNs Drives Excitatory
           Potentiation on D2-MSNs
    • Abstract: Publication date: Available online 17 June 2019Source: NeuronAuthor(s): T. Chase Francis, Hideaki Yano, Tyler G. Demarest, Hui Shen, Antonello BonciSummarySubtypes of nucleus accumbens medium spiny neurons (MSNs) promote dichotomous outcomes in motivated behaviors. However, recent reports indicate enhancing activity of either nucleus accumbens (NAc) core MSN subtype augments reward, suggesting coincident MSN activity may underlie this outcome. Here, we report a collateral excitation mechanism in which high-frequency, NAc core dopamine 1 (D1)-MSN activation causes long-lasting potentiation of excitatory transmission (LLP) on dopamine receptor 2 (D2)-MSNs. Our mechanistic investigation demonstrates that this form of plasticity requires release of the excitatory peptide substance P from D1-MSNs and robust cholinergic interneuron activation through neurokinin receptor stimulation. We also reveal that D2-MSN LLP requires muscarinic 1 receptor activation, intracellular calcium signaling, and GluR2-lacking AMPAR insertion. This study uncovers a mechanism for shaping NAc core activity through the transfer of excitatory information from D1-MSNs to D2-MSNs and may provide a means for altering goal-directed behavior through coordinated MSN activity.Graphical Graphical abstract for this article
  • Neuronally Enriched RUFY3 Is Required for Caspase-Mediated Axon
    • Abstract: Publication date: Available online 17 June 2019Source: NeuronAuthor(s): Nicholas T. Hertz, Eliza L. Adams, Ross A. Weber, Rebecca J. Shen, Melanie K. O’Rourke, David J. Simon, Henry Zebroski, Olav Olsen, Charles W. Morgan, Trevor R. Mileur, Angela M. Hitchcock, Nicholas A. Sinnott Armstrong, Michael Wainberg, Michael C. Bassik, Henrik Molina, James A. Wells, Marc Tessier-LavigneSummarySelective synaptic and axonal degeneration are critical aspects of both brain development and neurodegenerative disease. Inhibition of caspase signaling in neurons is a potential therapeutic strategy for neurodegenerative disease, but no neuron-specific modulators of caspase signaling have been described. Using a mass spectrometry approach, we discovered that RUFY3, a neuronally enriched protein, is essential for caspase-mediated degeneration of TRKA+ sensory axons in vitro and in vivo. Deletion of Rufy3 protects axons from degeneration, even in the presence of activated CASP3 that is competent to cleave endogenous substrates. Dephosphorylation of RUFY3 at residue S34 appears required for axon degeneration, providing a potential mechanism for neurons to locally control caspase-driven degeneration. Neuronally enriched RUFY3 thus provides an entry point for understanding non-apoptotic functions of CASP3 and a potential target to modulate caspase signaling specifically in neurons for neurodegenerative disease.Graphical Graphical abstract for this article
  • A Discrete Dorsal Raphe to Basal Amygdala 5-HT Circuit Calibrates Aversive
    • Abstract: Publication date: Available online 13 June 2019Source: NeuronAuthor(s): Ayesha Sengupta, Andrew HolmesSummaryDespite a wealth of clinical and preclinical data implicating the serotonin (5-HT) system in fear-related affective disorders, a precise definition of this neuromodulator’s role in fear remains elusive. Using convergent anatomical and functional approaches, we interrogate the contribution to fear of basal amygdala (BA) 5-HT inputs from the dorsal raphe nucleus (DRN). We show the DRN→BA 5-HT pathway is engaged during fear memory formation and retrieval, and activity of these projections facilitates fear and impairs extinction. The DRN→BA 5-HT pathway amplifies fear-associated BA neuronal firing and theta power and phase-locking. Although fear recruits 5-HT and VGluT3 co-expressing DRN neurons, the fear-potentiating influence of the DRN→BA 5-HT pathway requires signaling at BA 5-HT1A/2A receptors. Input-output mapping illustrates how the DRN→BA 5-HT pathway is anatomically distinct and connected with other brain regions that mediate fear. These findings reveal how a discrete 5-HT circuit orchestrates a broader neural network to calibrate aversive memory.Graphical Graphical abstract for this article
  • A Specialized Neural Circuit Gates Social Vocalizations in the Mouse
    • Abstract: Publication date: Available online 13 June 2019Source: NeuronAuthor(s): Katherine Tschida, Valerie Michael, Jun Takato, Bao-Xia Han, Shengli Zhao, Katsuyasu Sakurai, Richard Mooney, Fan WangSummaryVocalizations are fundamental to mammalian communication, but the underlying neural circuits await detailed characterization. Here, we used an intersectional genetic method to label and manipulate neurons in the midbrain periaqueductal gray (PAG) that are transiently active in male mice when they produce ultrasonic courtship vocalizations (USVs). Genetic silencing of PAG-USV neurons rendered males unable to produce USVs and impaired their ability to attract females. Conversely, activating PAG-USV neurons selectively triggered USV production, even in the absence of any female cues. Optogenetic stimulation combined with axonal tracing indicates that PAG-USV neurons gate downstream vocal-patterning circuits. Indeed, activating PAG neurons that innervate the nucleus retroambiguus, but not those innervating the parabrachial nucleus, elicited USVs in both male and female mice. These experiments establish that a dedicated population of PAG neurons gives rise to a descending circuit necessary and sufficient for USV production while also demonstrating the communicative salience of male USVs.Graphical Graphical abstract for this article
  • Prefrontal Cortex Regulates Sensory Filtering through a Basal
           Ganglia-to-Thalamus Pathway
    • Abstract: Publication date: Available online 12 June 2019Source: NeuronAuthor(s): Miho Nakajima, L.Ian Schmitt, Michael M. HalassaSummaryTo make adaptive decisions, organisms must appropriately filter sensory inputs, augmenting relevant signals and suppressing noise. The prefrontal cortex (PFC) partly implements this process by regulating thalamic activity through modality-specific thalamic reticular nucleus (TRN) subnetworks. However, because the PFC does not directly project to sensory TRN subnetworks, the circuitry underlying this process had been unknown. Here, using anatomical tracing, functional manipulations, and optical identification of PFC projection neurons, we find that the PFC regulates sensory thalamic activity through a basal ganglia (BG) pathway. Engagement of this PFC-BG-thalamus pathway enables selection between vision and audition by primarily suppressing the distracting modality. This pathway also enhances sensory discrimination and is used for goal-directed background noise suppression. Overall, our results identify a new pathway for attentional filtering and reveal its multiple roles in sensory processing on the basis of internal goals.
  • A VTA GABAergic Neural Circuit Mediates Visually Evoked Innate Defensive
    • Abstract: Publication date: Available online 12 June 2019Source: NeuronAuthor(s): Zheng Zhou, Xuemei Liu, Shanping Chen, Zhijian Zhang, Yuanming Liu, Quentin Montardy, Yongqiang Tang, Pengfei Wei, Nan Liu, Lei Li, Ru Song, Juan Lai, Xiaobin He, Chen Chen, Guoqiang Bi, Guoping Feng, Fuqiang Xu, Liping WangSummaryInnate defensive responses are essential for animal survival and are conserved across species. The ventral tegmental area (VTA) plays important roles in learned appetitive and aversive behaviors, but whether it plays a role in mediating or modulating innate defensive responses is currently unknown. We report that VTAGABA+ neurons respond to a looming stimulus. Inhibition of VTAGABA+ neurons reduced looming-evoked defensive flight behavior, and photoactivation of these neurons resulted in defense-like flight behavior. Using viral tracing and electrophysiological recordings, we show that VTAGABA+ neurons receive direct excitatory inputs from the superior colliculus (SC). Furthermore, we show that glutamatergic SC-VTA projections synapse onto VTAGABA+ neurons that project to the central nucleus of the amygdala (CeA) and that the CeA is involved in mediating the defensive behavior. Our findings demonstrate that aerial threat-related visual information is relayed to VTAGABA+ neurons mediating innate behavioral responses, suggesting a more general role of the VTA.Graphical Graphical abstract for this article
  • Cerebellar Contribution to Preparatory Activity in Motor Neocortex
    • Abstract: Publication date: Available online 11 June 2019Source: NeuronAuthor(s): Francois P. Chabrol, Antonin Blot, Thomas D. Mrsic-FlogelSummaryIn motor neocortex, preparatory activity predictive of specific movements is maintained by a positive feedback loop with the thalamus. Motor thalamus receives excitatory input from the cerebellum, which learns to generate predictive signals for motor control. The contribution of this pathway to neocortical preparatory signals remains poorly understood. Here, we show that, in a virtual reality conditioning task, cerebellar output neurons in the dentate nucleus exhibit preparatory activity similar to that in anterolateral motor cortex prior to reward acquisition. Silencing activity in dentate nucleus by photoactivating inhibitory Purkinje cells in the cerebellar cortex caused robust, short-latency suppression of preparatory activity in anterolateral motor cortex. Our results suggest that preparatory activity is controlled by a learned decrease of Purkinje cell firing in advance of reward under supervision of climbing fiber inputs signaling reward delivery. Thus, cerebellar computations exert a powerful influence on preparatory activity in motor neocortex.
  • Open Source Brain: A Collaborative Resource for Visualizing, Analyzing,
           Simulating, and Developing Standardized Models of Neurons and Circuits
    • Abstract: Publication date: Available online 11 June 2019Source: NeuronAuthor(s): Padraig Gleeson, Matteo Cantarelli, Boris Marin, Adrian Quintana, Matt Earnshaw, Sadra Sadeh, Eugenio Piasini, Justas Birgiolas, Robert C. Cannon, N. Alex Cayco-Gajic, Sharon Crook, Andrew P. Davison, Salvador Dura-Bernal, András Ecker, Michael L. Hines, Giovanni Idili, Frederic Lanore, Stephen D. Larson, William W. Lytton, Amitava MajumdarSummaryComputational models are powerful tools for exploring the properties of complex biological systems. In neuroscience, data-driven models of neural circuits that span multiple scales are increasingly being used to understand brain function in health and disease. But their adoption and reuse has been limited by the specialist knowledge required to evaluate and use them. To address this, we have developed Open Source Brain, a platform for sharing, viewing, analyzing, and simulating standardized models from different brain regions and species. Model structure and parameters can be automatically visualized and their dynamical properties explored through browser-based simulations. Infrastructure and tools for collaborative interaction, development, and testing are also provided. We demonstrate how existing components can be reused by constructing new models of inhibition-stabilized cortical networks that match recent experimental results. These features of Open Source Brain improve the accessibility, transparency, and reproducibility of models and facilitate their reuse by the wider community.Graphical Graphical abstract for this article
  • Paraventricular Thalamus Projection Neurons Integrate Cortical and
           Hypothalamic Signals for Cue-Reward Processing
    • Abstract: Publication date: Available online 10 June 2019Source: NeuronAuthor(s): James M. Otis, ManHua Zhu, Vijay M.K. Namboodiri, Cory A. Cook, Oksana Kosyk, Ana M. Matan, Rose Ying, Yoshiko Hashikawa, Koichi Hashikawa, Ivan Trujillo-Pisanty, Jiami Guo, Randall L. Ung, Jose Rodriguez-Romaguera, E.S. Anton, Garret D. StuberSummaryThe paraventricular thalamus (PVT) is an interface for brain reward circuits, with input signals arising from structures, such as prefrontal cortex and hypothalamus, that are broadcast to downstream limbic targets. However, the precise synaptic connectivity, activity, and function of PVT circuitry for reward processing are unclear. Here, using in vivo two-photon calcium imaging, we find that PVT neurons projecting to the nucleus accumbens (PVT-NAc) develop inhibitory responses to reward-predictive cues coding for both cue-reward associative information and behavior. The multiplexed activity in PVT-NAc neurons is directed by opposing activity patterns in prefrontal and lateral hypothalamic afferent axons. Further, we find that prefrontal cue encoding may maintain accurate cue-reward processing, as optogenetic disruption of this encoding induced long-lasting effects on downstream PVT-NAc cue responses and behavioral cue discrimination. Together, these data reveal that PVT-NAc neurons act as an interface for reward processing by integrating relevant inputs to accurately inform reward-seeking behavior.
  • Subcortical Substrates of Explore-Exploit Decisions in Primates
    • Abstract: Publication date: Available online 10 June 2019Source: NeuronAuthor(s): Vincent D. Costa, Andrew R. Mitz, Bruno B. AverbeckSummaryThe explore-exploit dilemma refers to the challenge of deciding when to forego immediate rewards and explore new opportunities that could lead to greater rewards in the future. While motivational neural circuits facilitate learning based on past choices and outcomes, it is unclear whether they also support computations relevant for deciding when to explore. We recorded neural activity in the amygdala and ventral striatum of rhesus macaques as they solved a task that required them to balance novelty-driven exploration with exploitation of what they had already learned. Using a partially observable Markov decision process (POMDP) model to quantify explore-exploit trade-offs, we identified that the ventral striatum and amygdala differ in how they represent the immediate value of exploitative choices and the future value of exploratory choices. These findings show that subcortical motivational circuits are important in guiding explore-exploit decisions.
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Heriot-Watt University
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