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  • Grid scale drives the scale and long-term stability of place maps
    Nat. Neurosci. (IF 17.839) Pub Date : 2018-01-15
    Caitlin S. Mallory, Kiah Hardcastle, Jason S. Bant, Lisa M. Giocomo

    Medial entorhinal cortex (MEC) grid cells fire at regular spatial intervals and project to the hippocampus, where place cells are active in spatially restricted locations. One feature of the grid population is the increase in grid spatial scale along the dorsal–ventral MEC axis. However, the difficulty in perturbing grid scale without impacting the properties of other functionally defined MEC cell types has obscured how grid scale influences hippocampal coding and spatial memory. Here we use a targeted viral approach to knock out HCN1 channels selectively in MEC, causing the grid scale to expand while leaving other MEC spatial and velocity signals intact. Grid scale expansion resulted in place scale expansion in fields located far from environmental boundaries, reduced long-term place field stability and impaired spatial learning. These observations, combined with simulations of a grid-to-place cell model and position decoding of place cells, illuminate how grid scale impacts place coding and spatial memory.

    更新日期:2018-01-15
  • In vivo simultaneous transcriptional activation of multiple genes in the brain using CRISPR–dCas9-activator transgenic mice
    Nat. Neurosci. (IF 17.839) Pub Date : 2018-01-15
    Haibo Zhou, Junlai Liu, Changyang Zhou, Ni Gao, Zhiping Rao, He Li, Xinde Hu, Changlin Li, Xuan Yao, Xiaowen Shen, Yidi Sun, Yu Wei, Fei Liu, Wenqin Ying, Junming Zhang, Cheng Tang, Xu Zhang, Huatai Xu, Linyu Shi, Leping Cheng, Pengyu Huang, Hui Yang

    Despite rapid progresses in the genome-editing field, in vivo simultaneous overexpression of multiple genes remains challenging. We generated a transgenic mouse using an improved dCas9 system that enables simultaneous and precise in vivo transcriptional activation of multiple genes and long noncoding RNAs in the nervous system. As proof of concept, we were able to use targeted activation of endogenous neurogenic genes in these transgenic mice to directly and efficiently convert astrocytes into functional neurons in vivo. This system provides a flexible and rapid screening platform for studying complex gene networks and gain-of-function phenotypes in the mammalian brain.

    更新日期:2018-01-15
  • Conserved properties of dentate gyrus neurogenesis across postnatal development revealed by single-cell RNA sequencing
    Nat. Neurosci. (IF 17.839) Pub Date : 2018-01-15
    Hannah Hochgerner, Amit Zeisel, Peter Lönnerberg, Sten Linnarsson

    The dentate gyrus of the hippocampus is a brain region in which neurogenesis persists into adulthood; however, the relationship between developmental and adult dentate gyrus neurogenesis has not been examined in detail. Here we used single-cell RNA sequencing to reveal the molecular dynamics and diversity of dentate gyrus cell types in perinatal, juvenile, and adult mice. We found distinct quiescent and proliferating progenitor cell types, linked by transient intermediate states to neuroblast stages and fully mature granule cells. We observed shifts in the molecular identity of quiescent and proliferating radial glia and granule cells during the postnatal period that were then maintained through adult stages. In contrast, intermediate progenitor cells, neuroblasts, and immature granule cells were nearly indistinguishable at all ages. These findings demonstrate the fundamental similarity of postnatal and adult neurogenesis in the hippocampus and pinpoint the early postnatal transformation of radial glia from embryonic progenitors to adult quiescent stem cells.

    更新日期:2018-01-15
  • Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response
    Nat. Neurosci. (IF 17.839) Pub Date : 2018-01-15
    Giuseppe Faraco, David Brea, Lidia Garcia-Bonilla, Gang Wang, Gianfranco Racchumi, Haejoo Chang, Izaskun Buendia, Monica M. Santisteban, Steven G. Segarra, Kenzo Koizumi, Yukio Sugiyama, Michelle Murphy, Henning Voss, Joseph Anrather, Costantino Iadecola

    A diet rich in salt is linked to an increased risk of cerebrovascular diseases and dementia, but it remains unclear how dietary salt harms the brain. We report that, in mice, excess dietary salt suppresses resting cerebral blood flow and endothelial function, leading to cognitive impairment. The effect depends on expansion of TH17 cells in the small intestine, resulting in a marked increase in plasma interleukin-17 (IL-17). Circulating IL-17, in turn, promotes endothelial dysfunction and cognitive impairment by the Rho kinase–dependent inhibitory phosphorylation of endothelial nitric oxide synthase and reduced nitric oxide production in cerebral endothelial cells. The findings reveal a new gut–brain axis linking dietary habits to cognitive impairment through a gut-initiated adaptive immune response compromising brain function via circulating IL-17. Thus, the TH17 cell–IL-17 pathway is a putative target to counter the deleterious brain effects induced by dietary salt and other diseases associated with TH17 polarization.

    更新日期:2018-01-15
  • Dentate network activity is necessary for spatial working memory by supporting CA3 sharp-wave ripple generation and prospective firing of CA3 neurons
    Nat. Neurosci. (IF 17.839) Pub Date : 2018-01-15
    Takuya Sasaki, Verónica C. Piatti, Ernie Hwaun, Siavash Ahmadi, John E. Lisman, Stefan Leutgeb, Jill K. Leutgeb

    Complex spatial working memory tasks have been shown to require both hippocampal sharp-wave ripple (SWR) activity and dentate gyrus (DG) neuronal activity. We therefore asked whether DG inputs to CA3 contribute to spatial working memory by promoting SWR generation. Recordings from DG and CA3 while rats performed a dentate-dependent working memory task on an eight-arm radial maze revealed that the activity of dentate neurons and the incidence rate of SWRs both increased during reward consumption. We then found reduced reward-related CA3 SWR generation without direct input from dentate granule neurons. Furthermore, CA3 cells with place fields in not-yet-visited arms preferentially fired during SWRs at reward locations, and these prospective CA3 firing patterns were more pronounced for correct trials and were dentate-dependent. These results indicate that coordination of CA3 neuronal activity patterns by DG is necessary for the generation of neuronal firing patterns that support goal-directed behavior and memory.

    更新日期:2018-01-15
  • N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications
    Nat. Neurosci. (IF 17.839) Pub Date : 2018-01-15
    Yang Wang, Yue Li, Minghui Yue, Jun Wang, Sandeep Kumar, Robert J. Wechsler-Reya, Zhaolei Zhang, Yuya Ogawa, Manolis Kellis, Gregg Duester, Jing Crystal Zhao

    Internal N6-methyladenosine (m6A) modification is widespread in messenger RNAs (mRNAs) and is catalyzed by heterodimers of methyltransferase-like protein 3 (Mettl3) and Mettl14. To understand the role of m6A in development, we deleted Mettl14 in embryonic neural stem cells (NSCs) in a mouse model. Phenotypically, NSCs lacking Mettl14 displayed markedly decreased proliferation and premature differentiation, suggesting that m6A modification enhances NSC self-renewal. Decreases in the NSC pool led to a decreased number of late-born neurons during cortical neurogenesis. Mechanistically, we discovered a genome-wide increase in specific histone modifications in Mettl14 knockout versus control NSCs. These changes correlated with altered gene expression and observed cellular phenotypes, suggesting functional significance of altered histone modifications in knockout cells. Finally, we found that m6A regulates histone modification in part by destabilizing transcripts that encode histone-modifying enzymes. Our results suggest an essential role for m6A in development and reveal m6A-regulated histone modifications as a previously unknown mechanism of gene regulation in mammalian cells.

    更新日期:2018-01-15
  • Hexadirectional coding of visual space in human entorhinal cortex
    Nat. Neurosci. (IF 17.839) Pub Date : 2018-01-08
    Matthias Nau, Tobias Navarro Schröder, Jacob L. S. Bellmund, Christian F. Doeller

    Entorhinal grid cells map the local environment, but their involvement beyond spatial navigation remains elusive. We examined human functional MRI responses during a highly controlled visual tracking task and show that entorhinal cortex exhibited a sixfold rotationally symmetric signal encoding gaze direction. Our results provide evidence for a grid-like entorhinal code for visual space and suggest a more general role of the entorhinal grid system in coding information along continuous dimensions.

    更新日期:2018-01-09
  • Simple integration of fast excitation and offset, delayed inhibition computes directional selectivity in Drosophila
    Nat. Neurosci. (IF 17.839) Pub Date : 2018-01-08
    Eyal Gruntman, Sandro Romani, Michael B. Reiser

    A neuron that extracts directionally selective motion information from upstream signals lacking this selectivity must compare visual responses from spatially offset inputs. Distinguishing among prevailing algorithmic models for this computation requires measuring fast neuronal activity and inhibition. In the Drosophila melanogaster visual system, a fourth-order neuron—T4—is the first cell type in the ON pathway to exhibit directionally selective signals. Here we use in vivo whole-cell recordings of T4 to show that directional selectivity originates from simple integration of spatially offset fast excitatory and slow inhibitory inputs, resulting in a suppression of responses to the nonpreferred motion direction. We constructed a passive, conductance-based model of a T4 cell that accurately predicts the neuron’s response to moving stimuli. These results connect the known circuit anatomy of the motion pathway to the algorithmic mechanism by which the direction of motion is computed.

    更新日期:2018-01-09
  • Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans
    Nat. Neurosci. (IF 17.839) Pub Date : 2018-01-08
    Thomas Gstrein, Andrew Edwards, Anna Přistoupilová, Ines Leca, Martin Breuss, Sandra Pilat-Carotta, Andi H. Hansen, Ratna Tripathy, Anna K. Traunbauer, Tobias Hochstoeger, Gavril Rosoklija, Marco Repic, Lukas Landler, Viktor Stránecký, Gerhard Dürnberger, Thomas M. Keane, Johannes Zuber, David J. Adams, Jonathan Flint, Tomas Honzik, Marta Gut, Sergi Beltran, Karl Mechtler, Elliott Sherr, Stanislav Kmoch, Ivo Gut, David A. Keays

    The formation of the vertebrate brain requires the generation, migration, differentiation and survival of neurons. Genetic mutations that perturb these critical cellular events can result in malformations of the telencephalon, providing a molecular window into brain development. Here we report the identification of an N-ethyl-N-nitrosourea-induced mouse mutant characterized by a fractured hippocampal pyramidal cell layer, attributable to defects in neuronal migration. We show that this is caused by a hypomorphic mutation in Vps15 that perturbs endosomal–lysosomal trafficking and autophagy, resulting in an upregulation of Nischarin, which inhibits Pak1 signaling. The complete ablation of Vps15 results in the accumulation of autophagic substrates, the induction of apoptosis and severe cortical atrophy. Finally, we report that mutations in VPS15 are associated with cortical atrophy and epilepsy in humans. These data highlight the importance of the Vps15–Vps34 complex and the Nischarin–Pak1 signaling hub in the development of the telencephalon.

    更新日期:2018-01-09
  • Human entorhinal cortex represents visual space using a boundary-anchored grid
    Nat. Neurosci. (IF 17.839) Pub Date : 2018-01-08
    Joshua B. Julian, Alexandra T. Keinath, Giulia Frazzetta, Russell A. Epstein

    When participants performed a visual search task, functional MRI responses in entorhinal cortex exhibited a sixfold periodic modulation by gaze-movement direction. The orientation of this modulation was determined by the shape and orientation of the bounded search space. These results indicate that human entorhinal cortex represents visual space using a boundary-anchored grid, analogous to that used by rodents to represent navigable space.

    更新日期:2018-01-09
  • Social transmission and buffering of synaptic changes after stress
    Nat. Neurosci. (IF 17.839) Pub Date : 2018-01-08
    Toni-Lee Sterley, Dinara Baimoukhametova, Tamás Füzesi, Agnieszka A. Zurek, Nuria Daviu, Neilen P. Rasiah, David Rosenegger, Jaideep S. Bains

    Stress can trigger enduring changes in neural circuits and synapses. The behavioral and hormonal consequences of stress can also be transmitted to others, but whether this transmitted stress has similar effects on synapses is not known. We found that authentic stress and transmitted stress in mice primed paraventricular nucleus of the hypothalamus (PVN) corticotropin-releasing hormone (CRH) neurons, enabling the induction of metaplasticity at glutamate synapses. In female mice that were subjected to authentic stress, this metaplasticity was diminished following interactions with a naive partner. Transmission from the stressed subject to the naive partner required the activation of PVN CRH neurons in both subject and partner to drive and detect the release of a putative alarm pheromone from the stressed mouse. Finally, metaplasticity could be transmitted sequentially from the stressed subject to multiple partners. Our findings demonstrate that transmitted stress has the same lasting effects on glutamate synapses as authentic stress and reveal an unexpected role for PVN CRH neurons in transmitting distress signals among individuals.

    更新日期:2018-01-09
  • TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD
    Nat. Neurosci. (IF 17.839) Pub Date : 2018-01-08
    Ching-Chieh Chou, Yi Zhang, Mfon E. Umoh, Spencer W. Vaughan, Ileana Lorenzini, Feilin Liu, Melissa Sayegh, Paul G. Donlin-Asp, Yu Han Chen, Duc M. Duong, Nicholas T. Seyfried, Maureen A. Powers, Thomas Kukar, Chadwick M. Hales, Marla Gearing, Nigel J. Cairns, Kevin B. Boylan, Dennis W. Dickson, Rosa Rademakers, Yong-Jie Zhang, Leonard Petrucelli, Rita Sattler, Daniela C. Zarnescu, Jonathan D. Glass, Wilfried Rossoll

    The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins and transport factors, and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts and induced pluripotent stem cell–derived neurons. Nuclear pore pathology is present in brain tissue in cases of sporadic ALS and those involving genetic mutations in TARDBP and C9orf72. Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD.

    更新日期:2018-01-09
  • Studying and modifying brain function with non-invasive brain stimulation
    Nat. Neurosci. (IF 17.839) Pub Date : 2018-01-08
    Rafael Polanía, Michael A. Nitsche, Christian C. Ruff

    In the past three decades, our understanding of brain–behavior relationships has been significantly shaped by research using non-invasive brain stimulation (NIBS) techniques. These methods allow non-invasive and safe modulation of neural processes in the healthy brain, enabling researchers to directly study how experimentally altered neural activity causally affects behavior. This unique property of NIBS methods has, on the one hand, led to groundbreaking findings on the brain basis of various aspects of behavior and has raised interest in possible clinical and practical applications of these methods. On the other hand, it has also triggered increasingly critical debates about the properties and possible limitations of these methods. In this review, we discuss these issues, clarify the challenges associated with the use of currently available NIBS techniques for basic research and practical applications, and provide recommendations for studies using NIBS techniques to establish brain–behavior relationships.

    更新日期:2018-01-09
  • Generalizable representations of pain, cognitive control, and negative emotion in medial frontal cortex
    Nat. Neurosci. (IF 17.839) Pub Date : 2018-01-01
    Philip A. Kragel, Michiko Kano, Lukas Van Oudenhove, Huynh Giao Ly, Patrick Dupont, Amandine Rubio, Chantal Delon-Martin, Bruno L. Bonaz, Stephen B. Manuck, Peter J. Gianaros, Marta Ceko, Elizabeth A. Reynolds Losin, Choong-Wan Woo, Thomas E. Nichols, Tor D. Wager

    The medial frontal cortex, including anterior midcingulate cortex, has been linked to multiple psychological domains, including cognitive control, pain, and emotion. However, it is unclear whether this region encodes representations of these domains that are generalizable across studies and subdomains. Additionally, if there are generalizable representations, do they reflect a single underlying process shared across domains or multiple domain-specific processes? We decomposed multivariate patterns of functional MRI activity from 270 participants across 18 studies into study-specific, subdomain-specific, and domain-specific components and identified latent multivariate representations that generalized across subdomains but were specific to each domain. Pain representations were localized to anterior midcingulate cortex, negative emotion representations to ventromedial prefrontal cortex, and cognitive control representations to portions of the dorsal midcingulate. These findings provide evidence for medial frontal cortex representations that generalize across studies and subdomains but are specific to distinct psychological domains rather than reducible to a single underlying process.

    更新日期:2018-01-01
  • Stay alert, don’t get hurt
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-21
    Stephen V. Mahler

    Stay alert, don’t get hurtStay alert, don’t get hurt, Published online: 21 December 2017; doi:10.1038/s41593-017-0045-5Both nucleus accumbens and orexin play clear roles in motivated behavior, but the functions of orexin projections to accumbens are poorly understood. Blomeley et al. show that this pathway, via specific orexin excitation of dopamine D2 receptor–expressing neurons, can inhibit reward seeking and exploratory drive when danger is perceived.

    更新日期:2017-12-22
  • The diversity and disparity of the glial scar
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-21
    Katrina L. Adams, Vittorio Gallo

    Injury or disease to the CNS results in multifaceted cellular and molecular responses. One such response, the glial scar, is a structural formation of reactive glia around an area of severe tissue damage. While traditionally viewed as a barrier to axon regeneration, beneficial functions of the glial scar have also been recently identified. In this Perspective, we discuss the divergent roles of the glial scar during CNS regeneration and explore the possibility that these disparities are due to functional heterogeneity within the cells of the glial scar—specifically, astrocytes, NG2 glia and microglia.

    更新日期:2017-12-22
  • Promoting diversity in neuroscience
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-21

    Promoting diversity in neurosciencePromoting diversity in neuroscience, Published online: 21 December 2017; doi:10.1038/s41593-017-0052-6Neuroscience is not spared from wrestling with gender disparity issues. Progress toward more balanced representation has been slow, but improvement is possible with consistent and focused efforts.

    更新日期:2017-12-22
  • From entorhinal neural codes to navigation
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-21
    Caitlin S. Mallory, Lisa M. Giocomo

    From entorhinal neural codes to navigationFrom entorhinal neural codes to navigation, Published online: 21 December 2017; doi:10.1038/s41593-017-0048-2The medial entorhinal cortex contains spatially selective grid cells, whose lattice-like firing patterns are proposed to support path-integration-based navigation. However, direct behavioral evidence has been lacking. Gil et al. disrupt grid cells in a targeted manner, establishing a clear link between grid cell codes and navigation.

    更新日期:2017-12-22
  • Calcium control of myelin sheath growth
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-21
    Robert H. Miller

    Calcium control of myelin sheath growthCalcium control of myelin sheath growth, Published online: 21 December 2017; doi:10.1038/s41593-017-0043-7New studies provide compelling evidence that the number and length of myelin sheaths generated by oligodendrocytes in the CNS are controlled by local calcium levels, linking axonal activity to individual myelin sheath formation.

    更新日期:2017-12-22
  • Munc13 marks the spot
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-21
    Timothy A. Ryan

    Munc13 marks the spotMunc13 marks the spot, Published online: 21 December 2017; doi:10.1038/s41593-017-0042-8Super-resolution optical imaging of presynaptic terminals shows that a protein essential to all known forms of neurotransmitter release is clustered in small assemblies that likely correspond to release sites for synaptic vesicle fusion.

    更新日期:2017-12-22
  • Publisher Correction: Viewpoints: how the hippocampus contributes to memory, navigation and cognition
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-20
    John Lisman, György Buzsáki, Howard Eichenbaum, Lynn Nadel, Charan Ranganath, A David Redish

    Publisher Correction: Viewpoints: how the hippocampus contributes to memory, navigation and cognition Publisher Correction: Viewpoints: how the hippocampus contributes to memory, navigation and cognition, Published online: 20 December 2017; doi:10.1038/s41593-017-0034-8 Publisher Correction: Viewpoints: how the hippocampus contributes to memory, navigation and cognition

    更新日期:2017-12-20
  • Author Correction: Synuclein and dopamine: the Bonnie and Clyde of Parkinson's disease
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-20
    Subhojit Roy

    Author Correction: Synuclein and dopamine: the Bonnie and Clyde of Parkinson's disease Author Correction: Synuclein and dopamine: the Bonnie and Clyde of Parkinson's disease, Published online: 20 December 2017; doi:10.1038/s41593-017-0035-7 Author Correction: Synuclein and dopamine: the Bonnie and Clyde of Parkinson's disease

    更新日期:2017-12-20
  • Publisher Correction: An interactive framework for whole-brain maps at cellular resolution
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-18
    Daniel Fürth, Thomas Vaissière, Ourania Tzortzi, Yang Xuan, Antje Märtin, Iakovos Lazaridis, Giada Spigolon, Gilberto Fisone, Raju Tomer, Karl Deisseroth, Marie Carlén, Courtney A. Miller, Gavin Rumbaugh, Konstantinos Meletis

    Publisher Correction: An interactive framework for whole-brain maps at cellular resolution Publisher Correction: An interactive framework for whole-brain maps at cellular resolution, Published online: 18 December 2017; doi:10.1038/s41593-017-0058-0 Publisher Correction: An interactive framework for whole-brain maps at cellular resolution

    更新日期:2017-12-18
  • Genome-wide association study of delay discounting in 23,217 adult research participants of European ancestry
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-11
    Sandra Sanchez-Roige, Pierre Fontanillas, Sarah L. Elson, Anita Pandit, Ellen M. Schmidt, Johanna R. Foerster, Gonçalo R. Abecasis, Joshua C. Gray, Harriet de Wit, Lea K. Davis, James MacKillop, Abraham A. Palmer

    Delay discounting (DD), the tendency to discount the value of delayed versus current rewards, is elevated in a constellation of diseases and behavioral conditions. We performed a genome-wide association study of DD using 23,127 research participants of European ancestry. The most significantly associated single-nucleotide polymorphism was rs6528024 (P = 2.40 × 10−8), which is located in an intron of the gene GPM6B. We also showed that 12% of the variance in DD was accounted for by genotype and that the genetic signature of DD overlapped with attention-deficit/hyperactivity disorder, schizophrenia, major depression, smoking, personality, cognition and body weight.

    更新日期:2017-12-11
  • Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-11
    Sinisa Hrvatin, Daniel R. Hochbaum, M. Aurel Nagy, Marcelo Cicconet, Keiramarie Robertson, Lucas Cheadle, Rapolas Zilionis, Alex Ratner, Rebeca Borges-Monroy, Allon M. Klein, Bernardo L. Sabatini, Michael E. Greenberg

    Activity-dependent transcriptional responses shape cortical function. However, a comprehensive understanding of the diversity of these responses across the full range of cortical cell types, and how these changes contribute to neuronal plasticity and disease, is lacking. To investigate the breadth of transcriptional changes that occur across cell types in the mouse visual cortex after exposure to light, we applied high-throughput single-cell RNA sequencing. We identified significant and divergent transcriptional responses to stimulation in each of the 30 cell types characterized, thus revealing 611 stimulus-responsive genes. Excitatory pyramidal neurons exhibited inter- and intralaminar heterogeneity in the induction of stimulus-responsive genes. Non-neuronal cells showed clear transcriptional responses that may regulate experience-dependent changes in neurovascular coupling and myelination. Together, these results reveal the dynamic landscape of the stimulus-dependent transcriptional changes occurring across cell types in the visual cortex; these changes are probably critical for cortical function and may be sites of deregulation in developmental brain disorders.

    更新日期:2017-12-11
  • Integration of grid maps in merged environments
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-11
    Tanja Wernle, Torgeir Waaga, Maria Mørreaunet, Alessandro Treves, May-Britt Moser, Edvard I. Moser

    Natural environments are represented by local maps of grid cells and place cells that are stitched together. The manner by which transitions between map fragments are generated is unknown. We recorded grid cells while rats were trained in two rectangular compartments, A and B (each 1 m × 2 m), separated by a wall. Once distinct grid maps were established in each environment, we removed the partition and allowed the rat to explore the merged environment (2 m × 2 m). The grid patterns were largely retained along the distal walls of the box. Nearer the former partition line, individual grid fields changed location, resulting almost immediately in local spatial periodicity and continuity between the two original maps. Grid cells belonging to the same grid module retained phase relationships during the transformation. Thus, when environments are merged, grid fields reorganize rapidly to establish spatial periodicity in the area where the environments meet.

    更新日期:2017-12-11
  • Impaired path integration in mice with disrupted grid cell firing
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-11
    Mariana Gil, Mihai Ancau, Magdalene I. Schlesiger, Angela Neitz, Kevin Allen, Rodrigo J. De Marco, Hannah Monyer

    Path integration (PI) is a highly conserved, self-motion-based navigation strategy. Since the discovery of grid cells in the medial entorhinal cortex, neurophysiological data and computational models have suggested that these neurons serve PI. However, more direct empirical evidence supporting this hypothesis has been missing due to a lack of selective manipulations of grid cell activity and suitable behavioral assessments. Here we report that selective disruption of grid cell activity in mice can be achieved by removing NMDA glutamate receptors from the retro-hippocampal region and that disrupted grid cell firing accounts for impaired PI performance. Notably, the genetic manipulation did not affect the activity of other spatially selective cells in the medial entorhinal cortex and the hippocampus. By directly linking grid cell activity to PI, these results contribute to a better understanding of how grid cells support navigation and spatial memory.

    更新日期:2017-12-11
  • The C-terminal tails of endogenous GluA1 and GluA2 differentially contribute to hippocampal synaptic plasticity and learning
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-11
    Zikai Zhou, An Liu, Shuting Xia, Celeste Leung, Junxia Qi, Yanghong Meng, Wei Xie, Pojeong Park, Graham L. Collingridge, Zhengping Jia

    Long-term potentiation (LTP) and depression (LTD) at glutamatergic synapses are intensively investigated processes for understanding the synaptic basis for learning and memory, but the underlying molecular mechanisms remain poorly understood. We have made three mouse lines where the C-terminal domains (CTDs) of endogenous AMPA receptors (AMPARs), the principal mediators of fast excitatory synaptic transmission, are specifically exchanged. These mice display profound deficits in synaptic plasticity without any effects on basal synaptic transmission. Our study reveals that the CTDs of GluA1 and GluA2, the key subunits of AMPARs, are necessary and sufficient to drive NMDA receptor–dependent LTP and LTD, respectively. In addition, these domains exert differential effects on spatial and contextual learning and memory. These results establish dominant roles of AMPARs in governing bidirectional synaptic and behavioral plasticity in the CNS.

    更新日期:2017-12-11
  • Synaptic weight set by Munc13-1 supramolecular assemblies
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-11
    Hirokazu Sakamoto, Tetsuroh Ariyoshi, Naoya Kimpara, Kohtaroh Sugao, Isamu Taiko, Kenji Takikawa, Daisuke Asanuma, Shigeyuki Namiki, Kenzo Hirose

    The weight of synaptic connections, which is controlled not only postsynaptically but also presynaptically, is a key determinant in neuronal network dynamics. The mechanisms controlling synaptic weight, especially on the presynaptic side, remain elusive. Using single-synapse imaging of the neurotransmitter glutamate combined with super-resolution imaging of presynaptic proteins, we identify a presynaptic mechanism for setting weight in central glutamatergic synapses. In the presynaptic terminal, Munc13-1 molecules form multiple and discrete supramolecular self-assemblies that serve as independent vesicular release sites by recruiting syntaxin-1, a soluble N-ethylmaleimide-sensitive-factor attachment receptor (SNARE) protein essential for synaptic vesicle exocytosis. The multiplicity of these Munc13-1 assemblies affords multiple stable states conferring presynaptic weight, potentially encoding several bits of information at individual synapses. Supramolecular assembling enables a stable synaptic weight, which confers robustness of synaptic computation on neuronal circuits and may be a general mechanism by which biological processes operate despite the presence of molecular noise.

    更新日期:2017-12-11
  • Ca 2+ activity signatures of myelin sheath formation and growth in vivo
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-11
    Marion Baraban, Sigrid Koudelka, David A. Lyons

    During myelination, individual oligodendrocytes initially over-produce short myelin sheaths, which are either retracted or stabilized. By live-imaging oligodendrocyte Ca2+ activity in vivo, we find that high-amplitude, long-duration Ca2+ transients in sheaths prefigure retractions, mediated by calpain. Following stabilization, myelin sheaths grow along axons, and we find that higher-frequency Ca2+ transient activity in sheaths precedes faster elongation. Our data implicate local Ca2+ signaling in regulating distinct stages of myelination.

    更新日期:2017-12-11
  • Synaptotagmin-1 drives synchronous Ca2+-triggered fusion by C2B-domain-mediated synaptic-vesicle-membrane attachment
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-11
    Shuwen Chang, Thorsten Trimbuch, Christian Rosenmund

    The synaptic vesicle (SV) protein synaptotagmin-1 (Syt1) is the Ca2+ sensor for fast synchronous release. Biochemical and structural data suggest that Syt1 interacts with phospholipids and SNARE complex, but the manner in which these interactions translate into SV fusion remains poorly understood. Using flash-and-freeze electron microscopy, which triggers action potentials with light and coordinately arrests synaptic structures with rapid freezing, we found that synchronous-release-impairing mutations in the Syt1 C2B domain (K325, 327; R398, 399) also disrupt SV-active-zone plasma-membrane attachment. Single action potential induction rescued membrane attachment in these mutants within less than 10 ms through activation of the Syt1 Ca2+-binding site. The rapid SV membrane translocation temporarily correlates with resynchronization of release and paired pulse facilitation. On the basis of these findings, we redefine the role of Syt1 as part of the Ca2+-dependent vesicle translocation machinery and propose that Syt1 enables fast neurotransmitter release by means of its dynamic membrane attachment activities.

    更新日期:2017-12-11
  • An interactive framework for whole-brain maps at cellular resolution
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-04
    Daniel Fürth, Thomas Vaissière, Ourania Tzortzi, Yang Xuan, Antje Märtin, Iakovos Lazaridis, Giada Spigolon, Gilberto Fisone, Raju Tomer, Karl Deisseroth, Marie Carlén, Courtney A. Miller, Gavin Rumbaugh, Konstantinos Meletis

    To deconstruct the architecture and function of brain circuits, it is necessary to generate maps of neuronal connectivity and activity on a whole-brain scale. New methods now enable large-scale mapping of the mouse brain at cellular and subcellular resolution. We developed a framework to automatically annotate, analyze, visualize and easily share whole-brain data at cellular resolution, based on a scale-invariant, interactive mouse brain atlas. This framework enables connectivity and mapping projects in individual laboratories and across imaging platforms, as well as multiplexed quantitative information on the molecular identity of single neurons. As a proof of concept, we generated a comparative connectivity map of five major neuron types in the corticostriatal circuit, as well as an activity-based map to identify hubs mediating the behavioral effects of cocaine. Thus, this computational framework provides the necessary tools to generate brain maps that integrate data from connectivity, neuron identity and function.

    更新日期:2017-12-05
  • Proteomic analysis of postsynaptic proteins in regions of the human neocortex
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-04
    Marcia Roy, Oksana Sorokina, Nathan Skene, Clémence Simonnet, Francesca Mazzo, Ruud Zwart, Emanuele Sher, Colin Smith, J. Douglas Armstrong, Seth G. N. Grant

    The postsynaptic proteome of excitatory synapses comprises ~1,000 highly conserved proteins that control the behavioral repertoire, and mutations disrupting their function cause >130 brain diseases. Here, we document the composition of postsynaptic proteomes in human neocortical regions and integrate it with genetic, functional and structural magnetic resonance imaging, positron emission tomography imaging, and behavioral data. Neocortical regions show signatures of expression of individual proteins, protein complexes, biochemical and metabolic pathways. We characterized the compositional signatures in brain regions involved with language, emotion and memory functions. Integrating large-scale GWAS with regional proteome data identifies the same cortical region for smoking behavior as found with fMRI data. The neocortical postsynaptic proteome data resource can be used to link genetics to brain imaging and behavior, and to study the role of postsynaptic proteins in localization of brain functions.

    更新日期:2017-12-05
  • Flexible timing by temporal scaling of cortical responses
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-12-04
    Jing Wang, Devika Narain, Eghbal A. Hosseini, Mehrdad Jazayeri

    Musicians can perform at different tempos, speakers can control the cadence of their speech, and children can flexibly vary their temporal expectations of events. To understand the neural basis of such flexibility, we recorded from the medial frontal cortex of nonhuman primates trained to produce different time intervals with different effectors. Neural responses were heterogeneous, nonlinear, and complex, and they exhibited a remarkable form of temporal invariance: firing rate profiles were temporally scaled to match the produced intervals. Recording from downstream neurons in the caudate and from thalamic neurons projecting to the medial frontal cortex indicated that this phenomenon originates within cortical networks. Recurrent neural network models trained to perform the task revealed that temporal scaling emerges from nonlinearities in the network and that the degree of scaling is controlled by the strength of external input. These findings demonstrate a simple and general mechanism for conferring temporal flexibility upon sensorimotor and cognitive functions.

    更新日期:2017-12-05
  • Whole genome sequencing in psychiatric disorders: the WGSPD consortium
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-28
    Stephan J. Sanders, Benjamin M. Neale, Hailiang Huang, Donna M. Werling, Joon-Yong An, Shan Dong, Goncalo Abecasis, P. Alexander Arguello, John Blangero, Michael Boehnke, Mark J. Daly, Kevin Eggan, Daniel H. Geschwind, David C. Glahn, David B. Goldstein, Raquel E. Gur, Robert E. Handsaker, Steven A. McCarroll, Roel A. Ophoff, Aarno Palotie, Carlos N. Pato, Chiara Sabatti, Matthew W. State, A. Jeremy Willsey, Steven E. Hyman, Anjene M. Addington, Thomas Lehner, Nelson B. Freimer

    Whole genome sequencing in psychiatric disorders: the WGSPD consortium Whole genome sequencing in psychiatric disorders: the WGSPD consortium, Published online: 28 November 2017; doi:10.1038/s41593-017-0017-9 As technology advances, whole genome sequencing (WGS) is likely to supersede other genotyping technologies. The rate of this change depends on its relative cost and utility. Variants identified uniquely through WGS may reveal novel biological pathways underlying complex disorders and provide high-resolution insight into when, where, and in which cell type these pathways are affected. Alternatively, cheaper and less computationally intensive approaches may yield equivalent insights. Understanding the role of rare variants in the noncoding gene-regulating genome through pilot WGS projects will be critical to determining which of these two extremes best represents reality. With large cohorts, well-defined risk loci, and a compelling need to understand the underlying biology, psychiatric disorders have a role to play in this preliminary WGS assessment. The Whole Genome Sequencing for Psychiatric Disorders Consortium will integrate data for 18,000 individuals with psychiatric disorders, beginning with autism spectrum disorder, schizophrenia, bipolar disorder, and major depressive disorder, along with over 150,000 controls.

    更新日期:2017-11-29
  • Breaking down a meal
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-28
    Mathias Pessiglione, Antonius Wiehler

    Breaking down a meal Breaking down a meal, Published online: 28 November 2017; doi:10.1038/s41593-017-0016-x To decide how much we would like to eat a food item, our brain automatically decomposes it into constituent nutrients. The quantities of the different nutrients are represented in distinct parts of the lateral orbitofrontal cortex and then integrated by the medial orbitofrontal cortex to provide a global value judgment.

    更新日期:2017-11-29
  • An opening for humor in melancholy
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-28
    E. David Leonardo, Alex Dranovsky

    An opening for humor in melancholy An opening for humor in melancholy, Published online: 28 November 2017; doi:10.1038/s41593-017-0015-y A leaky blood–brain barrier may contribute to neuropsychiatric disease. Chronic stress is shown to alter blood–brain barrier permeability, allowing an inflammatory response to penetrate the brain. The deficit is mostly around the nucleus accumbens, an area central to motivation. The affected animals exhibit features of depression.

    更新日期:2017-11-29
  • The underdog pathway gets a boost
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-28
    Brian B. Jeon, Sandra J. Kuhlman

    The underdog pathway gets a boost The underdog pathway gets a boost, Published online: 28 November 2017; doi:10.1038/s41593-017-0019-7 Sommeijer et al. describe a previously unrecognized role of the thalamus: development of inhibition in the thalamus regulates ocular dominance plasticity, a form of critical-period plasticity regulation previously ascribed solely to the cortex.

    更新日期:2017-11-29
  • Thalamic functions in distributed cognitive control
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-28
    Michael M. Halassa, Sabine Kastner

    Cognition can be conceptualized as a set of algorithmic control functions whose real-time deployment determines how an organism stores and uses information to guide thought and action. A subset of these functions is required for goal-directed selection and amplification of sensory signals—broadly referred to as attention—and for its flexible control and its interaction with processes such as working memory and decision making. While the contribution of recurrent cortical microcircuits to cognition has been extensively studied, the role of the thalamus is just beginning to be elucidated. Here we highlight recent studies across rodents and primates showing how thalamus contributes to attentional control. In addition to high-fidelity information relay to or between cortical regions, thalamic circuits shift and sustain functional interactions within and across cortical areas. This thalamic process enables rapid coordination of spatially segregated cortical computations, thereby constructing task-relevant functional networks. Because such function may be critical for cognitive flexibility, clarifying its mechanisms will likely expand our basic understanding of cognitive control and its perturbation in disease.

    更新日期:2017-11-29
  • Accumbal D2 cells orchestrate innate risk-avoidance according to orexin signals
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-27
    Craig Blomeley, Celia Garau, Denis Burdakov

    Excitation of accumbal D2 cells governs vital actions, including avoidance of learned risks, but the origins of this excitation and roles of D2 cells in innate risk-avoidance are unclear. Hypothalamic neurons producing orexins (also called hypocretins) enhance innate risk-avoidance via poorly understood neurocircuits. We describe a direct orexin→D2 excitatory circuit and show that D2 cell activity is necessary for orexin-dependent innate risk-avoidance in mice, thus revealing an unsuspected hypothalamus–accumbens interplay in action selection.

    更新日期:2017-11-28
  • Altered responses to social chemosignals in autism spectrum disorder
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-27
    Yaara Endevelt-Shapira, Ofer Perl, Aharon Ravia, Daniel Amir, Ami Eisen, Vered Bezalel, Liron Rozenkrantz, Eva Mishor, Liron Pinchover, Timna Soroka, Danielle Honigstein, Noam Sobel

    Autism spectrum disorder (ASD) is characterized by impaired social communication, often attributed to misreading of emotional cues. Why individuals with ASD misread emotions remains unclear. Given that terrestrial mammals rely on their sense of smell to read conspecific emotions, we hypothesized that misreading of emotional cues in ASD partially reflects altered social chemosignaling. We found no difference between typically developed (TD) and cognitively able adults with ASD at explicit detection and perception of social chemosignals. Nevertheless, TD and ASD participants dissociated in their responses to subliminal presentation of these same compounds: the undetected ‘smell of fear’ (skydiver sweat) increased physiological arousal and reduced explicit and implicit measures of trust in TD but acted opposite in ASD participants. Moreover, two different undetected synthetic putative social chemosignals increased or decreased arousal in TD but acted opposite in ASD participants. These results implicate social chemosignaling as a sensory substrate of social impairment in ASD.

    更新日期:2017-11-28
  • Accumbal D2 cells orchestrate innate risk-avoidance according to orexin signals
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-27
    Craig Blomeley, Celia Garau, Denis Burdakov

    Excitation of accumbal D2 cells governs vital actions, including avoidance of learned risks, but the origins of this excitation and roles of D2 cells in innate risk-avoidance are unclear. Hypothalamic neurons producing orexins (also called hypocretins) enhance innate risk-avoidance via poorly understood neurocircuits. We describe a direct orexin→D2 excitatory circuit and show that D2 cell activity is necessary for orexin-dependent innate risk-avoidance in mice, thus revealing an unsuspected hypothalamus–accumbens interplay in action selection.

    更新日期:2017-11-28
  • Altered responses to social chemosignals in autism spectrum disorder
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-27
    Yaara Endevelt-Shapira, Ofer Perl, Aharon Ravia, Daniel Amir, Ami Eisen, Vered Bezalel, Liron Rozenkrantz, Eva Mishor, Liron Pinchover, Timna Soroka, Danielle Honigstein, Noam Sobel

    Autism spectrum disorder (ASD) is characterized by impaired social communication, often attributed to misreading of emotional cues. Why individuals with ASD misread emotions remains unclear. Given that terrestrial mammals rely on their sense of smell to read conspecific emotions, we hypothesized that misreading of emotional cues in ASD partially reflects altered social chemosignaling. We found no difference between typically developed (TD) and cognitively able adults with ASD at explicit detection and perception of social chemosignals. Nevertheless, TD and ASD participants dissociated in their responses to subliminal presentation of these same compounds: the undetected ‘smell of fear’ (skydiver sweat) increased physiological arousal and reduced explicit and implicit measures of trust in TD but acted opposite in ASD participants. Moreover, two different undetected synthetic putative social chemosignals increased or decreased arousal in TD but acted opposite in ASD participants. These results implicate social chemosignaling as a sensory substrate of social impairment in ASD.

    更新日期:2017-11-28
  • Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-20
    Daniel J. Apicco, Peter E. A. Ash, Brandon Maziuk, Chelsey LeBlang, Maria Medalla, Ali Al Abdullatif, Antonio Ferragud, Emily Botelho, Heather I. Ballance, Uma Dhawan, Samantha Boudeau, Anna Lourdes Cruz, Daniel Kashy, Aria Wong, Lisa R. Goldberg, Neema Yazdani, Cheng Zhang, Choong Y. Ung, Yorghos Tripodis, Nicholas M. Kanaan, Tsuneya Ikezu, Pietro Cottone, John Leszyk, Hu Li, Jennifer Luebke, Camron D. Bryant, Benjamin Wolozin

    Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles. Despite the increase in neurofibrillary tangles, TIA1 reduction increased neuronal survival and rescued behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a model in which dysfunction of the translational stress response leads to tau-mediated pathology.

    更新日期:2017-11-21
  • Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-20
    Daniel J. Apicco, Peter E. A. Ash, Brandon Maziuk, Chelsey LeBlang, Maria Medalla, Ali Al Abdullatif, Antonio Ferragud, Emily Botelho, Heather I. Ballance, Uma Dhawan, Samantha Boudeau, Anna Lourdes Cruz, Daniel Kashy, Aria Wong, Lisa R. Goldberg, Neema Yazdani, Cheng Zhang, Choong Y. Ung, Yorghos Tripodis, Nicholas M. Kanaan, Tsuneya Ikezu, Pietro Cottone, John Leszyk, Hu Li, Jennifer Luebke, Camron D. Bryant, Benjamin Wolozin

    Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles. Despite the increase in neurofibrillary tangles, TIA1 reduction increased neuronal survival and rescued behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a model in which dysfunction of the translational stress response leads to tau-mediated pathology.

    更新日期:2017-11-21
  • Author Correction: Dorsal hippocampus contributes to model-based planning
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-17
    Kevin J. Miller, Matthew M. Botvinick, Carlos D. Brody

    Author Correction: Dorsal hippocampus contributes to model-based planning Author Correction: Dorsal hippocampus contributes to model-based planning, Published online: 17 November 2017; doi:10.1038/s41593-017-0026-8

    更新日期:2017-11-19
  • Author Correction: Dorsal hippocampus contributes to model-based planning
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-17
    Kevin J. Miller, Matthew M. Botvinick, Carlos D. Brody

    Author Correction: Dorsal hippocampus contributes to model-based planning Author Correction: Dorsal hippocampus contributes to model-based planning, Published online: 17 November 2017; doi:10.1038/s41593-017-0026-8

    更新日期:2017-11-19
  • A multiregional proteomic survey of the postnatal human brain
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-13
    Becky C. Carlyle, Robert R. Kitchen, Jean E. Kanyo, Edward Z. Voss, Mihovil Pletikos, André M. M. Sousa, TuKiet T. Lam, Mark B. Gerstein, Nenad Sestan, Angus C. Nairn

    Detailed observations of transcriptional, translational and post-translational events in the human brain are essential to improving our understanding of its development, function and vulnerability to disease. Here, we exploited label-free quantitative tandem mass-spectrometry to create an in-depth proteomic survey of regions of the postnatal human brain, ranging in age from early infancy to adulthood. Integration of protein data with existing matched whole-transcriptome sequencing (RNA-seq) from the BrainSpan project revealed varied patterns of protein–RNA relationships, with generally increased magnitudes of protein abundance differences between brain regions compared to RNA. Many of the differences amplified in protein data were reflective of cytoarchitectural and functional variation between brain regions. Comparing structurally similar cortical regions revealed significant differences in the abundances of receptor-associated and resident plasma membrane proteins that were not readily observed in the RNA expression data.

    更新日期:2017-11-13
  • Lateral geniculate neurons projecting to primary visual cortex show ocular dominance plasticity in adult mice
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-13
    Juliane Jaepel, Mark Hübener, Tobias Bonhoeffer, Tobias Rose

    Experience-dependent plasticity in the mature visual system is widely considered to be cortical. Using chronic two-photon Ca2+ imaging of thalamic afferents in layer 1 of binocular visual cortex, we provide evidence against this tenet: the respective dorsal lateral geniculate nucleus (dLGN) cells showed pronounced ocular dominance (OD) shifts after monocular deprivation in adult mice. Most (86%), but not all, of dLGN cell boutons were monocular during normal visual experience. Following deprivation, initially deprived-eye-dominated boutons reduced or lost their visual responsiveness to that eye and frequently became responsive to the non-deprived eye. This cannot be explained by eye-specific cortical changes propagating to dLGN via cortico-thalamic feedback because the shift in dLGN responses was largely resistant to cortical inactivation using the GABAA receptor agonist muscimol. Our data suggest that OD shifts observed in the binocular visual cortex of adult mice may at least partially reflect plasticity of eye-specific inputs onto dLGN neurons.

    更新日期:2017-11-13
  • Oxytocin-receptor-expressing neurons in the parabrachial nucleus regulate fluid intake
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-13
    Philip J. Ryan, Silvano I. Ross, Carlos A. Campos, Victor A. Derkach, Richard D. Palmiter

    Brain regions that regulate fluid satiation are not well characterized, yet are essential for understanding fluid homeostasis. We found that oxytocin-receptor-expressing neurons in the parabrachial nucleus of mice (OxtrPBN neurons) are key regulators of fluid satiation. Chemogenetic activation of OxtrPBN neurons robustly suppressed noncaloric fluid intake, but did not decrease food intake after fasting or salt intake following salt depletion; inactivation increased saline intake after dehydration and hypertonic saline injection. Under physiological conditions, OxtrPBN neurons were activated by fluid satiation and hypertonic saline injection. OxtrPBN neurons were directly innervated by oxytocin neurons in the paraventricular hypothalamus (OxtPVH neurons), which mildly attenuated fluid intake. Activation of neurons in the nucleus of the solitary tract substantially suppressed fluid intake and activated OxtrPBN neurons. Our results suggest that OxtrPBN neurons act as a key node in the fluid satiation neurocircuitry, which acts to decrease water and/or saline intake to prevent or attenuate hypervolemia and hypernatremia.

    更新日期:2017-11-13
  • A craniofacial-specific monosynaptic circuit enables heightened affective pain
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-13
    Erica Rodriguez, Katsuyasu Sakurai, Jennie Xu, Yong Chen, Koji Toda, Shengli Zhao, Bao-Xia Han, David Ryu, Henry Yin, Wolfgang Liedtke, Fan Wang

    Humans often rank craniofacial pain as more severe than body pain. Evidence suggests that a stimulus of the same intensity induces stronger pain in the face than in the body. However, the underlying neural circuitry for the differential processing of facial versus bodily pain remains unknown. Interestingly, the lateral parabrachial nucleus (PBL), a critical node in the affective pain circuit, is activated more strongly by noxious stimulation of the face than of the hindpaw. Using a novel activity-dependent technology called CANE developed in our laboratory, we identified and selectively labeled noxious-stimulus-activated PBL neurons and performed comprehensive anatomical input–output mapping. Surprisingly, we uncovered a hitherto uncharacterized monosynaptic connection between cranial sensory neurons and the PBL-nociceptive neurons. Optogenetic activation of this monosynaptic craniofacial-to-PBL projection induced robust escape and avoidance behaviors and stress calls, whereas optogenetic silencing specifically reduced facial nociception. The monosynaptic circuit revealed here provides a neural substrate for heightened craniofacial affective pain.

    更新日期:2017-11-13
  • Temporally precise single-cell-resolution optogenetics
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-13
    Or A. Shemesh, Dimitrii Tanese, Valeria Zampini, Changyang Linghu, Kiryl Piatkevich, Emiliano Ronzitti, Eirini Papagiakoumou, Edward S. Boyden, Valentina Emiliani

    Optogenetic control of individual neurons with high temporal precision within intact mammalian brain circuitry would enable powerful explorations of how neural circuits operate. Two-photon computer-generated holography enables precise sculpting of light and could in principle enable simultaneous illumination of many neurons in a network, with the requisite temporal precision to simulate accurate neural codes. We designed a high-efficacy soma-targeted opsin, finding that fusing the N-terminal 150 residues of kainate receptor subunit 2 (KA2) to the recently discovered high-photocurrent channelrhodopsin CoChR restricted expression of this opsin primarily to the cell body of mammalian cortical neurons. In combination with two-photon holographic stimulation, we found that this somatic CoChR (soCoChR) enabled photostimulation of individual cells in mouse cortical brain slices with single-cell resolution and <1-ms temporal precision. We used soCoChR to perform connectivity mapping on intact cortical circuits.

    更新日期:2017-11-13
  • Social stress induces neurovascular pathology promoting depression
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-13
    Caroline Menard, Madeline L. Pfau, Georgia E. Hodes, Veronika Kana, Victoria X. Wang, Sylvain Bouchard, Aki Takahashi, Meghan E. Flanigan, Hossein Aleyasin, Katherine B. LeClair, William G. Janssen, Benoit Labonté, Eric M. Parise, Zachary S. Lorsch, Sam A. Golden, Mitra Heshmati, Carol Tamminga, Gustavo Turecki, Matthew Campbell, Zahi A. Fayad, Cheuk Ying Tang, Miriam Merad, Scott J. Russo

    Studies suggest that heightened peripheral inflammation contributes to the pathogenesis of major depressive disorder. We investigated the effect of chronic social defeat stress, a mouse model of depression, on blood–brain barrier (BBB) permeability and infiltration of peripheral immune signals. We found reduced expression of the endothelial cell tight junction protein claudin-5 (Cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 downregulation was sufficient to induce depression-like behaviors following subthreshold social stress whereas chronic antidepressant treatment rescued Cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or mice injected with adeno-associated virus expressing shRNA against Cldn5 caused infiltration of the peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors. These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein Cldn5, promoting peripheral IL-6 passage across the BBB and depression.

    更新日期:2017-11-13
  • A multiregional proteomic survey of the postnatal human brain
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-13
    Becky C. Carlyle, Robert R. Kitchen, Jean E. Kanyo, Edward Z. Voss, Mihovil Pletikos, André M. M. Sousa, TuKiet T. Lam, Mark B. Gerstein, Nenad Sestan, Angus C. Nairn

    Detailed observations of transcriptional, translational and post-translational events in the human brain are essential to improving our understanding of its development, function and vulnerability to disease. Here, we exploited label-free quantitative tandem mass-spectrometry to create an in-depth proteomic survey of regions of the postnatal human brain, ranging in age from early infancy to adulthood. Integration of protein data with existing matched whole-transcriptome sequencing (RNA-seq) from the BrainSpan project revealed varied patterns of protein–RNA relationships, with generally increased magnitudes of protein abundance differences between brain regions compared to RNA. Many of the differences amplified in protein data were reflective of cytoarchitectural and functional variation between brain regions. Comparing structurally similar cortical regions revealed significant differences in the abundances of receptor-associated and resident plasma membrane proteins that were not readily observed in the RNA expression data.

    更新日期:2017-11-13
  • Lateral geniculate neurons projecting to primary visual cortex show ocular dominance plasticity in adult mice
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-13
    Juliane Jaepel, Mark Hübener, Tobias Bonhoeffer, Tobias Rose

    Experience-dependent plasticity in the mature visual system is widely considered to be cortical. Using chronic two-photon Ca2+ imaging of thalamic afferents in layer 1 of binocular visual cortex, we provide evidence against this tenet: the respective dorsal lateral geniculate nucleus (dLGN) cells showed pronounced ocular dominance (OD) shifts after monocular deprivation in adult mice. Most (86%), but not all, of dLGN cell boutons were monocular during normal visual experience. Following deprivation, initially deprived-eye-dominated boutons reduced or lost their visual responsiveness to that eye and frequently became responsive to the non-deprived eye. This cannot be explained by eye-specific cortical changes propagating to dLGN via cortico-thalamic feedback because the shift in dLGN responses was largely resistant to cortical inactivation using the GABAA receptor agonist muscimol. Our data suggest that OD shifts observed in the binocular visual cortex of adult mice may at least partially reflect plasticity of eye-specific inputs onto dLGN neurons.

    更新日期:2017-11-13
  • Oxytocin-receptor-expressing neurons in the parabrachial nucleus regulate fluid intake
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-13
    Philip J. Ryan, Silvano I. Ross, Carlos A. Campos, Victor A. Derkach, Richard D. Palmiter

    Brain regions that regulate fluid satiation are not well characterized, yet are essential for understanding fluid homeostasis. We found that oxytocin-receptor-expressing neurons in the parabrachial nucleus of mice (OxtrPBN neurons) are key regulators of fluid satiation. Chemogenetic activation of OxtrPBN neurons robustly suppressed noncaloric fluid intake, but did not decrease food intake after fasting or salt intake following salt depletion; inactivation increased saline intake after dehydration and hypertonic saline injection. Under physiological conditions, OxtrPBN neurons were activated by fluid satiation and hypertonic saline injection. OxtrPBN neurons were directly innervated by oxytocin neurons in the paraventricular hypothalamus (OxtPVH neurons), which mildly attenuated fluid intake. Activation of neurons in the nucleus of the solitary tract substantially suppressed fluid intake and activated OxtrPBN neurons. Our results suggest that OxtrPBN neurons act as a key node in the fluid satiation neurocircuitry, which acts to decrease water and/or saline intake to prevent or attenuate hypervolemia and hypernatremia.

    更新日期:2017-11-13
  • A craniofacial-specific monosynaptic circuit enables heightened affective pain
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-13
    Erica Rodriguez, Katsuyasu Sakurai, Jennie Xu, Yong Chen, Koji Toda, Shengli Zhao, Bao-Xia Han, David Ryu, Henry Yin, Wolfgang Liedtke, Fan Wang

    Humans often rank craniofacial pain as more severe than body pain. Evidence suggests that a stimulus of the same intensity induces stronger pain in the face than in the body. However, the underlying neural circuitry for the differential processing of facial versus bodily pain remains unknown. Interestingly, the lateral parabrachial nucleus (PBL), a critical node in the affective pain circuit, is activated more strongly by noxious stimulation of the face than of the hindpaw. Using a novel activity-dependent technology called CANE developed in our laboratory, we identified and selectively labeled noxious-stimulus-activated PBL neurons and performed comprehensive anatomical input–output mapping. Surprisingly, we uncovered a hitherto uncharacterized monosynaptic connection between cranial sensory neurons and the PBL-nociceptive neurons. Optogenetic activation of this monosynaptic craniofacial-to-PBL projection induced robust escape and avoidance behaviors and stress calls, whereas optogenetic silencing specifically reduced facial nociception. The monosynaptic circuit revealed here provides a neural substrate for heightened craniofacial affective pain.

    更新日期:2017-11-13
  • Temporally precise single-cell-resolution optogenetics
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-13
    Or A. Shemesh, Dimitrii Tanese, Valeria Zampini, Changyang Linghu, Kiryl Piatkevich, Emiliano Ronzitti, Eirini Papagiakoumou, Edward S. Boyden, Valentina Emiliani

    Optogenetic control of individual neurons with high temporal precision within intact mammalian brain circuitry would enable powerful explorations of how neural circuits operate. Two-photon computer-generated holography enables precise sculpting of light and could in principle enable simultaneous illumination of many neurons in a network, with the requisite temporal precision to simulate accurate neural codes. We designed a high-efficacy soma-targeted opsin, finding that fusing the N-terminal 150 residues of kainate receptor subunit 2 (KA2) to the recently discovered high-photocurrent channelrhodopsin CoChR restricted expression of this opsin primarily to the cell body of mammalian cortical neurons. In combination with two-photon holographic stimulation, we found that this somatic CoChR (soCoChR) enabled photostimulation of individual cells in mouse cortical brain slices with single-cell resolution and <1-ms temporal precision. We used soCoChR to perform connectivity mapping on intact cortical circuits.

    更新日期:2017-11-13
  • Social stress induces neurovascular pathology promoting depression
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-13
    Caroline Menard, Madeline L. Pfau, Georgia E. Hodes, Veronika Kana, Victoria X. Wang, Sylvain Bouchard, Aki Takahashi, Meghan E. Flanigan, Hossein Aleyasin, Katherine B. LeClair, William G. Janssen, Benoit Labonté, Eric M. Parise, Zachary S. Lorsch, Sam A. Golden, Mitra Heshmati, Carol Tamminga, Gustavo Turecki, Matthew Campbell, Zahi A. Fayad, Cheuk Ying Tang, Miriam Merad, Scott J. Russo

    Studies suggest that heightened peripheral inflammation contributes to the pathogenesis of major depressive disorder. We investigated the effect of chronic social defeat stress, a mouse model of depression, on blood–brain barrier (BBB) permeability and infiltration of peripheral immune signals. We found reduced expression of the endothelial cell tight junction protein claudin-5 (Cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 downregulation was sufficient to induce depression-like behaviors following subthreshold social stress whereas chronic antidepressant treatment rescued Cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or mice injected with adeno-associated virus expressing shRNA against Cldn5 caused infiltration of the peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors. These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein Cldn5, promoting peripheral IL-6 passage across the BBB and depression.

    更新日期:2017-11-13
  • Weak correlations between hemodynamic signals and ongoing neural activity during the resting state
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-11-06
    Aaron T. Winder, Christina Echagarruga, Qingguang Zhang, Patrick J. Drew

    Spontaneous fluctuations in hemodynamic signals in the absence of a task or overt stimulation are used to infer neural activity. We tested this coupling by simultaneously measuring neural activity and changes in cerebral blood volume (CBV) in the somatosensory cortex of awake, head-fixed mice during periods of true rest and during whisker stimulation and volitional whisking. We found that neurovascular coupling was similar across states and that large, spontaneous CBV changes in the absence of sensory input were driven by volitional whisker and body movements. Hemodynamic signals during periods of rest were weakly correlated with neural activity. Spontaneous fluctuations in CBV and vessel diameter persisted when local neural spiking and glutamatergic input were blocked, as well as during blockade of noradrenergic receptors, suggesting a non-neuronal origin for spontaneous CBV fluctuations. Spontaneous hemodynamic signals reflect a combination of behavior, local neural activity, and putatively non-neural processes.

    更新日期:2017-11-06
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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