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ISSN (Print) 0896-6273 - ISSN (Online) 1097-4199
Published by Elsevier Homepage  [3177 journals]
  • A Genetic Model of the Connectome
    • Abstract: Publication date: Available online 2 December 2019Source: NeuronAuthor(s): Dániel L. Barabási, Albert-László BarabásiSummaryThe connectomes of organisms of the same species show remarkable architectural and often local wiring similarity, raising the question: where and how is neuronal connectivity encoded' Here, we start from the hypothesis that the genetic identity of neurons guides synapse and gap-junction formation and show that such genetically driven wiring predicts the existence of specific biclique motifs in the connectome. We identify a family of large, statistically significant biclique subgraphs in the connectomes of three species and show that within many of the observed bicliques the neurons share statistically significant expression patterns and morphological characteristics, supporting our expectation of common genetic factors that drive the synapse formation within these subgraphs. The proposed connectome model offers a self-consistent framework to link the genetics of an organism to the reproducible architecture of its connectome, offering experimentally falsifiable predictions on the genetic factors that drive the formation of individual neuronal circuits.
  • Regulation of Recurrent Inhibition by Asynchronous Glutamate Release in
    • Abstract: Publication date: Available online 2 December 2019Source: NeuronAuthor(s): Suixin Deng, Junlong Li, Quansheng He, Xiaoxue Zhang, Jie Zhu, Liang Li, Zhen Mi, Xiufeng Yang, Man Jiang, Qiang Dong, Ying Mao, Yousheng ShuSummaryThe timing and size of inhibition are crucial for dynamic excitation-inhibition balance and information processing in the neocortex. The underlying mechanism for temporal control of inhibition remains unclear. We performed dual whole-cell recordings from pyramidal cells (PCs) and nearby inhibitory interneurons in layer 5 of rodent neocortical slices. We found asynchronous release (AR) of glutamate occurs at PC output synapses onto Martinotti cells (MCs), causing desynchronized and prolonged firing in MCs and thus imprecise and long-lasting inhibition in neighboring PCs. AR is much stronger at PC-MC synapses as compared with those onto fast-spiking cells and other PCs, and it is also dependent on PC subtypes, with crossed-corticostriatal PCs producing the strongest AR. Moreover, knocking out synaptotagmin-7 substantially reduces AR strength and recurrent inhibition. Our results highlight the effect of glutamate AR on the operation of microcircuits mediating slow recurrent inhibition, an important mechanism for controlling the timing and size of cortical inhibition.Graphical Graphical abstract for this article
  • Two Distinct Neural Timescales for Predictive Speech Processing
    • Abstract: Publication date: Available online 2 December 2019Source: NeuronAuthor(s): Peter W. Donhauser, Sylvain BailletSummaryDuring speech listening, the brain could use contextual predictions to optimize sensory sampling and processing. We asked if such predictive processing is organized dynamically into separate oscillatory timescales. We trained a neural network that uses context to predict speech at the phoneme level. Using this model, we estimated contextual uncertainty and surprise of natural speech as factors to explain neurophysiological activity in human listeners. We show, first, that speech-related activity is hierarchically organized into two timescales: fast responses (theta: 4–10 Hz), restricted to early auditory regions, and slow responses (delta: 0.5–4 Hz), dominating in downstream auditory regions. Neural activity in these bands is selectively modulated by predictions: the gain of early theta responses varies according to the contextual uncertainty of speech, while later delta responses are selective to surprising speech inputs. We conclude that theta sensory sampling is tuned to maximize expected information gain, while delta encodes only non-redundant information.
  • Discovering Precise Temporal Patterns in Large-Scale Neural Recordings
           through Robust and Interpretable Time Warping
    • Abstract: Publication date: Available online 27 November 2019Source: NeuronAuthor(s): Alex H. Williams, Ben Poole, Niru Maheswaranathan, Ashesh K. Dhawale, Tucker Fisher, Christopher D. Wilson, David H. Brann, Eric M. Trautmann, Stephen Ryu, Roman Shusterman, Dmitry Rinberg, Bence P. Ölveczky, Krishna V. Shenoy, Surya GanguliSummaryThough the temporal precision of neural computation has been studied intensively, a data-driven determination of this precision remains a fundamental challenge. Reproducible spike patterns may be obscured on single trials by uncontrolled temporal variability in behavior and cognition and may not be time locked to measurable signatures in behavior or local field potentials (LFP). To overcome these challenges, we describe a general-purpose time warping framework that reveals precise spike-time patterns in an unsupervised manner, even when these patterns are decoupled from behavior or are temporally stretched across single trials. We demonstrate this method across diverse systems: cued reaching in nonhuman primates, motor sequence production in rats, and olfaction in mice. This approach flexibly uncovers diverse dynamical firing patterns, including pulsatile responses to behavioral events, LFP-aligned oscillatory spiking, and even unanticipated patterns, such as 7 Hz oscillations in rat motor cortex that are not time locked to measured behaviors or LFP.Graphical Graphical abstract for this article
  • Rewiring Neuronal Glycerolipid Metabolism Determines the Extent of Axon
    • Abstract: Publication date: Available online 27 November 2019Source: NeuronAuthor(s): Chao Yang, Xu Wang, Jianying Wang, Xuejie Wang, Weitao Chen, Na Lu, Symeon Siniossoglou, Zhongping Yao, Kai LiuSummaryHow adult neurons coordinate lipid metabolism to regenerate axons remains elusive. We found that depleting neuronal lipin1, a key enzyme controlling the balanced synthesis of glycerolipids through the glycerol phosphate pathway, enhanced axon regeneration after optic nerve injury. Axotomy elevated lipin1 in retinal ganglion cells, which contributed to regeneration failure in the CNS by favorably producing triglyceride (TG) storage lipids rather than phospholipid (PL) membrane lipids in neurons. Regrowth induced by lipin1 depletion required TG hydrolysis and PL synthesis. Decreasing TG synthesis by deleting neuronal diglyceride acyltransferases (DGATs) and enhancing PL synthesis through the Kennedy pathway promoted axon regeneration. In addition, peripheral neurons adopted this mechanism for their spontaneous axon regeneration. Our study reveals a critical role of lipin1 and DGATs as intrinsic regulators of glycerolipid metabolism in neurons and indicates that directing neuronal lipid synthesis away from TG synthesis and toward PL synthesis may promote axon regeneration.Graphical Graphical abstract for this article
  • Nested Neuronal Dynamics Orchestrate a Behavioral Hierarchy across
    • Abstract: Publication date: Available online 27 November 2019Source: NeuronAuthor(s): Harris S. Kaplan, Oriana Salazar Thula, Niklas Khoss, Manuel ZimmerSummaryClassical and modern ethological studies suggest that animal behavior is organized hierarchically across timescales, such that longer-timescale behaviors are composed of specific shorter-timescale actions. Despite progress relating neuronal dynamics to single-timescale behavior, it remains unclear how different timescale dynamics interact to give rise to such higher-order behavioral organization. Here, we show, in the nematode Caenorhabditis elegans, that a behavioral hierarchy spanning three timescales is implemented by nested neuronal dynamics. At the uppermost hierarchical level, slow neuronal population dynamics spanning brain and motor periphery control two faster motor neuron oscillations, toggling them between different activity states and functional roles. At lower hierarchical levels, these faster oscillations are further nested in a manner that enables flexible behavioral control in an otherwise rigid hierarchical framework. Our findings establish nested neuronal activity patterns as a repeated dynamical motif of the C. elegans nervous system, which together implement a controllable hierarchical organization of behavior.Graphical Graphical abstract for this article
  • CaMKII Measures the Passage of Time to Coordinate Behavior and
           Motivational State
    • Abstract: Publication date: Available online 27 November 2019Source: NeuronAuthor(s): Stephen C. Thornquist, Kirill Langer, Stephen X. Zhang, Dragana Rogulja, Michael A. CrickmoreSummaryElectrical events in neurons occur on the order of milliseconds, but the brain can process and reproduce intervals millions of times longer. We present what we believe to be the first neuronal mechanism for timing intervals longer than a few seconds. The activation and gradual relaxation of calcium-independent CaMKII measure a 6-min time window to coordinate two male-specific events during Drosophila mating: sperm transfer and a simultaneous decrease in motivation. We localize these functions to four neurons whose electrical activity is necessary only to report the conclusion of the decline in CaMKII’s activity, not for the measurement of the interval. The computation of elapsed time is therefore largely invisible to standard methods of monitoring neuronal activity. Its broad conservation, ubiquitous expression, and tunable duration of activity suggest that CaMKII may time a wide variety of behavioral and cognitive processes.
  • Branched Photoswitchable Tethered Ligands Enable Ultra-efficient Optical
           Control and Detection of G Protein-Coupled Receptors In Vivo
    • Abstract: Publication date: Available online 26 November 2019Source: NeuronAuthor(s): Amanda Acosta-Ruiz, Vanessa A. Gutzeit, Mary Jane Skelly, Samantha Meadows, Joon Lee, Puja Parekh, Anna G. Orr, Conor Liston, Kristen E. Pleil, Johannes Broichhagen, Joshua LevitzSummaryThe limitations of classical drugs have spurred the development of covalently tethered photoswitchable ligands to control neuromodulatory receptors. However, a major shortcoming of tethered photopharmacology is the inability to obtain optical control with an efficacy comparable with that of the native ligand. To overcome this, we developed a family of branched photoswitchable compounds to target metabotropic glutamate receptors (mGluRs). These compounds permit photo-agonism of Gi/o-coupled group II mGluRs with near-complete efficiency relative to glutamate when attached to receptors via a range of orthogonal, multiplexable modalities. Through a chimeric approach, branched ligands also allow efficient optical control of Gq-coupled mGluR5, which we use to probe the spatiotemporal properties of receptor-induced calcium oscillations. In addition, we report branched, photoswitch-fluorophore compounds for simultaneous receptor imaging and manipulation. Finally, we demonstrate this approach in vivo in mice, where photoactivation of SNAP-mGluR2 in the medial prefrontal cortex reversibly modulates working memory in normal and disease-associated states.
  • Cortical Output Is Gated by Horizontally Projecting Neurons in the Deep
    • Abstract: Publication date: Available online 26 November 2019Source: NeuronAuthor(s): Robert Egger, Rajeevan T. Narayanan, Jason M. Guest, Arco Bast, Daniel Udvary, Luis F. Messore, Suman Das, Christiaan P.J. de Kock, Marcel OberlaenderSummaryPyramidal tract neurons (PTs) represent the major output cell type of the mammalian neocortex. Here, we report the origins of the PTs’ ability to respond to a broad range of stimuli with onset latencies that rival or even precede those of their intracortical input neurons. We find that neurons with extensive horizontally projecting axons cluster around the deep-layer terminal fields of primary thalamocortical axons. The strategic location of these corticocortical neurons results in high convergence of thalamocortical inputs, which drive reliable sensory-evoked responses that precede those in other excitatory cell types. The resultant fast and horizontal stream of excitation provides PTs throughout the cortical area with input that acts to amplify additional inputs from thalamocortical and other intracortical populations. The fast onsets and broadly tuned characteristics of PT responses hence reflect a gating mechanism in the deep layers, which assures that sensory-evoked input can be reliably transformed into cortical output.
  • Single-Cell Profiles of Retinal Ganglion Cells Differing in Resilience to
           Injury Reveal Neuroprotective Genes
    • Abstract: Publication date: Available online 26 November 2019Source: NeuronAuthor(s): Nicholas M. Tran, Karthik Shekhar, Irene E. Whitney, Anne Jacobi, Inbal Benhar, Guosong Hong, Wenjun Yan, Xian Adiconis, McKinzie E. Arnold, Jung Min Lee, Joshua Z. Levin, Dingchang Lin, Chen Wang, Charles M. Lieber, Aviv Regev, Zhigang He, Joshua R. SanesSummaryNeuronal types in the central nervous system differ dramatically in their resilience to injury or other insults. Here we studied the selective resilience of mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC), which severs their axons and leads to death of ∼80% of RGCs within 2 weeks. To identify expression programs associated with differential resilience, we first used single-cell RNA-seq (scRNA-seq) to generate a comprehensive molecular atlas of 46 RGC types in adult retina. We then tracked their survival after ONC; characterized transcriptomic, physiological, and morphological changes that preceded degeneration; and identified genes selectively expressed by each type. Finally, using loss- and gain-of-function assays in vivo, we showed that manipulating some of these genes improved neuronal survival and axon regeneration following ONC. This study provides a systematic framework for parsing type-specific responses to injury and demonstrates that differential gene expression can be used to reveal molecular targets for intervention.Graphical Graphical abstract for this article
  • Routing of Hippocampal Ripples to Subcortical Structures via the Lateral
    • Abstract: Publication date: Available online 26 November 2019Source: NeuronAuthor(s): David Tingley, György BuzsákiSummaryThe mnemonic functions of hippocampal sharp wave ripples (SPW-Rs) have been studied extensively. Because hippocampal outputs affect not only cortical but also subcortical targets, we examined the impact of SPW-Rs on the firing patterns of lateral septal (LS) neurons in behaving rats. A large fraction of SPW-Rs were temporally locked to high-frequency oscillations (HFOs) (120–180 Hz) in LS, with strongest coupling during non-rapid eye movement (NREM) sleep, followed by waking immobility. However, coherence and spike-local field potential (LFP) coupling between the two structures were low, suggesting that HFOs are generated locally within the LS GABAergic population. This hypothesis was supported by optogenetic induction of HFOs in LS. Spiking of LS neurons was largely independent of the sequential order of spiking in SPW-Rs but instead correlated with the magnitude of excitatory synchrony of the hippocampal output. Thus, LS is strongly activated by SPW-Rs and may convey hippocampal population events to its hypothalamic and brainstem targets.
  • GABAergic Restriction of Network Dynamics Regulates Interneuron Survival
           in the Developing Cortex
    • Abstract: Publication date: Available online 25 November 2019Source: NeuronAuthor(s): Zhe Ran S. Duan, Alicia Che, Philip Chu, Laura Modol, Yannick Bollmann, Rachel Babij, Robert N. Fetcho, Takumi Otsuka, Marc V. Fuccillo, Conor Liston, David J. Pisapia, Rosa Cossart, Natalia V. De Marco GarcíaSummaryDuring neonatal development, sensory cortices generate spontaneous activity patterns shaped by both sensory experience and intrinsic influences. How these patterns contribute to the assembly of neuronal circuits is not clearly understood. Using longitudinal in vivo calcium imaging in un-anesthetized mouse pups, we show that spatially segregated functional assemblies composed of interneurons and pyramidal cells are prominent in the somatosensory cortex by postnatal day (P) 7. Both reduction of GABA release and synaptic inputs onto pyramidal cells erode the emergence of functional topography, leading to increased network synchrony. This aberrant pattern effectively blocks interneuron apoptosis, causing increased survival of parvalbumin and somatostatin interneurons. Furthermore, the effect of GABA on apoptosis is mediated by inputs from medial ganglionic eminence (MGE)-derived but not caudal ganglionic eminence (CGE)-derived interneurons. These findings indicate that immature MGE interneurons are fundamental for shaping GABA-driven activity patterns that balance the number of interneurons integrating into maturing cortical networks.Graphical Graphical abstract for this article
  • CUL3 Deficiency Causes Social Deficits and Anxiety-like Behaviors by
           Impairing Excitation-Inhibition Balance through the Promotion of
           Cap-Dependent Translation
    • Abstract: Publication date: Available online 25 November 2019Source: NeuronAuthor(s): Zhaoqi Dong, Wenbing Chen, Chao Chen, Hongsheng Wang, Wanpeng Cui, Zhibing Tan, Heath Robinson, Nannan Gao, Bin Luo, Lei Zhang, Kai Zhao, Wen-Cheng Xiong, Lin MeiSummaryAutism spectrum disorders (ASD) are a group of neurodevelopmental disorders with symptoms including social deficits, anxiety, and communication difficulties. However, ASD pathogenic mechanisms are poorly understood. Mutations of CUL3, which encodes Cullin 3 (CUL3), a component of an E3 ligase complex, are thought of as risk factors for ASD and schizophrenia (SCZ). CUL3 is abundant in the brain, yet little is known of its function. Here, we show that CUL3 is critical for neurodevelopment. CUL3-deficient mice exhibited social deficits and anxiety-like behaviors with enhanced glutamatergic transmission and neuronal excitability. Proteomic analysis revealed eIF4G1, a protein for Cap-dependent translation, as a potential target of CUL3. ASD-associated cellular and behavioral deficits could be rescued by pharmacological inhibition of the eIF4G1 function and chemogenetic inhibition of neuronal activity. Thus, CUL3 is critical to neural development, neurotransmission, and excitation-inhibition (E-I) balance. Our study provides novel insight into the pathophysiological mechanisms of ASD and SCZ.
  • Assemblies of Perisomatic GABAergic Neurons in the Developing Barrel
    • Abstract: Publication date: Available online 25 November 2019Source: NeuronAuthor(s): Laura Modol, Yannick Bollmann, Thomas Tressard, Agnès Baude, Alicia Che, Zhe Ran S. Duan, Rachel Babij, Natalia V. De Marco García, Rosa CossartSummaryThe developmental journey of cortical interneurons encounters several activity-dependent milestones. During the early postnatal period in developing mice, GABAergic neurons are transient preferential recipients of thalamic inputs and undergo activity-dependent migration arrest, wiring, and programmed cell-death. Despite their importance for the emergence of sensory experience and the role of activity in their integration into cortical networks, the collective dynamics of GABAergic neurons during that neonatal period remain unknown. Here, we study coordinated activity in GABAergic cells of the mouse barrel cortex using in vivo calcium imaging. We uncover a transient structure in GABAergic population dynamics that disappears in a sensory-dependent process. Its building blocks are anatomically clustered GABAergic assemblies mostly composed by prospective parvalbumin-expressing cells. These progressively widen their territories until forming a uniform perisomatic GABAergic network. Such transient patterning of GABAergic activity is a functional scaffold that links the cortex to the external world prior to active exploration.
  • TMC1 and TMC2 Proteins Are Pore-Forming Subunits of Mechanosensitive Ion
    • Abstract: Publication date: Available online 21 November 2019Source: NeuronAuthor(s): Yanyan Jia, Yimeng Zhao, Tsukasa Kusakizako, Yao Wang, Chengfang Pan, Yuwei Zhang, Osamu Nureki, Motoyuki Hattori, Zhiqiang YanSummaryTransmembrane channel-like (TMC) 1 and 2 are required for the mechanotransduction of mouse inner ear hair cells and localize to the site of mechanotransduction in mouse hair cell stereocilia. However, it remains unclear whether TMC1 and TMC2 are indeed ion channels and whether they can sense mechanical force directly. Here we express TMC1 from the green sea turtle (CmTMC1) and TMC2 from the budgerigar (MuTMC2) in insect cells, purify and reconstitute the proteins, and show that liposome-reconstituted CmTMC1 and MuTMC2 proteins possess ion channel activity. Furthermore, by applying pressure to proteoliposomes, we demonstrate that both CmTMC1 and MuTMC2 proteins can indeed respond to mechanical stimuli. In addition, CmTMC1 mutants corresponding to human hearing loss mutants exhibit reduced or no ion channel activity. Taken together, our results show that the CmTMC1 and MuTMC2 proteins are pore-forming subunits of mechanosensitive ion channels, supporting TMC1 and TMC2 as hair cell transduction channels.
  • An Adaptive-Threshold Mechanism for Odor Sensation and Animal Navigation
    • Abstract: Publication date: Available online 21 November 2019Source: NeuronAuthor(s): Sagi Levy, Cornelia I. BargmannSummaryIdentifying the environmental information and computations that drive sensory detection is key for understanding animal behavior. Using experimental and theoretical analysis of AWCON, a well-described olfactory neuron in C. elegans, here we derive a general and broadly useful model that matches stimulus history to odor sensation and behavioral responses. We show that AWCON sensory activity is regulated by an absolute signal threshold that continuously adapts to odor history, allowing animals to compare present and past odor concentrations. The model predicts sensory activity and probabilistic behavior during animal navigation in different odor gradients and across a broad stimulus regime. Genetic studies demonstrate that the cGMP-dependent protein kinase EGL-4 determines the timescale of threshold adaptation, defining a molecular basis for a critical model feature. The adaptive threshold model efficiently filters stimulus noise, allowing reliable sensation in fluctuating environments, and represents a feedforward sensory mechanism with implications for other sensory systems.
  • Xenotransplanted Human Cortical Neurons Reveal Species-Specific
           Development and Functional Integration into Mouse Visual Circuits
    • Abstract: Publication date: Available online 21 November 2019Source: NeuronAuthor(s): Daniele Linaro, Ben Vermaercke, Ryohei Iwata, Arjun Ramaswamy, Baptiste Libé-Philippot, Leila Boubakar, Brittany A. Davis, Keimpe Wierda, Kristofer Davie, Suresh Poovathingal, Pier-Andrée Penttila, Angéline Bilheu, Lore De Bruyne, David Gall, Karl-Klaus Conzelmann, Vincent Bonin, Pierre VanderhaeghenSummaryHow neural circuits develop in the human brain has remained almost impossible to study at the neuronal level. Here, we investigate human cortical neuron development, plasticity, and function using a mouse/human chimera model in which xenotransplanted human cortical pyramidal neurons integrate as single cells into the mouse cortex. Combined neuronal tracing, electrophysiology, and in vivo structural and functional imaging of the transplanted cells reveal a coordinated developmental roadmap recapitulating key milestones of human cortical neuron development. The human neurons display a prolonged developmental timeline, indicating the neuron-intrinsic retention of juvenile properties as an important component of human brain neoteny. Following maturation, human neurons in the visual cortex display tuned, decorrelated responses to visual stimuli, like mouse neurons, demonstrating their capacity for physiological synaptic integration in host cortical circuits. These findings provide new insights into human neuronal development and open novel avenues for the study of human neuronal function and disease.Graphical Graphical abstract for this article
  • Nanoscale Location Matters: Emerging Principles of Ca2+ Channel
           Organization at the Presynaptic Active Zone
    • Abstract: Publication date: 20 November 2019Source: Neuron, Volume 104, Issue 4Author(s): Changliang Liu, Pascal S. KaeserHow does diversity in the organization of secretory machines determine properties of neurotransmitter release' In this issue of Neuron, Rebola et al. (2019) found that distinct nanoscale assemblies of Ca2+ channels and Munc13, not overall channel abundance, mediate differing release characteristics of two cerebellar synapses.
  • Genetic and Stress-Induced Loss of NG2 Glia Triggers Emergence of
           Depressive-like Behaviors through Reduced Secretion of FGF2
    • Abstract: Publication date: 20 November 2019Source: Neuron, Volume 104, Issue 4Author(s): Fikri Birey, Michelle Kloc, Manideep Chavali, Israa Hussein, Michael Wilson, Daniel J. Christoffel, Tony Chen, Michael A. Frohman, John K. Robinson, Scott J. Russo, Arianna Maffei, Adan Aguirre
  • Structural and Functional Remodeling of Amygdala GABAergic Synapses in
           Associative Fear Learning
    • Abstract: Publication date: 20 November 2019Source: Neuron, Volume 104, Issue 4Author(s): Yu Kasugai, Elisabeth Vogel, Heide Hörtnagl, Sabine Schönherr, Enrica Paradiso, Markus Hauschild, Georg Göbel, Ivan Milenkovic, Yvan Peterschmitt, Ramon Tasan, Günther Sperk, Ryuichi Shigemoto, Werner Sieghart, Nicolas Singewald, Andreas Lüthi, Francesco FerragutiSummaryAssociative learning is thought to involve different forms of activity-dependent synaptic plasticity. Although previous studies have mostly focused on learning-related changes occurring at excitatory glutamatergic synapses, we found that associative learning, such as fear conditioning, also entails long-lasting functional and structural plasticity of GABAergic synapses onto pyramidal neurons of the murine basal amygdala. Fear conditioning-mediated structural remodeling of GABAergic synapses was associated with a change in mIPSC kinetics and an increase in the fraction of synaptic benzodiazepine-sensitive (BZD) GABAA receptors containing the α2 subunit without altering the intrasynaptic distribution and overall amount of BZD-GABAA receptors. These structural and functional synaptic changes were partly reversed by extinction training. These findings provide evidence that associative learning, such as Pavlovian fear conditioning and extinction, sculpts inhibitory synapses to regulate inhibition of active neuronal networks, a process that may tune amygdala circuit responses to threats.Graphical Graphical abstract for this article
  • Input-Specific Metaplasticity in the Visual Cortex Requires
           Homer1a-Mediated mGluR5 Signaling
    • Abstract: Publication date: 20 November 2019Source: Neuron, Volume 104, Issue 4Author(s): Varun Chokshi, Ming Gao, Bryce D. Grier, Ashley Owens, Hui Wang, Paul F. Worley, Hey-Kyoung LeeSummaryEffective sensory processing depends on sensory experience-dependent metaplasticity, which allows homeostatic maintenance of neural network activity and preserves feature selectivity. Following a strong increase in sensory drive, plasticity mechanisms that decrease the strength of excitatory synapses are preferentially engaged to maintain stability in neural networks. Such adaptation has been demonstrated in various model systems, including mouse primary visual cortex (V1), where excitatory synapses on layer 2/3 (L2/3) neurons undergo rapid reduction in strength when visually deprived mice are reexposed to light. Here, we report that this form of plasticity is specific to intracortical inputs to V1 L2/3 neurons and depends on the activity of NMDA receptors (NMDARs) and group I metabotropic glutamate receptor 5 (mGluR5). Furthermore, we found that expression of the immediate early gene (IEG) Homer1a (H1a) and its subsequent interaction with mGluR5s are necessary for this input-specific metaplasticity.Graphical Graphical abstract for this article
  • The eIF2α Kinase GCN2 Modulates Period and Rhythmicity of the Circadian
           Clock by Translational Control of Atf4
    • Abstract: Publication date: 20 November 2019Source: Neuron, Volume 104, Issue 4Author(s): Salil Saurav Pathak, Dong Liu, Tianbao Li, Nuria de Zavalia, Lei Zhu, Jin Li, Ramanujam Karthikeyan, Tommy Alain, Andrew C. Liu, Kai-Florian Storch, Randal J. Kaufman, Victor X. Jin, Shimon Amir, Nahum Sonenberg, Ruifeng CaoSummaryThe integrated stress response (ISR) is activated in response to diverse stress stimuli to maintain homeostasis in neurons. Central to this process is the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). Here, we report a critical role for ISR in regulating the mammalian circadian clock. The eIF2α kinase GCN2 rhythmically phosphorylates eIF2α in the suprachiasmatic circadian clock. Increased eIF2α phosphorylation shortens the circadian period in both fibroblasts and mice, whereas reduced eIF2α phosphorylation lengthens the circadian period and impairs circadian rhythmicity in animals. Mechanistically, phosphorylation of eIF2α promotes mRNA translation of Atf4. ATF4 binding motifs are identified in multiple clock genes, including Per2, Per3, Cry1, Cry2, and Clock. ATF4 binds to the TTGCAGCA motif in the Per2 promoter and activates its transcription. Together, these results demonstrate a significant role for ISR in circadian physiology and provide a potential link between dysregulated ISR and circadian dysfunction in brain diseases.Graphical Graphical abstract for this article
  • Visual Cortex Gains Independence from Peripheral Drive before Eye Opening
    • Abstract: Publication date: 20 November 2019Source: Neuron, Volume 104, Issue 4Author(s): Alexandra Gribizis, Xinxin Ge, Tanya L. Daigle, James B. Ackman, Hongkui Zeng, Daeyeol Lee, Michael C. CrairSummaryVisual spatial perception in the mammalian brain occurs through two parallel pathways: one reaches the primary visual cortex (V1) through the thalamus and another the superior colliculus (SC) via direct projections from the retina. The origin, development, and relative function of these two evolutionarily distinct pathways remain obscure. We examined the early functional development of both pathways by simultaneously imaging pre- and post-synaptic spontaneous neuronal activity. We observed that the quality of retinal activity transfer to the thalamus and superior colliculus does not change across the first two postnatal weeks. However, beginning in the second postnatal week, retinal activity does not drive V1 as strongly as earlier wave activity, suggesting that intrinsic cortical activity competes with signals from the sensory periphery as the cortex matures. Together, these findings bring new insight into the function of the SC and V1 and the role of peripheral activity in driving both circuits across development.
  • Distinct Nanoscale Calcium Channel and Synaptic Vesicle Topographies
           Contribute to the Diversity of Synaptic Function
    • Abstract: Publication date: 20 November 2019Source: Neuron, Volume 104, Issue 4Author(s): Nelson Rebola, Maria Reva, Tekla Kirizs, Miklos Szoboszlay, Andrea Lőrincz, Gael Moneron, Zoltan Nusser, David A. DiGregorioSummaryThe nanoscale topographical arrangement of voltage-gated calcium channels (VGCC) and synaptic vesicles (SVs) determines synaptic strength and plasticity, but whether distinct spatial distributions underpin diversity of synaptic function is unknown. We performed single bouton Ca2+ imaging, Ca2+ chelator competition, immunogold electron microscopic (EM) localization of VGCCs and the active zone (AZ) protein Munc13-1, at two cerebellar synapses. Unexpectedly, we found that weak synapses exhibited 3-fold more VGCCs than strong synapses, while the coupling distance was 5-fold longer. Reaction-diffusion modeling could explain both functional and structural data with two strikingly different nanotopographical motifs: strong synapses are composed of SVs that are tightly coupled (∼10 nm) to VGCC clusters, whereas at weak synapses VGCCs were excluded from the vicinity (∼50 nm) of docked vesicles. The distinct VGCC-SV topographical motifs also confer differential sensitivity to neuromodulation. Thus, VGCC-SV arrangements are not canonical, and their diversity could underlie functional heterogeneity across CNS synapses.
  • Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral
           and Neurophysiological Abnormalities by Activating the Immune Response
    • Abstract: Publication date: 20 November 2019Source: Neuron, Volume 104, Issue 4Author(s): Jennifer L. Johnson, Loredana Stoica, Yuwei Liu, Ping Jun Zhu, Abhisek Bhattacharya, Shelly A. Buffington, Redwan Huq, N. Tony Eissa, Ola Larsson, Bo T. Porse, Deepti Domingo, Urwah Nawaz, Renee Carroll, Lachlan Jolly, Tom S. Scerri, Hyung-Goo Kim, Amanda Brignell, Matthew J. Coleman, Ruth Braden, Usha KiniSummaryIn humans, disruption of nonsense-mediated decay (NMD) has been associated with neurodevelopmental disorders (NDDs) such as autism spectrum disorder and intellectual disability. However, the mechanism by which deficient NMD leads to neurodevelopmental dysfunction remains unknown, preventing development of targeted therapies. Here we identified novel protein-coding UPF2 (UP-Frameshift 2) variants in humans with NDD, including speech and language deficits. In parallel, we found that mice lacking Upf2 in the forebrain (Upf2 fb-KO mice) show impaired NMD, memory deficits, abnormal long-term potentiation (LTP), and social and communication deficits. Surprisingly, Upf2 fb-KO mice exhibit elevated expression of immune genes and brain inflammation. More importantly, treatment with two FDA-approved anti-inflammatory drugs reduced brain inflammation, restored LTP and long-term memory, and reversed social and communication deficits. Collectively, our findings indicate that impaired UPF2-dependent NMD leads to neurodevelopmental dysfunction and suggest that anti-inflammatory agents may prove effective for treatment of disorders with impaired NMD.Graphical Graphical abstract for this article
  • The Genetics of Neuropathic Pain from Model Organisms to Clinical
    • Abstract: Publication date: 20 November 2019Source: Neuron, Volume 104, Issue 4Author(s): Margarita Calvo, Alexander J. Davies, Harry L. Hébert, Greg A. Weir, Elissa J. Chesler, Nanna B. Finnerup, Roy C. Levitt, Blair H. Smith, G. Gregory Neely, Michael Costigan, David L. BennettNeuropathic pain (NeuP) arises due to injury of the somatosensory nervous system and is both common and disabling, rendering an urgent need for non-addictive, effective new therapies. Given the high evolutionary conservation of pain, investigative approaches from Drosophila mutagenesis to human Mendelian genetics have aided our understanding of the maladaptive plasticity underlying NeuP. Successes include the identification of ion channel variants causing hyper-excitability and the importance of neuro-immune signaling. Recent developments encompass improved sensory phenotyping in animal models and patients, brain imaging, and electrophysiology-based pain biomarkers, the collection of large well-phenotyped population cohorts, neurons derived from patient stem cells, and high-precision CRISPR generated genetic editing. We will discuss how to harness these resources to understand the pathophysiological drivers of NeuP, define its relationship with comorbidities such as anxiety, depression, and sleep disorders, and explore how to apply these findings to the prediction, diagnosis, and treatment of NeuP in the clinic.
  • Activity-Dependent Transcription Collaborates with Local Dendritic
    • Abstract: Publication date: 20 November 2019Source: Neuron, Volume 104, Issue 4Author(s): Anne E. WestA new study in Cell (Brigidi et al., 2019) shows that local dendritic versus somatic translation of the neuronal activity-inducible transcription factor NPAS4 drives the formation of distinct heterodimers that enable stimulus-specificity to be encoded into the pattern of NPAS4 binding across the genome.
  • Cortex-wide Computations in Complex Decision Making in Mice
    • Abstract: Publication date: 20 November 2019Source: Neuron, Volume 104, Issue 4Author(s): Pankaj K. Gupta, Timothy H. MurphySeemingly, a paradox exists between reports of wide-scale task-dependent cortical activity and the causal requirement for only a restricted number of motor and sensory cortical areas in some behavioral studies. In this issue of Neuron, Pinto et al. (2019) indicate that scenarios where mice must accumulate evidence and hold it during a delay period are causally linked to wide regions of cortex.
  • Decreasing Influence of Retinal Inputs on the Developing Visual Cortex
    • Abstract: Publication date: 20 November 2019Source: Neuron, Volume 104, Issue 4Author(s): Wei WeiBefore vision matures, spontaneous retinal activity drives downstream visual targets. In this issue of Neuron, Gribizis et al. (2019) image activity simultaneously in connected mouse visual areas and demonstrate distinct developmental patterns of signal transformation in thalamocortical versus retinocollicular pathways.
  • Control of Non-REM Sleep by Midbrain Neurotensinergic Neurons
    • Abstract: Publication date: 20 November 2019Source: Neuron, Volume 104, Issue 4Author(s): Peng Zhong, Zhe Zhang, Zeke Barger, Chenyan Ma, Danqian Liu, Xinlu Ding, Yang DanSummaryThe periaqueductal gray (PAG) in the midbrain is known to coordinate behavioral and autonomic responses to threat and injury through its descending projections to the brainstem. Here, we show that neurotensin (NTS)-expressing glutamatergic neurons in the ventrolateral PAG (vlPAG) powerfully promote non-rapid eye movement (NREM) sleep partly through their projection to the caudal medulla. Optogenetic and chemogenetic activation of vlPAG NTS neurons strongly enhanced NREM sleep, whereas their inactivation increased wakefulness. Calcium imaging and optrode recording showed that they are preferentially active during NREM sleep. The NREM-promoting effect of vlPAG NTS neurons is partly mediated by their projection to the caudal ventromedial medulla, where they excite GABAergic neurons. Bidirectional optogenetic and chemogenetic manipulations showed that the medullary GABAergic neurons also promote NREM sleep, and they innervate multiple monoaminergic populations. Together, these findings reveal a novel pathway for NREM sleep generation, in which glutamatergic neurons drive broad GABAergic inhibition of wake-promoting neuronal populations.
  • NMD Takes the Immune Road to NDD
    • Abstract: Publication date: 20 November 2019Source: Neuron, Volume 104, Issue 4Author(s): Eunha Kim, Jun R. HuhProper mRNA quality control prevents immune activation; when it goes awry, mice and flies develop abnormal behavioral phenotypes. In this issue of Neuron, Johnson et al. (2019) report that inhibiting nonsense-mediated mRNA decay (NMD) contributes to the pathogenesis of neurodevelopmental disorder (NDD) phenotypes by triggering aberrant immune activation.
  • The Critically Tuned Cortex
    • Abstract: Publication date: 20 November 2019Source: Neuron, Volume 104, Issue 4Author(s): John M. BeggsThe criticality hypothesis predicts that cortex operates near a critical point for optimum information processing. In this issue of Neuron, Ma et al. (2019) find evidence consistent with a mechanism that tunes cortex to criticality, even in the face of a strong perturbation over several days.
  • Task-Dependent Changes in the Large-Scale Dynamics and Necessity of
           Cortical Regions
    • Abstract: Publication date: 20 November 2019Source: Neuron, Volume 104, Issue 4Author(s): Lucas Pinto, Kanaka Rajan, Brian DePasquale, Stephan Y. Thiberge, David W. Tank, Carlos D. BrodySummaryNeural activity throughout the cortex is correlated with perceptual decisions, but inactivation studies suggest that only a small number of areas are necessary for these behaviors. Here we show that the number of required cortical areas and their dynamics vary across related tasks with different cognitive computations. In a visually guided virtual T-maze task, bilateral inactivation of only a few dorsal cortical regions impaired performance. In contrast, in tasks requiring evidence accumulation and/or post-stimulus memory, performance was impaired by inactivation of widespread cortical areas with diverse patterns of behavioral deficits across areas and tasks. Wide-field imaging revealed widespread ramps of Ca2+ activity during the accumulation and visually guided tasks. Additionally, during accumulation, different regions had more diverse activity profiles, leading to reduced inter-area correlations. Using a modular recurrent neural network model trained to perform analogous tasks, we argue that differences in computational strategies alone could explain these findings.
  • Amyloid-Beta (Aβ) Plaques Promote Seeding and Spreading of
           Alpha-Synuclein and Tau in a Mouse Model of Lewy Body Disorders with Aβ
    • Abstract: Publication date: Available online 20 November 2019Source: NeuronAuthor(s): Fares Bassil, Hannah J. Brown, Shankar Pattabhiraman, Joe E. Iwasyk, Chantal M. Maghames, Emily S. Meymand, Timothy O. Cox, Dawn M. Riddle, Bin Zhang, John Q. Trojanowski, Virginia M.-Y. LeeSummaryStudies have shown an overlap of Aβ plaques, tau tangles, and α-synuclein (α-syn) pathologies in the brains of Alzheimer’s disease (AD) and Parkinson’s disease (PD) with dementia (PDD) patients, with increased pathological burden correlating with severity of cognitive and motor symptoms. Despite the observed co-pathology and concomitance of motor and cognitive phenotypes, the consequences of the primary amyloidogenic protein on the secondary pathologies remain poorly understood. To better define the relationship between α-syn and Aβ plaques, we injected α-syn preformed fibrils (α-syn mpffs) into mice with abundant Aβ plaques. Aβ deposits dramatically accelerated α-syn pathogenesis and spread throughout the brain. Remarkably, hyperphosphorylated tau (p-tau) was induced in α-syn mpff-injected 5xFAD mice. Finally, α-syn mpff-injected 5xFAD mice showed neuron loss that correlated with the progressive decline of cognitive and motor performance. Our findings suggest a “feed-forward” mechanism whereby Aβ plaques enhance endogenous α-syn seeding and spreading over time post-injection with mpffs.
  • Somatic and Dendritic Encoding of Spatial Variables in Retrosplenial
           Cortex Differs during 2D Navigation
    • Abstract: Publication date: Available online 20 November 2019Source: NeuronAuthor(s): Jakob Voigts, Mark T. HarnettSummaryActive amplification of organized synaptic inputs in dendrites can endow individual neurons with the ability to perform complex computations. However, whether dendrites in behaving animals perform independent local computations is not known. Such activity may be particularly important for complex behavior, where neurons integrate multiple streams of information. Head-restrained imaging has yielded important insights into cellular and circuit function, but this approach limits behavior and the underlying computations. We describe a method for full-featured 2-photon imaging in awake mice during free locomotion with volitional head rotation. We examine head direction and position encoding in simultaneously imaged apical tuft dendrites and their respective cell bodies in retrosplenial cortex, an area that encodes multi-modal navigational information. Activity in dendrites was not determined solely by somatic activity but reflected distinct navigational variables, fulfilling the requirements for dendritic computation. Our approach provides a foundation for studying sub-cellular processes during complex behaviors.Graphical Graphical abstract for this article
  • Complementary Genetic Targeting and Monosynaptic Input Mapping Reveal
           Recruitment and Refinement of Distributed Corticostriatal Ensembles by
    • Abstract: Publication date: Available online 20 November 2019Source: NeuronAuthor(s): Nicholas R. Wall, Peter A. Neumann, Kevin T. Beier, Ava K. Mokhtari, Liqun Luo, Robert C. MalenkaSummaryDrugs of abuse elicit powerful experiences that engage populations of neurons broadly distributed throughout the brain. To determine how synaptic connectivity is organized to enable robust communication between populations of drug-activated neurons, we developed a complementary targeting system for monosynaptic rabies virus (RV) tracing that identifies direct inputs to activated versus nonactivated neuronal populations. Analysis of over 100,000 synaptic input neurons demonstrated that cocaine-activated neurons comprise selectively connected but broadly distributed corticostriatal networks. Electrophysiological assays using optogenetics to stimulate activated versus nonactivated inputs revealed stronger synapses between coactivated cortical pyramidal neurons and neurons in the dorsal striatum (DS). Repeated cocaine exposure further enhanced the connectivity specifically between drug-activated neurons in the orbitofrontal cortex (OFC) and coactive DS neurons. Selective chemogenetic silencing of cocaine-activated OFC neurons or their terminals in the DS disrupted behavioral sensitization, demonstrating the utility of this methodology for identifying novel circuit elements that contribute to behavioral plasticity.
  • Layer 5 Circuits in V1 Differentially Control Visuomotor Behavior
    • Abstract: Publication date: Available online 19 November 2019Source: NeuronAuthor(s): Lan Tang, Michael J. HigleySummaryNeocortical sensory areas are thought to act as distribution hubs, transmitting information about the external environment to downstream areas. Within primary visual cortex, various populations of pyramidal neurons (PNs) send axonal projections to distinct targets, suggesting multiple cellular networks may be independently engaged during behavior. We investigated whether PN subpopulations differentially support visual detection by training mice on a novel eyeblink conditioning task. Applying 2-photon calcium imaging and optogenetic manipulation of anatomically defined PNs, we show that layer 5 corticopontine neurons strongly encode sensory and motor task information and are selectively necessary for performance. Our findings support a model in which target-specific cortical subnetworks form the basis for adaptive behavior by directing relevant information to distinct brain areas. Overall, this work highlights the potential for neurons to form physically interspersed but functionally segregated networks capable of parallel, independent control of perception and behavior.
  • Natural Variation in a Dendritic Scaffold Protein Remodels
           Experience-Dependent Plasticity by Altering Neuropeptide Expression
    • Abstract: Publication date: Available online 19 November 2019Source: NeuronAuthor(s): Isabel Beets, Gaotian Zhang, Lorenz A. Fenk, Changchun Chen, Geoffrey M. Nelson, Marie-Anne Félix, Mario de BonoSummaryThe extent to which behavior is shaped by experience varies between individuals. Genetic differences contribute to this variation, but the neural mechanisms are not understood. Here, we dissect natural variation in the behavioral flexibility of two Caenorhabditis elegans wild strains. In one strain, a memory of exposure to 21% O2 suppresses CO2-evoked locomotory arousal; in the other, CO2 evokes arousal regardless of previous O2 experience. We map that variation to a polymorphic dendritic scaffold protein, ARCP-1, expressed in sensory neurons. ARCP-1 binds the Ca2+-dependent phosphodiesterase PDE-1 and co-localizes PDE-1 with molecular sensors for CO2 at dendritic ends. Reducing ARCP-1 or PDE-1 activity promotes CO2 escape by altering neuropeptide expression in the BAG CO2 sensors. Variation in ARCP-1 alters behavioral plasticity in multiple paradigms. Our findings are reminiscent of genetic accommodation, an evolutionary process by which phenotypic flexibility in response to environmental variation is reset by genetic change.
  • Excitatory and Inhibitory Subnetworks Are Equally Selective during
           Decision-Making and Emerge Simultaneously during Learning
    • Abstract: Publication date: Available online 18 November 2019Source: NeuronAuthor(s): Farzaneh Najafi, Gamaleldin F. Elsayed, Robin Cao, Eftychios Pnevmatikakis, Peter E. Latham, John P. Cunningham, Anne K. ChurchlandSummaryInhibitory neurons, which play a critical role in decision-making models, are often simplified as a single pool of non-selective neurons lacking connection specificity. This assumption is supported by observations in the primary visual cortex: inhibitory neurons are broadly tuned in vivo and show non-specific connectivity in slice. The selectivity of excitatory and inhibitory neurons within decision circuits and, hence, the validity of decision-making models are unknown. We simultaneously measured excitatory and inhibitory neurons in the posterior parietal cortex of mice judging multisensory stimuli. Surprisingly, excitatory and inhibitory neurons were equally selective for the animal’s choice, both at the single-cell and population level. Further, both cell types exhibited similar changes in selectivity and temporal dynamics during learning, paralleling behavioral improvements. These observations, combined with modeling, argue against circuit architectures assuming non-selective inhibitory neurons. Instead, they argue for selective subnetworks of inhibitory and excitatory neurons that are shaped by experience to support expert decision-making.Graphical Graphical abstract for this article
  • Disruption of Oligodendrogenesis Impairs Memory Consolidation in Adult
    • Abstract: Publication date: Available online 18 November 2019Source: NeuronAuthor(s): Patrick E. Steadman, Frances Xia, Moriam Ahmed, Andrew J. Mocle, Amber R.A. Penning, Anna C. Geraghty, Hendrik W. Steenland, Michelle Monje, Sheena A. Josselyn, Paul W. FranklandSummaryThe generation of myelin-forming oligodendrocytes persists throughout life and is regulated by neural activity. Here we tested whether experience-driven changes in oligodendrogenesis are important for memory consolidation. We found that water maze learning promotes oligodendrogenesis and de novo myelination in the cortex and associated white matter tracts. Preventing these learning-induced increases in oligodendrogenesis without affecting existing oligodendrocytes impaired memory consolidation of water maze, as well as contextual fear, memories. These results suggest that de novo myelination tunes activated circuits, promoting coordinated activity that is important for memory consolidation. Consistent with this, contextual fear learning increased the coupling of hippocampal sharp wave ripples and cortical spindles, and these learning-induced increases in ripple-spindle coupling were blocked when oligodendrogenesis was suppressed. Our results identify a non-neuronal form of plasticity that remodels hippocampal-cortical networks following learning and is required for memory consolidation.Graphical Graphical abstract for this article
  • mGlu2 and mGlu3 Negative Allosteric Modulators Divergently Enhance
           Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects
    • Abstract: Publication date: Available online 14 November 2019Source: NeuronAuthor(s): Max E. Joffe, Chiaki I. Santiago, Kendra H. Oliver, James Maksymetz, Nicholas A. Harris, Julie L. Engers, Craig W. Lindsley, Danny G. Winder, P. Jeffrey ConnSummaryNon-selective antagonists of metabotropic glutamate receptor subtypes 2 (mGlu2) and 3 (mGlu3) exert rapid antidepressant-like effects by enhancing prefrontal cortex (PFC) glutamate transmission; however, the receptor subtype contributions and underlying mechanisms remain unclear. Here, we leveraged newly developed negative allosteric modulators (NAMs), transgenic mice, and viral-assisted optogenetics to test the hypothesis that selective inhibition of mGlu2 or mGlu3 potentiates PFC excitatory transmission and confers antidepressant efficacy in preclinical models. We found that systemic treatment with an mGlu2 or mGlu3 NAM rapidly activated biophysically unique PFC pyramidal cell ensembles. Mechanistic studies revealed that mGlu2 and mGlu3 NAMs enhance thalamocortical transmission and inhibit long-term depression by mechanistically distinct presynaptic and postsynaptic actions. Consistent with these actions, systemic treatment with either NAM decreased passive coping and reversed anhedonia in two independent chronic stress models, suggesting that both mGlu2 and mGlu3 NAMs induce antidepressant-like effects through related but divergent mechanisms of action.Graphical Graphical abstract for this article
  • Resolving and Rescuing Developmental Miswiring in a Mouse Model of
           Cognitive Impairment
    • Abstract: Publication date: Available online 13 November 2019Source: NeuronAuthor(s): Mattia Chini, Jastyn A. Pöpplau, Christoph Lindemann, Laura Carol-Perdiguer, Marilena Hnida, Victoria Oberländer, Xiaxia Xu, Joachim Ahlbeck, Sebastian H. Bitzenhofer, Christoph Mulert, Ileana L. Hanganu-OpatzSummaryCognitive deficits, core features of mental illness, largely result from dysfunction of prefrontal networks. This dysfunction emerges during early development, before a detectable behavioral readout, yet the cellular elements controlling the abnormal maturation are still unknown. Here, we address this open question by combining in vivo electrophysiology, optogenetics, neuroanatomy, and behavioral assays during development in mice mimicking the dual genetic-environmental etiology of psychiatric disorders. We report that pyramidal neurons in superficial layers of the prefrontal cortex are key elements causing disorganized oscillatory entrainment of local circuits in beta-gamma frequencies. Their abnormal firing rate and timing relate to sparser dendritic arborization and lower spine density. Administration of minocycline during the first postnatal week, potentially acting via microglial cells, rescues the neuronal deficits and restores pre-juvenile cognitive abilities. Elucidation of the cellular substrate of developmental miswiring causing later cognitive deficits opens new perspectives for identification of neurobiological targets amenable to therapies.Graphical Graphical abstract for this article
  • A Distinct Class of Bursting Neurons with Strong Gamma Synchronization and
           Stimulus Selectivity in Monkey V1
    • Abstract: Publication date: Available online 12 November 2019Source: NeuronAuthor(s): Irene Onorato, Sergio Neuenschwander, Jennifer Hoy, Bruss Lima, Katia-Simone Rocha, Ana Clara Broggini, Cem Uran, Georgios Spyropoulos, Johanna Klon-Lipok, Thilo Womelsdorf, Pascal Fries, Cristopher Niell, Wolf Singer, Martin VinckSummaryCortical computation depends on interactions between excitatory and inhibitory neurons. The contributions of distinct neuron types to sensory processing and network synchronization in primate visual cortex remain largely undetermined. We show that in awake monkey V1, there exists a distinct cell type (››30% of neurons) that has narrow-waveform (NW) action potentials and high spontaneous discharge rates and fires in high-frequency bursts. These neurons are more stimulus selective and phase locked to 30- to 80-Hz gamma oscillations than other neuron types. Unlike other neuron types, their gamma-phase locking is highly predictive of orientation tuning. We find evidence for strong rhythmic inhibition in these neurons, suggesting that they interact with interneurons to act as excitatory pacemakers for the V1 gamma rhythm. We did not find a similar class of NW bursting neurons in L2-L4 of mouse V1. Given its properties, this class of NW bursting neurons should be pivotal for the encoding and transmission of stimulus information.
  • Targeted Cortical Manipulation of Auditory Perception
    • Abstract: Publication date: Available online 11 November 2019Source: NeuronAuthor(s): Sebastian Ceballo, Zuzanna Piwkowska, Jacques Bourg, Aurélie Daret, Brice BathellierSummaryDriving perception by direct activation of neural ensembles in cortex is a necessary step for achieving a causal understanding of the neural code for auditory perception and developing central sensory rehabilitation methods. Here, using optogenetic manipulations during an auditory discrimination task in mice, we show that auditory cortex can be short-circuited by coarser pathways for simple sound identification. Yet when the sensory decision becomes more complex, involving temporal integration of information, auditory cortex activity is required for sound discrimination and targeted activation of specific cortical ensembles changes perceptual decisions, as predicted by our readout of the cortical code. Hence, auditory cortex representations contribute to sound discriminations by refining decisions from parallel routes.
  • A Critical Role for Neocortical Processing of Threat Memory
    • Abstract: Publication date: Available online 11 November 2019Source: NeuronAuthor(s): Tamas Dalmay, Elisabeth Abs, Rogier B. Poorthuis, Jan Hartung, De-Lin Pu, Sebastian Onasch, Yave R. Lozano, Jérémy Signoret-Genest, Philip Tovote, Julijana Gjorgjieva, Johannes J. LetzkusSummaryMemory of cues associated with threat is critical for survival and a leading model for elucidating how sensory information is linked to adaptive behavior by learning. Although the brain-wide circuits mediating auditory threat memory have been intensely investigated, it remains unclear whether the auditory cortex is critically involved. Here we use optogenetic activity manipulations in defined cortical areas and output pathways, viral tracing, pathway-specific in vivo 2-photon calcium imaging, and computational analyses of population plasticity to reveal that the auditory cortex is selectively required for conditioning to complex stimuli, whereas the adjacent temporal association cortex controls all forms of auditory threat memory. More temporal areas have a stronger effect on memory and more neurons projecting to the lateral amygdala, which control memory to complex stimuli through a balanced form of population plasticity that selectively supports discrimination of significant sensory stimuli. Thus, neocortical processing plays a critical role in cued threat memory.
  • Holographic Reconstruction of Axonal Pathways in the Human Brain
    • Abstract: Publication date: Available online 7 November 2019Source: NeuronAuthor(s): Mikkel V. Petersen, Jeffrey Mlakar, Suzanne N. Haber, Martin Parent, Yoland Smith, Peter L. Strick, Mark A. Griswold, Cameron C. McIntyreSummaryThree-dimensional documentation of the axonal pathways connecting gray matter components of the human brain has wide-ranging scientific and clinical applications. Recent attempts to map human structural connectomes have concentrated on using tractography results derived from diffusion-weighted imaging data, but tractography is an indirect method with numerous limitations. Advances in holographic visualization platforms provide a new medium to integrate anatomical data, as well as a novel working environment for collaborative interaction between neuroanatomists and brain-imaging scientists. Therefore, we developed the first holographic interface for building axonal pathways, populated it with human histological and structural MRI data, and assembled world expert neuroanatomists to interactively define axonal trajectories of the cortical, basal ganglia, and cerebellar systems. This blending of advanced visualization hardware, software development, and neuroanatomy data enabled the translation of decades of amassed knowledge into a human axonal pathway atlas that can be applied to educational, scientific, or clinical investigations.
  • No Extraction of Spine Neck Resistance from Underdetermined Equations
    • Abstract: Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(s): Boris Barbour
  • Paradoxical Rules of Spike Train Decoding Revealed at the Sensitivity
           Limit of Vision
    • Abstract: Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(s): Lina Smeds, Daisuke Takeshita, Tuomas Turunen, Jussi Tiihonen, Johan Westö, Nataliia Martyniuk, Aarni Seppänen, Petri Ala-LaurilaSummaryAll sensory information is encoded in neural spike trains. It is unknown how the brain utilizes this neural code to drive behavior. Here, we unravel the decoding rules of the brain at the most elementary level by linking behavioral decisions to retinal output signals in a single-photon detection task. A transgenic mouse line allowed us to separate the two primary retinal outputs, ON and OFF pathways, carrying information about photon absorptions as increases and decreases in spiking, respectively. We measured the sensitivity limit of rods and the most sensitive ON and OFF ganglion cells and correlated these results with visually guided behavior using markerless head and eye tracking. We show that behavior relies only on the ON pathway even when the OFF pathway would allow higher sensitivity. Paradoxically, behavior does not rely on the spike code with maximal information but instead relies on a decoding strategy based on increases in spiking.Graphical Graphical abstract for this article
  • Discrete Evaluative and Premotor Circuits Enable Vocal Learning in
    • Abstract: Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(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.
  • A Neural Circuit Arbitrates between Persistence and Withdrawal in Hungry
    • Abstract: Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(s): Sercan Sayin, Jean-Francois De Backer, K.P. Siju, Marina E. Wosniack, Laurence P. Lewis, Lisa-Marie Frisch, Benedikt Gansen, Philipp Schlegel, Amelia Edmondson-Stait, Nadiya Sharifi, Corey B. Fisher, Steven A. Calle-Schuler, J. Scott Lauritzen, Davi D. Bock, Marta Costa, Gregory S.X.E. Jefferis, Julijana Gjorgjieva, Ilona C. Grunwald KadowSummaryIn pursuit of food, hungry animals mobilize significant energy resources and overcome exhaustion and fear. How need and motivation control the decision to continue or change behavior is not understood. Using a single fly treadmill, we show that hungry flies persistently track a food odor and increase their effort over repeated trials in the absence of reward suggesting that need dominates negative experience. We further show that odor tracking is regulated by two mushroom body output neurons (MBONs) connecting the MB to the lateral horn. These MBONs, together with dopaminergic neurons and Dop1R2 signaling, control behavioral persistence. Conversely, an octopaminergic neuron, VPM4, which directly innervates one of the MBONs, acts as a brake on odor tracking by connecting feeding and olfaction. Together, our data suggest a function for the MB in internal state-dependent expression of behavior that can be suppressed by external inputs conveying a competing behavioral drive.Graphical Graphical abstract for this article
  • Phase Separation-Mediated TARP/MAGUK Complex Condensation and AMPA
           Receptor Synaptic Transmission
    • Abstract: Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(s): Menglong Zeng, Javier Díaz-Alonso, Fei Ye, Xudong Chen, Jia Xu, Zeyang Ji, Roger A. Nicoll, Mingjie ZhangSummaryTransmembrane AMPA receptor (AMPAR) regulatory proteins (TARPs) modulate AMPAR synaptic trafficking and transmission via disc-large (DLG) subfamily of membrane-associated guanylate kinases (MAGUKs). Despite extensive studies, the molecular mechanism governing specific TARP/MAGUK interaction remains elusive. Using stargazin and PSD-95 as the representatives, we discover that the entire tail of stargazin (Stg_CT) is required for binding to PSD-95. The PDZ binding motif (PBM) and an Arg-rich motif upstream of PBM conserved in TARPs bind to multiple sites on PSD-95, thus resulting in a highly specific and multivalent stargazin/PSD-95 complex. Stargazin in complex with PSD-95 or PSD-95-assembled postsynaptic complexes form highly concentrated and dynamic condensates via phase separation, reminiscent of stargazin/PSD-95-mediated AMPAR synaptic clustering and trapping. Importantly, charge neutralization mutations in TARP_CT Arg-rich motif weakened TARP’s condensation with PSD-95 and impaired TARP-mediated AMPAR synaptic transmission in mice hippocampal neurons. The TARP_CT/PSD-95 interaction mode may have implications for understanding clustering of other synaptic transmembrane proteins.Graphical Graphical abstract for this article
  • Nucleome Dynamics during Retinal Development
    • Abstract: Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(s): Jackie L. Norrie, Marybeth S. Lupo, Beisi Xu, Issam Al Diri, Marc Valentine, Daniel Putnam, Lyra Griffiths, Jiakun Zhang, Dianna Johnson, John Easton, Ying Shao, Victoria Honnell, Sharon Frase, Shondra Miller, Valerie Stewart, Xin Zhou, Xiang Chen, Michael A. DyerSummaryMore than 8,000 genes are turned on or off as progenitor cells produce the 7 classes of retinal cell types during development. Thousands of enhancers are also active in the developing retinae, many having features of cell- and developmental stage-specific activity. We studied dynamic changes in the 3D chromatin landscape important for precisely orchestrated changes in gene expression during retinal development by ultra-deep in situ Hi-C analysis on murine retinae. We identified developmental-stage-specific changes in chromatin compartments and enhancer-promoter interactions. We developed a machine learning-based algorithm to map euchromatin and heterochromatin domains genome-wide and overlaid it with chromatin compartments identified by Hi-C. Single-cell ATAC-seq and RNA-seq were integrated with our Hi-C and previous ChIP-seq data to identify cell- and developmental-stage-specific super-enhancers (SEs). We identified a bipolar neuron-specific core regulatory circuit SE upstream of Vsx2, whose deletion in mice led to the loss of bipolar neurons.Graphical Graphical abstract for this article
  • Agonist Selectivity and Ion Permeation in the α3β4 Ganglionic
           Nicotinic Receptor
    • Abstract: Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(s): Anant Gharpure, Jinfeng Teng, Yuxuan Zhuang, Colleen M. Noviello, Richard M. Walsh, Rico Cabuco, Rebecca J. Howard, Nurulain T. Zaveri, Erik Lindahl, Ryan E. HibbsSummaryNicotinic acetylcholine receptors are pentameric ion channels that mediate fast chemical neurotransmission. The α3β4 nicotinic receptor subtype forms the principal relay between the central and peripheral nervous systems in the autonomic ganglia. This receptor is also expressed focally in brain areas that affect reward circuits and addiction. Here, we present structures of the α3β4 nicotinic receptor in lipidic and detergent environments, using functional reconstitution to define lipids appropriate for structural analysis. The structures of the receptor in complex with nicotine, as well as the α3β4-selective ligand AT-1001, complemented by molecular dynamics, suggest principles of agonist selectivity. The structures further reveal much of the architecture of the intracellular domain, where mutagenesis experiments and simulations define residues governing ion conductance.
  • Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability
    • Abstract: Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(s): Peter Dongmin Sohn, Cindy Tzu-Ling Huang, Rui Yan, Li Fan, Tara E. Tracy, Carolina M. Camargo, Kelly M. Montgomery, Taylor Arhar, Sue-Ann Mok, Rebecca Freilich, Justin Baik, Manni He, Shiaoching Gong, Erik D. Roberson, Celeste M. Karch, Jason E. Gestwicki, Ke Xu, Kenneth S. Kosik, Li GanSummaryDysregulation of neuronal excitability underlies the pathogenesis of tauopathies, including frontotemporal dementia (FTD) with tau inclusions. A majority of FTD-causing tau mutations are located in the microtubule-binding domain, but how these mutations alter neuronal excitability is largely unknown. Here, using CRISPR/Cas9-based gene editing in human pluripotent stem cell (iPSC)-derived neurons and isogenic controls, we show that the FTD-causing V337M tau mutation impairs activity-dependent plasticity of the cytoskeleton in the axon initial segment (AIS). Extracellular recordings by multi-electrode arrays (MEAs) revealed that the V337M tau mutation in human neurons leads to an abnormal increase in neuronal activity in response to chronic depolarization. Stochastic optical reconstruction microscopy of human neurons with this mutation showed that AIS plasticity is impaired by the abnormal accumulation of end-binding protein 3 (EB3) in the AIS submembrane region. These findings expand our understanding of how FTD-causing tau mutations dysregulate components of the neuronal cytoskeleton, leading to network dysfunction.Graphical Graphical abstract for this article
  • Functional Logic of Layer 2/3 Inhibitory Connectivity in the Ferret Visual
    • Abstract: Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(s): Benjamin Scholl, Daniel E. Wilson, Juliane Jaepel, David FitzpatrickSummaryUnderstanding how cortical inhibition shapes circuit function requires identifying the connectivity rules relating the response properties of inhibitory interneurons and their postsynaptic targets. Here we explore the orientation tuning of layer 2/3 inhibitory inputs in the ferret visual cortex using a combination of in vivo axon imaging, functional input mapping, and physiology. Inhibitory boutons exhibit robust orientation-tuned responses with preferences that can differ significantly from the cortical column in which they reside. Inhibitory input fields measured with patterned optogenetic stimulation and intracellular recordings revealed that these inputs originate from a wide range of orientation domains, inconsistent with a model of co-tuned inhibition and excitation. Intracellular synaptic conductance measurements confirm that individual neurons can depart from a co-tuned regime. Our results argue against a simple rule for the arrangement of inhibitory inputs supplied by layer 2/3 circuits and suggest that heterogeneity in presynaptic inhibitory networks contributes to neural response properties.
  • Microglia/Brain Macrophages as Central Drivers of Brain Tumor Pathobiology
    • Abstract: Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(s): David H. Gutmann, Helmut KettenmannOne of the most common brain tumors in children and adults is glioma or astrocytoma. There are few effective therapies for these cancers, and patients with malignant glioma fare poorly, even after aggressive surgery, chemotherapy, and radiation. Over the past decade, it is now appreciated that these tumors are composed of numerous distinct neoplastic and non-neoplastic cell populations, which could each influence overall tumor biology and response to therapy. Among these noncancerous cell types, monocytes (microglia and macrophages) predominate. In this Review, we discuss the complex interactions involving microglia and macrophages relevant to glioma formation, progression, and response to therapy.
  • Electrodiffusion Theory to Map the Voltage Distribution in Dendritic
           Spines at a Nanometer Scale
    • Abstract: Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(s): Jerome Cartailler, David Holcman
  • Retinal Circuits for Seeing in the Dark
    • Abstract: Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(s): Yongrong Qiu, Thomas EulerHow can we relate processing in the retina to an animal’s behavior' In this issue of Neuron, Smeds et al. (2019) report that when “every photon counts,” mice trade sensitivity for reliability to master visual tasks.
  • “One Must Imagine Sisyphus Happy”: Unveiling the Intimate Secrets of a
           Tenacious Fruitfly
    • Abstract: Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(s): Thomas Preat, Pierre-Yves PlaçaisPerseverance in foraging is a high-risk/high-gain strategy. In this issue of Neuron, Sayin et al. (2019) decipher the neuronal circuit that arbitrates this choice in Drosophila. The fly’s remarkable tenacity illuminates the interaction between working memory and decision making.
  • Nicotine Bound to Its Receptors: New Structures for a Vexing
           Pathopharmacological Problem
    • Abstract: Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(s): Henry A. Lester, Dennis A. DoughertyIn this issue of Neuron, Gharpure et al. (2019) nearly complete atomic-level descriptions for binding, permeation, and subunit interactions at the two major heteropentameric nicotinic receptors—those governing nicotine’s rewarding and aversive effects. Can we finally design highly selective and useful nicotinic drugs'
  • Solving the Mysteries of Dementia: FTD Mutant Tau Impairs Structural Axon
           Initial Segment Plasticity
    • Abstract: Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(s): Joanna Lipka, Casper C. HoogenraadAccumulation of abnormal Tau is a characteristic feature of a number of neurodegenerative disorders, called tauopathies. What is the reason for Tau toxicity in neuronal cells' In this issue of Neuron, Sohn et al. (2019) found that FTD mutant Tau-V337M blocks axon initial segment (AIS) plasticity, causing neuronal hyperexcitability.
  • Hippocampal-Prefrontal Theta Transmission Regulates Avoidance Behavior
    • Abstract: Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(s): Nancy Padilla-Coreano, Sarah Canetta, Rachel M. Mikofsky, Emily Alway, Johannes Passecker, Maxym V. Myroshnychenko, Alvaro L. Garcia-Garcia, Richard Warren, Eric Teboul, Dakota R. Blackman, Mitchell P. Morton, Sofiya Hupalo, Kay M. Tye, Christoph Kellendonk, David A. Kupferschmidt, Joshua A. GordonSummaryLong-range synchronization of neural oscillations correlates with distinct behaviors, yet its causal role remains unproven. In mice, tests of avoidance behavior evoke increases in theta-frequency (∼8 Hz) oscillatory synchrony between the ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC). To test the causal role of this synchrony, we dynamically modulated vHPC-mPFC terminal activity using optogenetic stimulation. Oscillatory stimulation at 8 Hz maximally increased avoidance behavior compared to 2, 4, and 20 Hz. Moreover, avoidance behavior was selectively increased when 8-Hz stimulation was delivered in an oscillatory, but not pulsatile, manner. Furthermore, 8-Hz oscillatory stimulation enhanced vHPC-mPFC neurotransmission and entrained neural activity in the vHPC-mPFC network, resulting in increased synchrony between vHPC theta activity and mPFC spiking. These data suggest a privileged role for vHPC-mPFC theta-frequency communication in generating avoidance behavior and provide direct evidence that synchronized oscillations play a role in facilitating neural transmission and behavior.
  • A Modality-Independent Network Underlies the Retrieval of Large-Scale
           Spatial Environments in the Human Brain
    • Abstract: Publication date: 6 November 2019Source: Neuron, Volume 104, Issue 3Author(s): Derek J. Huffman, Arne D. EkstromSummaryIn humans, the extent to which body-based cues, such as vestibular, somatosensory, and motoric cues, are necessary for normal expression of spatial representations remains unclear. Recent breakthroughs in immersive virtual reality technology allowed us to test how body-based cues influence spatial representations of large-scale environments in humans. Specifically, we manipulated the availability of body-based cues during navigation using an omnidirectional treadmill and a head-mounted display, investigating brain differences in levels of activation (i.e., univariate analysis), patterns of activity (i.e., multivariate pattern analysis), and putative network interactions between spatial retrieval tasks using fMRI. Our behavioral and neuroimaging results support the idea that there is a core, modality-independent network supporting spatial memory retrieval in the human brain. Thus, for well-learned spatial environments, at least in humans, primarily visual input may be sufficient for expression of complex representations of spatial environments.Video Abstract
  • Combinatorial Targeting of Distributed Forebrain Networks Reverses Noise
           Hypersensitivity in a Model of Autism Spectrum Disorder
    • Abstract: Publication date: Available online 21 October 2019Source: NeuronAuthor(s): Miho Nakajima, L. Ian Schmitt, Guoping Feng, Michael M. HalassaSummaryAutism spectrum disorder (ASD) is associated with noise hypersensitivity, the suboptimal extraction of meaningful signals in noisy environments. Because sensory filtering can involve distinct automatic and executive circuit mechanisms, however, developing circuit-specific therapeutic strategies for ASD noise hypersensitivity can be challenging. Here, we find that both of these processes are individually perturbed in one monogenic form of ASD, Ptchd1 deletion. Although Ptchd1 is preferentially expressed in the thalamic reticular nucleus during development, pharmacological rescue of thalamic perturbations in knockout (KO) mice only normalized automatic sensory filtering. By discovering a separate prefrontal perturbation in these animals and adopting a combinatorial pharmacological approach that also rescued its associated goal-directed noise filtering deficit, we achieved full normalization of noise hypersensitivity in this model. Overall, our work highlights the importance of identifying large-scale functional circuit architectures and utilizing them as access points for behavioral disease correction.
  • Spatial Clustering of Inhibition in Mouse Primary Visual Cortex
    • Abstract: Publication date: Available online 14 October 2019Source: NeuronAuthor(s): Rinaldo D. D’Souza, Pawan Bista, Andrew M. Meier, Weiqing Ji, Andreas BurkhalterSummaryWhether mouse visual cortex contains orderly feature maps is debated. The overlapping pattern of geniculocortical inputs with M2 muscarinic acetylcholine receptor-rich patches in layer 1 (L1) suggests a non-random architecture. Here, we found that L1 inputs from the lateral posterior thalamus (LP) avoid patches and target interpatches. Channelrhodopsin-2-assisted mapping of excitatory postsynaptic currents (EPSCs) in L2/3 shows that the relative excitation of parvalbumin-expressing interneurons (PVs) and pyramidal neurons (PNs) by dLGN, LP, and cortical feedback is distinct and depends on whether the neurons reside in clusters aligned with patches or interpatches. Paired recordings from PVs and PNs show that unitary inhibitory postsynaptic currents (uIPSCs) are larger in interpatches than in patches. The spatial clustering of inhibition is matched by dense clustering of PV terminals in interpatches. The results show that the excitation/inhibition balance across V1 is organized into patch and interpatch subnetworks, which receive distinct long-range inputs and are specialized for the processing of distinct spatiotemporal features.
  • Recapitulation and Reversal of Schizophrenia-Related Phenotypes in
           Setd1a-Deficient Mice
    • Abstract: Publication date: Available online 9 October 2019Source: NeuronAuthor(s): Jun Mukai, Enrico Cannavò, Gregg W. Crabtree, Ziyi Sun, Anastasia Diamantopoulou, Pratibha Thakur, Chia-Yuan Chang, Yifei Cai, Stavros Lomvardas, Atsushi Takata, Bin Xu, Joseph A. GogosSummarySETD1A, a lysine-methyltransferase, is a key schizophrenia susceptibility gene. Mice carrying a heterozygous loss-of-function mutation of the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics accompanied by working memory deficits. We show that Setd1a binds both promoters and enhancers with a striking overlap between Setd1a and Mef2 on enhancers. Setd1a targets are highly expressed in pyramidal neurons and display a complex pattern of transcriptional up- and downregulations shaped by presumed opposing functions of Setd1a on promoters and Mef2-bound enhancers. Notably, evolutionarily conserved Setd1a targets are associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues cognitive deficits. Finally, we identify LSD1 as a major counteracting demethylase for Setd1a and show that its pharmacological antagonism results in a full rescue of the behavioral and morphological deficits in Setd1a-deficient mice. Our findings advance understanding of how SETD1A mutations predispose to schizophrenia (SCZ) and point to novel therapeutic interventions.
  • An ER Assembly Line of AMPA-Receptors Controls Excitatory
           Neurotransmission and Its Plasticity
    • Abstract: Publication date: Available online 8 October 2019Source: NeuronAuthor(s): Jochen Schwenk, Sami Boudkkazi, Maciej K. Kocylowski, Aline Brechet, Gerd Zolles, Thorsten Bus, Kaue Costa, Astrid Kollewe, Johannes Jordan, Julia Bank, Wolfgang Bildl, Rolf Sprengel, Akos Kulik, Jochen Roeper, Uwe Schulte, Bernd FaklerSummaryExcitatory neurotransmission and its activity-dependent plasticity are largely determined by AMPA-receptors (AMPARs), ion channel complexes whose cell physiology is encoded by their interactome. Here, we delineate the assembly of AMPARs in the endoplasmic reticulum (ER) of native neurons as multi-state production line controlled by distinct interactome constituents: ABHD6 together with porcupine stabilizes pore-forming GluA monomers, and the intellectual-disability-related FRRS1l-CPT1c complexes promote GluA oligomerization and co-assembly of GluA tetramers with cornichon and transmembrane AMPA-regulatory proteins (TARP) to render receptor channels ready for ER exit. Disruption of the assembly line by FRRS1l deletion largely reduces AMPARs in the plasma membrane, impairs synapse formation, and abolishes activity-dependent synaptic plasticity, while FRRS1l overexpression has the opposite effect. As a consequence, FRSS1l knockout mice display severe deficits in learning tasks and behavior. Our results provide mechanistic insight into the stepwise biogenesis of AMPARs in native ER membranes and establish FRRS1l as a powerful regulator of synaptic signaling and plasticity.Graphical Graphical abstract for this article
  • Cortical Circuit Dynamics Are Homeostatically Tuned to Criticality
           In Vivo
    • Abstract: Publication date: Available online 7 October 2019Source: NeuronAuthor(s): Zhengyu Ma, Gina G. Turrigiano, Ralf Wessel, Keith B. HengenSummaryHomeostatic mechanisms stabilize neuronal activity in vivo, but whether this process gives rise to balanced network dynamics is unknown. Here, we continuously monitored the statistics of network spiking in visual cortical circuits in freely behaving rats for 9 days. Under control conditions in light and dark, networks were robustly organized around criticality, a regime that maximizes information capacity and transmission. When input was perturbed by visual deprivation, network criticality was severely disrupted and subsequently restored to criticality over 48 h. Unexpectedly, the recovery of excitatory dynamics preceded homeostatic plasticity of firing rates by>30 h. We utilized model investigations to manipulate firing rate homeostasis in a cell-type-specific manner at the onset of visual deprivation. Our results suggest that criticality in excitatory networks is established by inhibitory plasticity and architecture. These data establish that criticality is consistent with a homeostatic set point for visual cortical dynamics and suggest a key role for homeostatic regulation of inhibition.
  • Orofacial Movements Involve Parallel Corticobulbar Projections from Motor
           Cortex to Trigeminal Premotor Nuclei
    • Abstract: Publication date: Available online 3 October 2019Source: NeuronAuthor(s): Nicole Mercer Lindsay, Per M. Knutsen, Adrian F. Lozada, Daniel Gibbs, Harvey J. Karten, David KleinfeldSummaryHow do neurons in orofacial motor cortex (MCtx) orchestrate behaviors' We show that focal activation of MCtx corticobulbar neurons evokes behaviorally relevant concurrent movements of the forelimb, jaw, nose, and vibrissae. The projections from different locations in MCtx form gradients of boutons across premotor nuclei spinal trigeminal pars oralis (SpVO) and interpolaris rostralis (SpVIr). Furthermore, retrograde viral tracing from muscles that control orofacial actions shows that these premotor nuclei segregate their outputs. In the most dramatic case, both SpVO and SpVIr are premotor to forelimb and vibrissa muscles, while only SpVO is premotor to jaw muscles. Functional confirmation of the superimposed control by MCtx was obtained through selective optogenetic activation of corticobulbar neurons on the basis of their preferential projections to SpVO versus SpVIr. We conclude that neighboring projection neurons in orofacial MCtx form parallel pathways to distinct pools of trigeminal premotor neurons that coordinate motor actions into a behavior.
  • Identification of Spinal Neurons Contributing to the Dorsal Column
           Projection Mediating Fine Touch and Corrective Motor Movements
    • Abstract: Publication date: Available online 2 October 2019Source: NeuronAuthor(s): Sónia Paixão, Laura Loschek, Louise Gaitanos, Pilar Alcalà Morales, Martyn Goulding, Rüdiger KleinSummaryTactile stimuli are integrated and processed by neuronal circuits in the deep dorsal horn of the spinal cord. Several spinal interneuron populations have been implicated in tactile information processing. However, dorsal horn projection neurons that contribute to the postsynaptic dorsal column (PSDC) pathway transmitting tactile information to the brain are poorly characterized. Here, we show that spinal neurons marked by the expression of Zic2creER mediate light touch sensitivity and textural discrimination. A subset of Zic2creER neurons are PSDC neurons that project to brainstem dorsal column nuclei, and chemogenetic activation of Zic2 PSDC neurons increases sensitivity to light touch stimuli. Zic2 neurons receive direct input from the cortex and brainstem motor nuclei and are required for corrective motor movements. These results suggest that Zic2 neurons integrate sensory input from cutaneous afferents with descending signals from the brain to promote corrective movements and transmit processed touch information back to the brain.Graphical Graphical abstract for this article
School of Mathematical and Computer Sciences
Heriot-Watt University
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