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Journal Prestige (SJR): 10.654
Citation Impact (citeScore): 11
Number of Followers: 247  
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ISSN (Print) 0896-6273 - ISSN (Online) 1097-4199
Published by Elsevier Homepage  [3185 journals]
  • A Discrete Dorsal Raphe to Basal Amygdala 5-HT Circuit Calibrates Aversive
    • Abstract: Publication date: Available online 13 June 2019Source: NeuronAuthor(s): Ayesha Sengupta, Andrew HolmesSummaryDespite a wealth of clinical and preclinical data implicating the serotonin (5-HT) system in fear-related affective disorders, a precise definition of this neuromodulator’s role in fear remains elusive. Using convergent anatomical and functional approaches, we interrogate the contribution to fear of basal amygdala (BA) 5-HT inputs from the dorsal raphe nucleus (DRN). We show the DRN→BA 5-HT pathway is engaged during fear memory formation and retrieval, and activity of these projections facilitates fear and impairs extinction. The DRN→BA 5-HT pathway amplifies fear-associated BA neuronal firing and theta power and phase-locking. Although fear recruits 5-HT and VGluT3 co-expressing DRN neurons, the fear-potentiating influence of the DRN→BA 5-HT pathway requires signaling at BA 5-HT1A/2A receptors. Input-output mapping illustrates how the DRN→BA 5-HT pathway is anatomically distinct and connected with other brain regions that mediate fear. These findings reveal how a discrete 5-HT circuit orchestrates a broader neural network to calibrate aversive memory.Graphical Graphical abstract for this article
  • A Specialized Neural Circuit Gates Social Vocalizations in the Mouse
    • Abstract: Publication date: Available online 13 June 2019Source: NeuronAuthor(s): Katherine Tschida, Valerie Michael, Jun Takato, Bao-Xia Han, Shengli Zhao, Katsuyasu Sakurai, Richard Mooney, Fan WangSummaryVocalizations are fundamental to mammalian communication, but the underlying neural circuits await detailed characterization. Here, we used an intersectional genetic method to label and manipulate neurons in the midbrain periaqueductal gray (PAG) that are transiently active in male mice when they produce ultrasonic courtship vocalizations (USVs). Genetic silencing of PAG-USV neurons rendered males unable to produce USVs and impaired their ability to attract females. Conversely, activating PAG-USV neurons selectively triggered USV production, even in the absence of any female cues. Optogenetic stimulation combined with axonal tracing indicates that PAG-USV neurons gate downstream vocal-patterning circuits. Indeed, activating PAG neurons that innervate the nucleus retroambiguus, but not those innervating the parabrachial nucleus, elicited USVs in both male and female mice. These experiments establish that a dedicated population of PAG neurons gives rise to a descending circuit necessary and sufficient for USV production while also demonstrating the communicative salience of male USVs.Graphical Graphical abstract for this article
  • Prefrontal Cortex Regulates Sensory Filtering through a Basal
           Ganglia-to-Thalamus Pathway
    • Abstract: Publication date: Available online 12 June 2019Source: NeuronAuthor(s): Miho Nakajima, L.Ian Schmitt, Michael M. HalassaSummaryTo make adaptive decisions, organisms must appropriately filter sensory inputs, augmenting relevant signals and suppressing noise. The prefrontal cortex (PFC) partly implements this process by regulating thalamic activity through modality-specific thalamic reticular nucleus (TRN) subnetworks. However, because the PFC does not directly project to sensory TRN subnetworks, the circuitry underlying this process had been unknown. Here, using anatomical tracing, functional manipulations, and optical identification of PFC projection neurons, we find that the PFC regulates sensory thalamic activity through a basal ganglia (BG) pathway. Engagement of this PFC-BG-thalamus pathway enables selection between vision and audition by primarily suppressing the distracting modality. This pathway also enhances sensory discrimination and is used for goal-directed background noise suppression. Overall, our results identify a new pathway for attentional filtering and reveal its multiple roles in sensory processing on the basis of internal goals.
  • A VTA GABAergic Neural Circuit Mediates Visually Evoked Innate Defensive
    • Abstract: Publication date: Available online 12 June 2019Source: NeuronAuthor(s): Zheng Zhou, Xuemei Liu, Shanping Chen, Zhijian Zhang, Yuanming Liu, Quentin Montardy, Yongqiang Tang, Pengfei Wei, Nan Liu, Lei Li, Ru Song, Juan Lai, Xiaobin He, Chen Chen, Guoqiang Bi, Guoping Feng, Fuqiang Xu, Liping WangSummaryInnate defensive responses are essential for animal survival and are conserved across species. The ventral tegmental area (VTA) plays important roles in learned appetitive and aversive behaviors, but whether it plays a role in mediating or modulating innate defensive responses is currently unknown. We report that VTAGABA+ neurons respond to a looming stimulus. Inhibition of VTAGABA+ neurons reduced looming-evoked defensive flight behavior, and photoactivation of these neurons resulted in defense-like flight behavior. Using viral tracing and electrophysiological recordings, we show that VTAGABA+ neurons receive direct excitatory inputs from the superior colliculus (SC). Furthermore, we show that glutamatergic SC-VTA projections synapse onto VTAGABA+ neurons that project to the central nucleus of the amygdala (CeA) and that the CeA is involved in mediating the defensive behavior. Our findings demonstrate that aerial threat-related visual information is relayed to VTAGABA+ neurons mediating innate behavioral responses, suggesting a more general role of the VTA.Graphical Graphical abstract for this article
  • Cerebellar Contribution to Preparatory Activity in Motor Neocortex
    • Abstract: Publication date: Available online 11 June 2019Source: NeuronAuthor(s): Francois P. Chabrol, Antonin Blot, Thomas D. Mrsic-FlogelSummaryIn motor neocortex, preparatory activity predictive of specific movements is maintained by a positive feedback loop with the thalamus. Motor thalamus receives excitatory input from the cerebellum, which learns to generate predictive signals for motor control. The contribution of this pathway to neocortical preparatory signals remains poorly understood. Here, we show that, in a virtual reality conditioning task, cerebellar output neurons in the dentate nucleus exhibit preparatory activity similar to that in anterolateral motor cortex prior to reward acquisition. Silencing activity in dentate nucleus by photoactivating inhibitory Purkinje cells in the cerebellar cortex caused robust, short-latency suppression of preparatory activity in anterolateral motor cortex. Our results suggest that preparatory activity is controlled by a learned decrease of Purkinje cell firing in advance of reward under supervision of climbing fiber inputs signaling reward delivery. Thus, cerebellar computations exert a powerful influence on preparatory activity in motor neocortex.
  • Open Source Brain: A Collaborative Resource for Visualizing, Analyzing,
           Simulating, and Developing Standardized Models of Neurons and Circuits
    • Abstract: Publication date: Available online 11 June 2019Source: NeuronAuthor(s): Padraig Gleeson, Matteo Cantarelli, Boris Marin, Adrian Quintana, Matt Earnshaw, Sadra Sadeh, Eugenio Piasini, Justas Birgiolas, Robert C. Cannon, N. Alex Cayco-Gajic, Sharon Crook, Andrew P. Davison, Salvador Dura-Bernal, András Ecker, Michael L. Hines, Giovanni Idili, Frederic Lanore, Stephen D. Larson, William W. Lytton, Amitava MajumdarSummaryComputational models are powerful tools for exploring the properties of complex biological systems. In neuroscience, data-driven models of neural circuits that span multiple scales are increasingly being used to understand brain function in health and disease. But their adoption and reuse has been limited by the specialist knowledge required to evaluate and use them. To address this, we have developed Open Source Brain, a platform for sharing, viewing, analyzing, and simulating standardized models from different brain regions and species. Model structure and parameters can be automatically visualized and their dynamical properties explored through browser-based simulations. Infrastructure and tools for collaborative interaction, development, and testing are also provided. We demonstrate how existing components can be reused by constructing new models of inhibition-stabilized cortical networks that match recent experimental results. These features of Open Source Brain improve the accessibility, transparency, and reproducibility of models and facilitate their reuse by the wider community.Graphical Graphical abstract for this article
  • Paraventricular Thalamus Projection Neurons Integrate Cortical and
           Hypothalamic Signals for Cue-Reward Processing
    • Abstract: Publication date: Available online 10 June 2019Source: NeuronAuthor(s): James M. Otis, ManHua Zhu, Vijay M.K. Namboodiri, Cory A. Cook, Oksana Kosyk, Ana M. Matan, Rose Ying, Yoshiko Hashikawa, Koichi Hashikawa, Ivan Trujillo-Pisanty, Jiami Guo, Randall L. Ung, Jose Rodriguez-Romaguera, E.S. Anton, Garret D. StuberSummaryThe paraventricular thalamus (PVT) is an interface for brain reward circuits, with input signals arising from structures, such as prefrontal cortex and hypothalamus, that are broadcast to downstream limbic targets. However, the precise synaptic connectivity, activity, and function of PVT circuitry for reward processing are unclear. Here, using in vivo two-photon calcium imaging, we find that PVT neurons projecting to the nucleus accumbens (PVT-NAc) develop inhibitory responses to reward-predictive cues coding for both cue-reward associative information and behavior. The multiplexed activity in PVT-NAc neurons is directed by opposing activity patterns in prefrontal and lateral hypothalamic afferent axons. Further, we find that prefrontal cue encoding may maintain accurate cue-reward processing, as optogenetic disruption of this encoding induced long-lasting effects on downstream PVT-NAc cue responses and behavioral cue discrimination. Together, these data reveal that PVT-NAc neurons act as an interface for reward processing by integrating relevant inputs to accurately inform reward-seeking behavior.
  • Subcortical Substrates of Explore-Exploit Decisions in Primates
    • Abstract: Publication date: Available online 10 June 2019Source: NeuronAuthor(s): Vincent D. Costa, Andrew R. Mitz, Bruno B. AverbeckSummaryThe explore-exploit dilemma refers to the challenge of deciding when to forego immediate rewards and explore new opportunities that could lead to greater rewards in the future. While motivational neural circuits facilitate learning based on past choices and outcomes, it is unclear whether they also support computations relevant for deciding when to explore. We recorded neural activity in the amygdala and ventral striatum of rhesus macaques as they solved a task that required them to balance novelty-driven exploration with exploitation of what they had already learned. Using a partially observable Markov decision process (POMDP) model to quantify explore-exploit trade-offs, we identified that the ventral striatum and amygdala differ in how they represent the immediate value of exploitative choices and the future value of exploratory choices. These findings show that subcortical motivational circuits are important in guiding explore-exploit decisions.
  • Sleep Regulation by Neurotensinergic Neurons in a Thalamo-Amygdala Circuit
    • Abstract: Publication date: Available online 6 June 2019Source: NeuronAuthor(s): Chenyan Ma, Peng Zhong, Danqian Liu, Zeke Katsh Barger, Li Zhou, Wei-Cheng Chang, Brian Kim, Yang DanSummaryA crucial step in understanding the sleep-control mechanism is to identify sleep neurons. Through systematic anatomical screening followed by functional testing, we identified two sleep-promoting neuronal populations along a thalamo-amygdala pathway, both expressing neurotensin (NTS). Rabies-mediated monosynaptic retrograde tracing identified the central nucleus of amygdala (CeA) as a major source of GABAergic inputs to multiple wake-promoting populations; gene profiling revealed NTS as a prominent marker for these CeA neurons. Optogenetic activation and inactivation of NTS-expressing CeA neurons promoted and suppressed non-REM (NREM) sleep, respectively, and optrode recording showed they are sleep active. Further tracing showed that CeA GABAergic NTS neurons are innervated by glutamatergic NTS neurons in a posterior thalamic region, which also promote NREM sleep. CRISPR/Cas9-mediated NTS knockdown in either the thalamic or CeA neurons greatly reduced their sleep-promoting effect. These results reveal a novel thalamo-amygdala circuit for sleep generation in which NTS signaling is essential for both the upstream glutamatergic and downstream GABAergic neurons.Graphical Graphical abstract for this article
  • Widespread and Highly Correlated Somato-dendritic Activity in Cortical
           Layer 5 Neurons
    • Abstract: Publication date: Available online 6 June 2019Source: NeuronAuthor(s): Lou Beaulieu-Laroche, Enrique H.S. Toloza, Norma J. Brown, Mark T. HarnettSummaryDendritic integration can expand the information-processing capabilities of neurons. However, the recruitment of active dendritic processing in vivo and its relationship to somatic activity remain poorly understood. Here, we use two-photon GCaMP6f imaging to simultaneously monitor dendritic and somatic compartments in the awake primary visual cortex. Activity in layer 5 pyramidal neuron somata and distal apical trunk dendrites shows surprisingly high functional correlation. This strong coupling persists across neural activity levels and is unchanged by visual stimuli and locomotion. Ex vivo combined somato-dendritic patch-clamp and GCaMP6f recordings indicate that dendritic signals specifically reflect local electrogenesis triggered by dendritic inputs or high-frequency bursts of somatic action potentials. In contrast to the view that dendrites are only sparsely recruited under highly specific conditions in vivo, our results provide evidence that active dendritic integration is a widespread and intrinsic feature of cortical computation.Graphical Graphical abstract for this article
  • Interneurons: Learning on the Job
    • Abstract: Publication date: 5 June 2019Source: Neuron, Volume 102, Issue 5Author(s): Renata Batista-Brito, Gord FishellIn this issue, Wester et al. (2019) examine the obligate relationship between cortical interneurons and pyramidal neurons. By genetically converting superficial IT pyramidal cells into PT-like deep-layer pyramidal cells, they alter the position, connectivity, and gene expression within CGE-derived interneurons.
  • Central Amygdala Prepronociceptin-Expressing Neurons Mediate Palatable
           Food Consumption and Reward
    • Abstract: Publication date: 5 June 2019Source: Neuron, Volume 102, Issue 5Author(s): J. Andrew Hardaway, Lindsay R. Halladay, Christopher M. Mazzone, Dipanwita Pati, Daniel W. Bloodgood, Michelle Kim, Jennifer Jensen, Jeffrey F. DiBerto, Kristen M. Boyt, Ami Shiddapur, Ava Erfani, Olivia J. Hon, Sofia Neira, Christina M. Stanhope, Jonathan A. Sugam, Michael P. Saddoris, Greg Tipton, Zoe McElligott, Thomas C. Jhou, Garret D. Stuber
  • Universal Transform or Multiple Functionality' Understanding the
           Contribution of the Human Cerebellum across Task Domains
    • Abstract: Publication date: 5 June 2019Source: Neuron, Volume 102, Issue 5Author(s): Jörn Diedrichsen, Maedbh King, Carlos Hernandez-Castillo, Marty Sereno, Richard B. IvryAn impressive body of research over the past 30 years has implicated the human cerebellum in a broad range of functions, including motor control, perception, language, working memory, cognitive control, and social cognition. The relatively uniform anatomy and physiology of the cerebellar cortex has given rise to the idea that this structure performs the same computational function across diverse domains. Here we highlight evidence from the human neuroimaging literature that documents the striking functional heterogeneity of the cerebellum, both in terms of task-evoked activity patterns and, as measured under task-free conditions, functional connectivity with the neocortex. Building on these observations, we discuss the theoretical challenges these results present to the idea of a universal cerebellar computation and consider the alternative concept of multiple functionality, the idea that the same underlying circuit implements functionally distinct computations.
  • The Case for Neuroscience Research in the Classroom
    • Abstract: Publication date: 5 June 2019Source: Neuron, Volume 102, Issue 5Author(s): Gregory J. GageNeuroscience courses, largely relegated to advanced undergraduate or graduate universities, are now being offered in high schools and middle schools. Low-tech versions of advanced neuroscience research tools are being used in hands-on labs. In this NeuroView, I will argue the need for and provide an overview of neuroscience research beyond academia.
  • Shaking Paws Is Not the Same as Shaking Hands
    • Abstract: Publication date: 5 June 2019Source: Neuron, Volume 102, Issue 5Author(s): Nicholas E. Bush, Nadina O. Zweifel, Mitra J.Z. HartmannA recent Nature paper shows that activity in rodent forelimb somatosensory cortex is related to the animal’s behavioral report of vibration intensity and identifies candidate mechanoreceptors responsible for the cortical response. Results highlight striking anatomical and neural differences from primates.
  • Mitochondria Re-set Epilepsy
    • Abstract: Publication date: 5 June 2019Source: Neuron, Volume 102, Issue 5Author(s): Valerie Uytterhoeven, Natalie Kaempf, Patrik VerstrekenNeuronal networks maintain stable activity around a given set point, an enigmatic variable in homeostatic systems. In this issue of Neuron, Styr et al. (2019) now show that set points are regulated by mitochondria and propose a potential strategy to treat refractory forms of epilepsy.
  • A Chronic Pain in the ACC
    • Abstract: Publication date: 5 June 2019Source: Neuron, Volume 102, Issue 5Author(s): Nur Zeynep Gungor, Joshua JohansenIn this issue of Neuron, Meda et al. (2019) provide novel insights into how chronic pain alters connectivity and excitatory-inhibitory balance in a mediodorsal thalamus to anterior cingulate cortex circuit to promote aversive learning.
  • Leaving the Lights on Using Gamma Entrainment to Protect against
    • Abstract: Publication date: 5 June 2019Source: Neuron, Volume 102, Issue 5Author(s): Ana Catarina Ferreira, Joseph M. CastellanoThe brain generates natural oscillations from coordinated neuronal activity. Recent work exploring gamma oscillation entrainment raised the possibility that the phenomenon can be exploited to preserve neural function. In this issue of Neuron, Adaikkan et al. (2019) now show that chronic gamma entrainment using visual stimuli protects against several neurodegenerative phenotypes.
  • Cerebellar Control of Reach Kinematics for Endpoint Precision
    • Abstract: Publication date: Available online 4 June 2019Source: NeuronAuthor(s): Matthew I. Becker, Abigail L. PersonSummaryThe cerebellum is well appreciated to impart speed, smoothness, and precision to skilled movements such as reaching. How these functions are executed by the final output stage of the cerebellum, the cerebellar nuclei, remains unknown. Here, we identify a causal relationship between cerebellar output and mouse reach kinematics and show how that relationship is leveraged endogenously to enhance reach precision. Activity in the anterior interposed nucleus (IntA) was remarkably well aligned to reach endpoint, scaling with the magnitude of limb deceleration. Closed-loop optogenetic modulation of IntA activity, triggered on reach, supported a causal role for this activity in controlling reach velocity in real time. Relating endogenous neural variability to kinematic variability, we found that IntA endpoint activity is adaptively engaged relative to variations in initial reach velocity, supporting endpoint precision. Taken together, these results provide a framework for understanding the physiology and pathophysiology of the intermediate cerebellum during precise skilled movements.
  • Regional Heterogeneity in Gene Expression, Regulation, and Coherence in
           the Frontal Cortex and Hippocampus across Development and Schizophrenia
    • Abstract: Publication date: Available online 4 June 2019Source: NeuronAuthor(s): Leonardo Collado-Torres, Emily E. Burke, Amy Peterson, JooHeon Shin, Richard E. Straub, Anandita Rajpurohit, Stephen A. Semick, William S. Ulrich, BrainSeq Consortium, Amanda J. Price, Cristian Valencia, Ran Tao, Amy Deep-Soboslay, Thomas M. Hyde, Joel E. Kleinman, Daniel R. Weinberger, Andrew E. JaffeSummaryThe hippocampus formation, although prominently implicated in schizophrenia pathogenesis, has been overlooked in large-scale genomics efforts in the schizophrenic brain. We performed RNA-seq in hippocampi and dorsolateral prefrontal cortices (DLPFCs) from 551 individuals (286 with schizophrenia). We identified substantial regional differences in gene expression and found widespread developmental differences that were independent of cellular composition. We identified 48 and 245 differentially expressed genes (DEGs) associated with schizophrenia within the hippocampus and DLPFC, with little overlap between the brain regions. 124 of 163 (76.6%) of schizophrenia GWAS risk loci contained eQTLs in any region. Transcriptome-wide association studies in each region identified many novel schizophrenia risk features that were brain region-specific. Last, we identified potential molecular correlates of in vivo evidence of altered prefrontal-hippocampal functional coherence in schizophrenia. These results underscore the complexity and regional heterogeneity of the transcriptional correlates of schizophrenia and offer new insights into potentially causative biology.
  • SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse
    • Abstract: Publication date: Available online 3 June 2019Source: NeuronAuthor(s): Frank Koopmans, Pim van Nierop, Maria Andres-Alonso, Andrea Byrnes, Tony Cijsouw, Marcelo P. Coba, L. Niels Cornelisse, Ryan J. Farrell, Hana L. Goldschmidt, Daniel P. Howrigan, Natasha K. Hussain, Cordelia Imig, Arthur P.H. de Jong, Hwajin Jung, Mahdokht Kohansalnodehi, Barbara Kramarz, Noa Lipstein, Ruth C. Lovering, Harold MacGillavry, Vittoria MarianoSummarySynapses are fundamental information-processing units of the brain, and synaptic dysregulation is central to many brain disorders (“synaptopathies”). However, systematic annotation of synaptic genes and ontology of synaptic processes are currently lacking. We established SynGO, an interactive knowledge base that accumulates available research about synapse biology using Gene Ontology (GO) annotations to novel ontology terms: 87 synaptic locations and 179 synaptic processes. SynGO annotations are exclusively based on published, expert-curated evidence. Using 2,922 annotations for 1,112 genes, we show that synaptic genes are exceptionally well conserved and less tolerant to mutations than other genes. Many SynGO terms are significantly overrepresented among gene variations associated with intelligence, educational attainment, ADHD, autism, and bipolar disorder and among de novo variants associated with neurodevelopmental disorders, including schizophrenia. SynGO is a public, universal reference for synapse research and an online analysis platform for interpretation of large-scale -omics data ( and Graphical abstract for this article
  • Accurate Estimation of Neural Population Dynamics without Spike Sorting
    • Abstract: Publication date: Available online 3 June 2019Source: NeuronAuthor(s): Eric M. Trautmann, Sergey D. Stavisky, Subhaneil Lahiri, Katherine C. Ames, Matthew T. Kaufman, Daniel J. O’Shea, Saurabh Vyas, Xulu Sun, Stephen I. Ryu, Surya Ganguli, Krishna V. ShenoySummaryA central goal of systems neuroscience is to relate an organism’s neural activity to behavior. Neural population analyses often reduce the data dimensionality to focus on relevant activity patterns. A major hurdle to data analysis is spike sorting, and this problem is growing as the number of recorded neurons increases. Here, we investigate whether spike sorting is necessary to estimate neural population dynamics. The theory of random projections suggests that we can accurately estimate the geometry of low-dimensional manifolds from a small number of linear projections of the data. We recorded data using Neuropixels probes in motor cortex of nonhuman primates and reanalyzed data from three previous studies and found that neural dynamics and scientific conclusions are quite similar using multiunit threshold crossings rather than sorted neurons. This finding unlocks existing data for new analyses and informs the design and use of new electrode arrays for laboratory and clinical use.Graphical Graphical abstract for this article
  • Songbird Ventral Pallidum Sends Diverse Performance Error Signals to
           Dopaminergic Midbrain
    • Abstract: Publication date: Available online 29 May 2019Source: NeuronAuthor(s): Ruidong Chen, Pavel A. Puzerey, Andrea C. Roeser, Tori E. Riccelli, Archana Podury, Kamal Maher, Alexander R. Farhang, Jesse H. GoldbergSummaryMotor skills improve with practice, requiring outcomes to be evaluated against ever-changing performance benchmarks, yet it remains unclear how performance error signals are computed. Here, we show that the songbird ventral pallidum (VP) is required for song learning and sends diverse song timing and performance error signals to the ventral tegmental area (VTA). Viral tracing revealed inputs to VP from auditory and vocal motor thalamus, auditory and vocal motor cortex, and VTA. Our findings show that VP circuits, commonly associated with hedonic functions, signal performance error during motor sequence learning.
  • Temporally and Spatially Distinct Thirst Satiation Signals
    • Abstract: Publication date: Available online 29 May 2019Source: NeuronAuthor(s): Vineet Augustine, Haruka Ebisu, Yuan Zhao, Sangjun Lee, Brittany Ho, Grace O. Mizuno, Lin Tian, Yuki OkaSummaryFor thirsty animals, fluid intake provides both satiation and pleasure of drinking. How the brain processes these factors is currently unknown. Here, we identified neural circuits underlying thirst satiation and examined their contribution to reward signals. We show that thirst-driving neurons receive temporally distinct satiation signals by liquid-gulping-induced oropharyngeal stimuli and gut osmolality sensing. We demonstrate that individual thirst satiation signals are mediated by anatomically distinct inhibitory neural circuits in the lamina terminalis. Moreover, we used an ultrafast dopamine (DA) sensor to examine whether thirst satiation itself stimulates the reward-related circuits. Interestingly, spontaneous drinking behavior but not thirst drive reduction triggered DA release. Importantly, chemogenetic stimulation of thirst satiation neurons did not activate DA neurons under water-restricted conditions. Together, this study dissected the thirst satiation circuit, the activity of which is functionally separable from reward-related brain activity.Graphical Graphical abstract for this article
  • Rapid Plasticity of Higher-Order Thalamocortical Inputs during Sensory
    • Abstract: Publication date: Available online 28 May 2019Source: NeuronAuthor(s): Nicholas J. Audette, Sarah M. Bernhard, Ajit Ray, Luke T. Stewart, Alison L. BarthSummaryNeocortical circuits are sensitive to experience, showing both anatomical and electrophysiological changes in response to altered sensory input. We examined input- and cell-type-specific changes in thalamo- and intracortical pathways during learning using an automated, home-cage sensory association training (SAT) paradigm coupling multi-whisker stimulation to a water reward. We found that the posterior medial nucleus (POm) but not the ventral posterior medial (VPM) nucleus of the thalamus drives increased cortical activity after 24 h of SAT, when behavioral evidence of learning first emerges. Synaptic strengthening within the POm thalamocortical pathway was first observed at thalamic inputs to L5 and was not generated by sensory stimulation alone. Synaptic changes in L2 were delayed relative to L5, requiring 48 h of SAT to drive synaptic plasticity at thalamic and intracortical inputs onto L2 Pyr neurons. These data identify the POm thalamocortical circuit as a site of rapid synaptic plasticity during learning and suggest a temporal sequence to learning-evoked synaptic changes in the sensory cortex.
  • Thermoregulation via Temperature-Dependent PGD2 Production in
           Mouse Preoptic Area
    • Abstract: Publication date: Available online 28 May 2019Source: NeuronAuthor(s): Tongfei A. Wang, Chin Fen Teo, Malin Åkerblom, Chao Chen, Marena Tynan-La Fontaine, Vanille Juliette Greiner, Aaron Diaz, Michael T. McManus, Yuh Nung Jan, Lily Y. JanSummaryBody temperature control is essential for survival. In mammals, thermoregulation is mediated by the preoptic area of anterior hypothalamus (POA), with ∼30% of its neurons sensitive to brain temperature change. It is still unknown whether and how these temperature-sensitive neurons are involved in thermoregulation, because for eight decades they have only been identified via electrophysiological recording. By combining single-cell RNA-seq with whole-cell patch-clamp recordings, we identified Ptgds as a genetic marker for temperature-sensitive POA neurons. Then, we demonstrated these neurons’ role in thermoregulation via chemogenetics. Given that Ptgds encodes the enzyme that synthesizes prostaglandin D2 (PGD2), we further explored its role in thermoregulation. Our study revealed that rising temperature of POA alters the activity of Ptgds-expressing neurons so as to increase PGD2 production. PGD2 activates its receptor DP1 and excites downstream neurons in the ventral medial preoptic area (vMPO) that mediates body temperature decrease, a negative feedback loop for thermoregulation.Graphical Graphical abstract for this article
  • Neuronal Architecture of a Visual Center that Processes Optic Flow
    • Abstract: Publication date: Available online 27 May 2019Source: NeuronAuthor(s): Anna Kramer, Yunmin Wu, Herwig Baier, Fumi KuboSummaryAnimals use global image motion cues to actively stabilize their position by compensatory movements. Neurons in the zebrafish pretectum distinguish different optic flow patterns, e.g., rotation and translation, to drive appropriate behaviors. Combining functional imaging and morphological reconstruction of single cells, we revealed critical neuroanatomical features of this sensorimotor transformation. Terminals of direction-selective retinal ganglion cells (DS-RGCs) are located within the pretectal retinal arborization field 5 (AF5), where they meet dendrites of pretectal neurons with simple tuning to monocular optic flow. Translation-selective neurons, which respond selectively to optic flow in the same direction for both eyes, are intermingled with these simple cells but do not receive inputs from DS-RGCs. Mutually exclusive populations of pretectal projection neurons innervate either the reticular formation or the cerebellum, which in turn control motor responses. We posit that local computations in a defined pretectal circuit transform optic flow signals into neural commands driving optomotor behavior.Graphical Graphical abstract for this article
  • A Cellular-Resolution Atlas of the Larval Zebrafish Brain
    • Abstract: Publication date: Available online 27 May 2019Source: NeuronAuthor(s): Michael Kunst, Eva Laurell, Nouwar Mokayes, Anna Kramer, Fumi Kubo, António M. Fernandes, Dominique Förster, Marco Dal Maschio, Herwig BaierSummaryUnderstanding brain-wide neuronal dynamics requires a detailed map of the underlying circuit architecture. We built an interactive cellular-resolution atlas of the zebrafish brain at 6 days post-fertilization (dpf) based on the reconstructions of over 2,000 individually GFP-labeled neurons. We clustered our dataset in “morphotypes,” establishing a unique database of quantitatively described neuronal morphologies together with their spatial coordinates in vivo. Over 100 transgene expression patterns were imaged separately and co-registered with the single-neuron atlas. By annotating 72 non-overlapping brain regions, we generated from our dataset an inter-areal wiring diagram of the larval brain, which serves as ground truth for synapse-scale, electron microscopic reconstructions. Interrogating our atlas by “virtual tract tracing” has already revealed previously unknown wiring principles in the tectum and the cerebellum. In conclusion, we present here an evolving computational resource and visualization tool, which will be essential to map function to structure in a vertebrate brain.Graphical Graphical abstract for this article
  • Discrete Stepping and Nonlinear Ramping Dynamics Underlie Spiking
           Responses of LIP Neurons during Decision-Making
    • Abstract: Publication date: Available online 23 May 2019Source: NeuronAuthor(s): David M. Zoltowski, Kenneth W. Latimer, Jacob L. Yates, Alexander C. Huk, Jonathan W. PillowSummaryNeurons in LIP exhibit ramping trial-averaged responses during decision-making. Recent work sparked debate over whether single-trial LIP spike trains are better described by discrete “stepping” or continuous “ramping” dynamics. We extended latent dynamical spike train models and used Bayesian model comparison to address this controversy. First, we incorporated non-Poisson spiking into both models and found that more neurons were better described by stepping than ramping, even when conditioned on evidence or choice. Second, we extended the ramping model to include a non-zero baseline and compressive output nonlinearity. This model accounted for roughly as many neurons as the stepping model. However, latent dynamics inferred under this model exhibited high diffusion variance for many neurons, softening the distinction between continuous and discrete dynamics. Results generalized to additional datasets, demonstrating that substantial fractions of neurons are well described by either stepping or nonlinear ramping, which may be less categorically distinct than the original labels implied.
  • Busted! A Dope Ring with Activity Clocked at Dawn and Dusk
    • Abstract: Publication date: 22 May 2019Source: Neuron, Volume 102, Issue 4Author(s): Brad K. Hulse, Vivek JayaramanClock neurons generate circadian rhythms in behavioral activity, but the relevant pathways remain poorly understood. In this issue of Neuron, Liang et al. (2019) show that distinct clock neurons independently drive movement-promoting “ring neurons” in Drosophila through dopaminergic relays to support morning and evening locomotor activity.
  • The Scientific Case for Brain Simulations
    • Abstract: Publication date: 22 May 2019Source: Neuron, Volume 102, Issue 4Author(s): Gaute T. Einevoll, Alain Destexhe, Markus Diesmann, Sonja Grün, Viktor Jirsa, Marc de Kamps, Michele Migliore, Torbjørn V. Ness, Hans E. Plesser, Felix SchürmannA key element of the European Union’s Human Brain Project (HBP) and other large-scale brain research projects is the simulation of large-scale model networks of neurons. Here, we argue why such simulations will likely be indispensable for bridging the scales between the neuron and system levels in the brain, and why a set of brain simulators based on neuron models at different levels of biological detail should therefore be developed. To allow for systematic refinement of candidate network models by comparison with experiments, the simulations should be multimodal in the sense that they should predict not only action potentials, but also electric, magnetic, and optical signals measured at the population and system levels.
  • Charting the Structure of Neuroscience
    • Abstract: Publication date: 22 May 2019Source: Neuron, Volume 102, Issue 4Author(s): Matteo CarandiniWhat are neuroscientists actually interested in' To find out, I studied their itineraries at the annual meeting of the Society for Neuroscience. I obtained a chart where topics that were commonly in the same itineraries form clusters. The empty spaces between these clusters might constitute opportunities for future efforts.
  • Owning Ethical Innovation: Claims about Commercial Wearable Brain
    • Abstract: Publication date: 22 May 2019Source: Neuron, Volume 102, Issue 4Author(s): Iris Coates McCall, Chloe Lau, Nicole Minielly, Judy IllesThe wearable neurotechnology market targets consumers with promises of cognitive benefit and personal wellness. Scientific evidence is essential to substantiate claims about utility, safety, and efficacy and for informed choice and public trust.
  • Healthy Development as a Human Right: Lessons from Developmental Science
    • Abstract: Publication date: 22 May 2019Source: Neuron, Volume 102, Issue 4Author(s): B.J. CaseyHealthy psychological and brain development is not a privilege, but a fundamental right that requires special protections and opportunities for building cognitive, emotional, and social skills necessary for becoming a contributing member of our society.
  • Charles Gordon Gross (1936–2019)
    • Abstract: Publication date: 22 May 2019Source: Neuron, Volume 102, Issue 4Author(s): Earl K. Miller, Robert Desimone
  • Paul Greengard (1925–2019)
    • Abstract: Publication date: 22 May 2019Source: Neuron, Volume 102, Issue 4Author(s): Joshua R. Sanes
  • Patterns of Neural Oscillations in Emotional Memory Discrimination
    • Abstract: Publication date: 22 May 2019Source: Neuron, Volume 102, Issue 4Author(s): Marcelo G. Mattar, Deborah TalmiAn exciting experiment by Zheng et al. (2019) in this issue of Neuron identifies neural signatures of successful and unsuccessful emotional memory discrimination. By examining human intracranial recordings with high spatial and temporal resolution, this study provides a novel link between rodent and human research on pattern separation.
  • Swelling Gliotransmission by SWELL1 Channels
    • Abstract: Publication date: 22 May 2019Source: Neuron, Volume 102, Issue 4Author(s): Paulo Kofuji, Alfonso AraqueAstrocytes release glutamate, which can modulate nearby synapses, but how this release is accomplished remains debated. In this issue of Neuron, Yang et al. (2019) show that the volume-regulated anion channel Swell1 in astrocytes mediates the release of glutamate and impacts synaptic transmission, learning and memory, and neurotoxicity.
  • The SIZ of Pain
    • Abstract: Publication date: 22 May 2019Source: Neuron, Volume 102, Issue 4Author(s): Sharon R. Ha, Matthew N. RasbandThe site of action potential initiation in sensory neurons remains poorly understood. In this issue of Neuron, Goldstein et al. (2019) identified the location of the sodium-dependent spike initiation zone (Nav-SIZ) in nociceptive neurons, showing its plasticity under inflammatory conditions.
  • Tag-Team Genetics of Spinocerebellar Ataxia 6
    • Abstract: Publication date: 22 May 2019Source: Neuron, Volume 102, Issue 4Author(s): Eve-Ellen Govek, Mary E. HattenIn this issue of Neuron, Du et al. (2019) demonstrate that the bicistronic CACNA1A gene encodes a transcription factor α1ACT, mutations in which are associated with SCA6, that controls expression of genes important for cerebellar Purkinje cell development and excitability. Reduction of α1ACT in the adult is well tolerated, suggesting a potential new therapy for SCA6.
  • Huntingtin Lowering Strategies for Disease Modification in
           Huntington’s Disease
    • Abstract: Publication date: 22 May 2019Source: Neuron, Volume 102, Issue 4Author(s): Sarah J. Tabrizi, Rhia Ghosh, Blair R. Leavitt
  • Single-Cell RNA-Seq Analysis of Retinal Development Identifies NFI Factors
           as Regulating Mitotic Exit and Late-Born Cell Specification
    • Abstract: Publication date: Available online 22 May 2019Source: NeuronAuthor(s): Brian S. Clark, Genevieve L. Stein-O’Brien, Fion Shiau, Gabrielle H. Cannon, Emily Davis-Marcisak, Thomas Sherman, Clayton P. Santiago, Thanh V. Hoang, Fatemeh Rajaii, Rebecca E. James-Esposito, Richard M. Gronostajski, Elana J. Fertig, Loyal A. Goff, Seth BlackshawSummaryPrecise temporal control of gene expression in neuronal progenitors is necessary for correct regulation of neurogenesis and cell fate specification. However, the cellular heterogeneity of the developing CNS has posed a major obstacle to identifying the gene regulatory networks that control these processes. To address this, we used single-cell RNA sequencing to profile ten developmental stages encompassing the full course of retinal neurogenesis. This allowed us to comprehensively characterize changes in gene expression that occur during initiation of neurogenesis, changes in developmental competence, and specification and differentiation of each major retinal cell type. We identify the NFI transcription factors (Nfia, Nfib, and Nfix) as selectively expressed in late retinal progenitor cells and show that they control bipolar interneuron and Müller glia cell fate specification and promote proliferative quiescence.
  • Elevating Growth Factor Responsiveness and Axon Regeneration by Modulating
           Presynaptic Inputs
    • Abstract: Publication date: Available online 20 May 2019Source: NeuronAuthor(s): Yiling Zhang, Philip R. Williams, Anne Jacobi, Chen Wang, Anurag Goel, Arlene A. Hirano, Nicholas C. Brecha, Daniel Kerschensteiner, Zhigang HeSummaryDespite robust effects on immature neurons, growth factors minimally promote axon regeneration in the adult central nervous system (CNS). Attempting to improve growth-factor responsiveness in mature neurons by dedifferentiation, we overexpressed Lin28 in the retina. Lin28-treated retinas responded to insulin-like growth factor-1 (IGF1) by initiating retinal ganglion cell (RGC) axon regeneration after axotomy. Surprisingly, this effect was cell non-autonomous. Lin28 expression was required only in amacrine cells, inhibitory neurons that innervate RGCs. Ultimately, we found that optic-nerve crush pathologically upregulated activity in amacrine cells, which reduced RGC electrical activity and suppressed growth-factor signaling. Silencing amacrine cells or pharmacologically blocking inhibitory neurotransmission also induced IGF1 competence. Remarkably, RGCs regenerating across these manipulations localized IGF1 receptor to their primary cilia, which maintained their signaling competence and regenerative ability. Thus, our results reveal a circuit-based mechanism that regulates CNS axon regeneration and implicate primary cilia as a regenerative signaling hub.
  • Loss of Adaptive Myelination Contributes to Methotrexate
           Chemotherapy-Related Cognitive Impairment
    • Abstract: Publication date: Available online 20 May 2019Source: NeuronAuthor(s): Anna C. Geraghty, Erin M. Gibson, Reem A. Ghanem, Jacob J. Greene, Alfonso Ocampo, Andrea K. Goldstein, Lijun Ni, Tao Yang, Rebecca M. Marton, Sergiu P. Paşca, Michael E. Greenberg, Frank M. Longo, Michelle MonjeSummaryActivity-dependent myelination is thought to contribute to adaptive neurological function. However, the mechanisms by which activity regulates myelination and the extent to which myelin plasticity contributes to non-motor cognitive functions remain incompletely understood. Using a mouse model of chemotherapy-related cognitive impairment (CRCI), we recently demonstrated that methotrexate (MTX) chemotherapy induces complex glial dysfunction for which microglial activation is central. Here, we demonstrate that remote MTX exposure blocks activity-regulated myelination. MTX decreases cortical Bdnf expression, which is restored by microglial depletion. Bdnf-TrkB signaling is a required component of activity-dependent myelination. Oligodendrocyte precursor cell (OPC)-specific TrkB deletion in chemotherapy-naive mice results in impaired cognitive behavioral performance. A small-molecule TrkB agonist rescues both myelination and cognitive impairment after MTX chemotherapy. This rescue after MTX depends on intact TrkB expression in OPCs. Taken together, these findings demonstrate a molecular mechanism required for adaptive myelination that is aberrant in CRCI due to microglial activation.Graphical Graphical abstract for this article
  • Transient Confinement of CaV2.1 Ca2+-Channel Splice Variants Shapes
           Synaptic Short-Term Plasticity
    • Abstract: Publication date: Available online 16 May 2019Source: NeuronAuthor(s): Jennifer Heck, Pierre Parutto, Anna Ciuraszkiewicz, Arthur Bikbaev, Romy Freund, Jessica Mitlöhner, Maria Alonso, Anna Fejtova, David Holcman, Martin HeineSummaryThe precision and reliability of synaptic information transfer depend on the molecular organization of voltage-gated calcium channels (VGCCs) within the presynaptic membrane. Alternative splicing of exon 47 affects the C-terminal structure of VGCCs and their affinity to intracellular partners and synaptic vesicles (SVs). We show that hippocampal synapses expressing VGCCs either with exon 47 (CaV2.1+47) or without (CaV2.1Δ47) differ in release probability and short-term plasticity. Tracking single channels revealed transient visits (∼100 ms) of presynaptic VGCCs in nanodomains (∼80 nm) that were controlled by neuronal network activity. Surprisingly, despite harboring prominent binding sites to scaffold proteins, CaV2.1+47 persistently displayed higher mobility within nanodomains. Synaptic accumulation of CaV2.1 was accomplished by optogenetic clustering, but only CaV2.1+47 increased transmitter release and enhanced synaptic short-term depression. We propose that exon 47-related alternative splicing of CaV2.1 channels controls synapse-specific release properties at the level of channel mobility-dependent coupling between VGCCs and SVs.
  • A Fear Memory Engram and Its Plasticity in the Hypothalamic Oxytocin
    • Abstract: Publication date: Available online 16 May 2019Source: NeuronAuthor(s): Mazahir T. Hasan, Ferdinand Althammer, Miriam Silva da Gouveia, Stephanie Goyon, Marina Eliava, Arthur Lefevre, Damien Kerspern, Jonas Schimmer, Androniki Raftogianni, Jerome Wahis, H. Sophie Knobloch-Bollmann, Yan Tang, Xinying Liu, Apar Jain, Virginie Chavant, Yannick Goumon, Jan-Marek Weislogel, René Hurlemann, Sabine C. Herpertz, Claudia PitzerSummaryOxytocin (OT) release by axonal terminals onto the central nucleus of the amygdala exerts anxiolysis. To investigate which subpopulation of OT neurons contributes to this effect, we developed a novel method: virus-delivered genetic activity-induced tagging of cell ensembles (vGATE). With the vGATE method, we identified and permanently tagged a small subpopulation of OT cells, which, by optogenetic stimulation, strongly attenuated contextual fear-induced freezing, and pharmacogenetic silencing of tagged OT neurons impaired context-specific fear extinction, demonstrating that the tagged OT neurons are sufficient and necessary, respectively, to control contextual fear. Intriguingly, OT cell terminals of fear-experienced rats displayed enhanced glutamate release in the amygdala. Furthermore, rats exposed to another round of fear conditioning displayed 5-fold more activated magnocellular OT neurons in a novel environment than a familiar one, possibly for a generalized fear response. Thus, our results provide first evidence that hypothalamic OT neurons represent a fear memory engram.
  • A Flexible Model of Working Memory
    • Abstract: Publication date: Available online 15 May 2019Source: NeuronAuthor(s): Flora Bouchacourt, Timothy J. BuschmanSummaryWorking memory is fundamental to cognition, allowing one to hold information “in mind.” A defining characteristic of working memory is its flexibility: we can hold anything in mind. However, typical models of working memory rely on finely tuned, content-specific attractors to persistently maintain neural activity and therefore do not allow for the flexibility observed in behavior. Here, we present a flexible model of working memory that maintains representations through random recurrent connections between two layers of neurons: a structured “sensory” layer and a randomly connected, unstructured layer. As the interactions are untuned with respect to the content being stored, the network maintains any arbitrary input. However, in our model, this flexibility comes at a cost: the random connections overlap, leading to interference between representations and limiting the memory capacity of the network. Additionally, our model captures several other key behavioral and neurophysiological characteristics of working memory.
  • How Gastrin-Releasing Peptide Opens the Spinal Gate for Itch
    • Abstract: Publication date: Available online 15 May 2019Source: NeuronAuthor(s): Martina Pagani, Gioele W. Albisetti, Nandhini Sivakumar, Hendrik Wildner, Mirko Santello, Helge C. Johannssen, Hanns Ulrich ZeilhoferSummarySpinal transmission of pruritoceptive (itch) signals requires transneuronal signaling by gastrin-releasing peptide (GRP) produced by a subpopulation of dorsal horn excitatory interneurons. These neurons also express the glutamatergic marker vGluT2, raising the question of why glutamate alone is insufficient for spinal itch relay. Using optogenetics together with slice electrophysiology and mouse behavior, we demonstrate that baseline synaptic coupling between GRP and GRP receptor (GRPR) neurons is too weak for suprathreshold excitation. Only when we mimicked the endogenous firing of GRP neurons and stimulated them repetitively to fire bursts of action potentials did GRPR neurons depolarize progressively and become excitable by GRP neurons. GRPR but not glutamate receptor antagonism prevented this action. Provoking itch-like behavior by optogenetic activation of spinal GRP neurons required similar stimulation paradigms. These results establish a spinal gating mechanism for itch that requires sustained repetitive activity of presynaptic GRP neurons and postsynaptic GRP signaling to drive GRPR neuron output.Graphical Graphical abstract for this article
  • Increased Cocaine Motivation Is Associated with Degraded Spatial and
           Temporal Representations in IL-NAc Neurons
    • Abstract: Publication date: Available online 14 May 2019Source: NeuronAuthor(s): Courtney M. Cameron, Malavika Murugan, Jung Yoon Choi, Esteban A. Engel, Ilana B. WittenSummaryCraving for cocaine progressively increases in cocaine users during drug-free periods, contributing to relapse. The projection from the infralimbic cortex to the nucleus accumbens shell (IL-NAc) is thought to inhibit cocaine seeking. However, it is not known whether and how IL-NAc neurons contribute to the increased motivation associated with a drug-free period. We first performed cellular resolution imaging of IL-NAc neurons in rats during a drug-seeking test. This revealed neurons with spatial selectivity within the cocaine-associated context, a decrease in activity around the time of cocaine seeking, and an inverse relationship between cocaine-seeking activity and subsequent cocaine motivation. All these properties were reduced by a drug-free period. Next, we transiently activated this projection, which resulted in reduced drug seeking, regardless of the drug-free period. Taken together, this suggests that altered IL-NAc activity after a drug-free period may enhance cocaine motivation without fundamentally altering the projection’s ability to inhibit drug seeking.Graphical Graphical abstract for this article
  • Glutathione S-Transferase Regulates Mitochondrial Populations in Axons
           through Increased Glutathione Oxidation
    • Abstract: Publication date: Available online 14 May 2019Source: NeuronAuthor(s): Gaynor A. Smith, Tzu-Huai Lin, Amy E. Sheehan, Wynand Van der Goes van Naters, Lukas J. Neukomm, Hillary K. Graves, Dana M. Bis-Brewer, Stephan Züchner, Marc R. FreemanSummaryMitochondria are essential in long axons to provide metabolic support and sustain neuron integrity. A healthy mitochondrial pool is maintained by biogenesis, transport, mitophagy, fission, and fusion, but how these events are regulated in axons is not well defined. Here, we show that the Drosophila glutathione S-transferase (GST) Gfzf prevents mitochondrial hyperfusion in axons. Gfzf loss altered redox balance between glutathione (GSH) and oxidized glutathione (GSSG) and initiated mitochondrial fusion through the coordinated action of Mfn and Opa1. Gfzf functioned epistatically with the thioredoxin peroxidase Jafrac1 and the thioredoxin reductase 1 TrxR-1 to regulate mitochondrial dynamics. Altering GSH:GSSG ratios in mouse primary neurons in vitro also induced hyperfusion. Mitochondrial changes caused deficits in trafficking, the metabolome, and neuronal physiology. Changes in GSH and oxidative state are associated with neurodegenerative diseases like Alzheimer’s. Our demonstration that GSTs are key in vivo regulators of axonal mitochondrial length and number provides a potential mechanistic link.
  • Rapid Invariant Encoding of Scene Layout in Human OPA
    • Abstract: Publication date: Available online 13 May 2019Source: NeuronAuthor(s): Linda Henriksson, Marieke Mur, Nikolaus KriegeskorteSummarySuccessful visual navigation requires a sense of the geometry of the local environment. How do our brains extract this information from retinal images' Here we visually presented scenes with all possible combinations of five scene-bounding elements (left, right, and back walls; ceiling; floor) to human subjects during functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). The fMRI response patterns in the scene-responsive occipital place area (OPA) reflected scene layout with invariance to changes in surface texture. This result contrasted sharply with the primary visual cortex (V1), which reflected low-level image features of the stimuli, and the parahippocampal place area (PPA), which showed better texture than layout decoding. MEG indicated that the texture-invariant scene layout representation is computed from visual input within ∼100 ms, suggesting a rapid computational mechanism. Taken together, these results suggest that the cortical representation underlying our instant sense of the environmental geometry is located in the OPA.
  • Striatal Low-Threshold Spiking Interneurons Regulate Goal-Directed
    • Abstract: Publication date: Available online 13 May 2019Source: NeuronAuthor(s): Elizabeth N. Holly, M. Felicia Davatolhagh, Kyuhyun Choi, Opeyemi O. Alabi, Luigim Vargas Cifuentes, Marc V. FuccilloSummaryThe dorsomedial striatum (DMS) is critically involved in motor control and reward processing, but the specific neural circuit mediators are poorly understood. Recent evidence highlights the extensive connectivity of low-threshold spiking interneurons (LTSIs) within local striatal circuitry; however, the in vivo function of LTSIs remains largely unexplored. We employed fiber photometry to assess LTSI calcium activity in a range of DMS-mediated behaviors, uncovering specific reward-related activity that is down-modulated during goal-directed learning. Using two mechanistically distinct manipulations, we demonstrated that this down-modulation of LTSI activity is critical for acquisition of novel contingencies, but not for their modification. In contrast, continued LTSI activation slowed instrumental learning. Similar manipulations of fast-spiking interneurons did not reproduce these effects, implying a specific function of LTSIs. Finally, we revealed a role for the γ-aminobutyric acid (GABA)ergic functions of LTSIs in learning. Together, our data provide new insights into this striatal interneuron subclass as important gatekeepers of goal-directed learning.Graphical Graphical abstract for this article
  • Mitochondrial Dysfunction Leads to Cortical Under-Connectivity and
           Cognitive Impairment
    • Abstract: Publication date: Available online 9 May 2019Source: NeuronAuthor(s): Alejandra Fernandez, Daniel W. Meechan, Beverly A. Karpinski, Elizabeth M. Paronett, Corey A. Bryan, Hanna L. Rutz, Eric A. Radin, Noah Lubin, Erin R. Bonner, Anastas Popratiloff, Lawrence A. Rothblat, Thomas M. Maynard, Anthony-Samuel LaMantiaSummaryUnder-connectivity between cerebral cortical association areas may underlie cognitive deficits in neurodevelopmental disorders, including the 22q11.2 deletion syndrome (22q11DS). Using the LgDel 22q11DS mouse model, we assessed cellular, molecular, and developmental origins of under-connectivity and its consequences for cognitive function. Diminished 22q11 gene dosage reduces long-distance projections, limits axon and dendrite growth, and disrupts mitochondrial and synaptic integrity in layer 2/3 but not 5/6 projection neurons (PNs). Diminished dosage of Txnrd2, a 22q11 gene essential for reactive oxygen species catabolism in brain mitochondria, recapitulates these deficits in WT layer 2/3 PNs; Txnrd2 re-expression in LgDel layer 2/3 PNs rescues them. Anti-oxidants reverse LgDel- or Txnrd2-related layer 2/3 mitochondrial, circuit, and cognitive deficits. Accordingly, Txnrd2-mediated oxidative stress reduces layer 2/3 connectivity and impairs cognition in the context of 22q11 deletion. Anti-oxidant restoration of mitochondrial integrity, cortical connectivity, and cognitive behavior defines oxidative stress as a therapeutic target in neurodevelopmental disorders.Graphical Graphical abstract for this article
  • Reciprocal Activation within a Kinase-Effector Complex Underlying
           Persistence of Structural LTP
    • Abstract: Publication date: Available online 8 May 2019Source: NeuronAuthor(s): Takeo Saneyoshi, Hitomi Matsuno, Akio Suzuki, Hideji Murakoshi, Nathan G. Hedrick, Emily Agnello, Rory O’Connell, Margaret M. Stratton, Ryohei Yasuda, Yasunori HayashiSummaryLong-term synaptic plasticity requires a mechanism that converts short Ca2+ pulses into persistent biochemical signaling to maintain changes in the synaptic structure and function. Here, we present a novel mechanism of a positive feedback loop, formed by a reciprocally activating kinase-effector complex (RAKEC) in dendritic spines, enabling the persistence and confinement of a molecular memory. We found that stimulation of a single spine causes the rapid formation of a RAKEC consisting of CaMKII and Tiam1, a Rac-GEF. This interaction is mediated by a pseudo-autoinhibitory domain on Tiam1, which is homologous to the CaMKII autoinhibitory domain itself. Therefore, Tiam1 binding results in constitutive CaMKII activation, which in turn persistently phosphorylates Tiam1. Phosphorylated Tiam1 promotes stable actin-polymerization through Rac1, thereby maintaining the structure of the spine during LTP. The RAKEC can store biochemical information in small subcellular compartments, thus potentially serving as a general mechanism for prolonged and compartmentalized signaling.
  • Positional Strategies for Connection Specificity and Synaptic Organization
           in Spinal Sensory-Motor Circuits
    • Abstract: Publication date: Available online 7 May 2019Source: NeuronAuthor(s): Nikolaos Balaskas, L.F. Abbott, Thomas M. Jessell, David NgSummaryProprioceptive sensory axons in the spinal cord form selective connections with motor neuron partners, but the strategies that confer such selectivity remain uncertain. We show that muscle-specific sensory axons project to motor neurons along topographically organized angular trajectories and that motor pools exhibit diverse dendritic arbors. On the basis of spatial constraints on axo-dendritic interactions, we propose positional strategies that can account for sensory-motor connectivity and synaptic organization. These strategies rely on two patterning principles. First, the degree of axo-dendritic overlap reduces the number of potential post-synaptic partners. Second, a close correlation between the small angle of axo-dendritic approach and the formation of synaptic clusters imposes specificity of connections when sensory axons intersect multiple motor pools with overlapping dendritic arbors. Our study identifies positional strategies with prominent roles in the organization of spinal sensory-motor circuits.Graphical Graphical abstract for this article
  • Gamma Entrainment Binds Higher-Order Brain Regions and Offers
    • Abstract: Publication date: Available online 7 May 2019Source: NeuronAuthor(s): Chinnakkaruppan Adaikkan, Steven J. Middleton, Asaf Marco, Ping-Chieh Pao, Hansruedi Mathys, David Nam-Woo Kim, Fan Gao, Jennie Z. Young, Ho-Jun Suk, Edward S. Boyden, Thomas J. McHugh, Li-Huei TsaiSummaryNeuronal and synaptic loss is characteristic in many neurodegenerative diseases, such as frontotemporal dementia and Alzheimer’s disease. Recently, we showed that inducing gamma oscillations with visual stimulation (gamma entrainment using sensory stimuli, or GENUS) reduced amyloid plaques and phosphorylated tau in multiple mouse models. Whether GENUS can affect neurodegeneration or cognitive performance remains unknown. Here, we demonstrate that GENUS can entrain gamma oscillations in the visual cortex, hippocampus, and prefrontal cortex in Tau P301S and CK-p25 mouse models of neurodegeneration. Tau P301S and CK-p25 mice subjected to chronic, daily GENUS from the early stages of neurodegeneration showed a preservation of neuronal and synaptic density across multiple brain areas and modified cognitive performance. Our transcriptomic and phosphoproteomic data suggest that chronic GENUS shifts neurons to a less degenerative state, improving synaptic function, enhancing neuroprotective factors, and reducing DNA damage in neurons while also reducing inflammatory response in microglia.Graphical Graphical abstract for this article
  • A Neural Circuit Encoding the Experience of Copulation in Female
    • Abstract: Publication date: Available online 6 May 2019Source: NeuronAuthor(s): Lisha Shao, Phuong Chung, Allan Wong, Igor Siwanowicz, Clement F. Kent, Xi Long, Ulrike HeberleinSummaryFemale behavior changes profoundly after mating. In Drosophila, the mechanisms underlying the long-term changes led by seminal products have been extensively studied. However, the effect of the sensory component of copulation on the female’s internal state and behavior remains elusive. We pursued this question by dissociating the effect of coital sensory inputs from those of male ejaculate. We found that the sensory inputs of copulation cause a reduction of post-coital receptivity in females, referred to as the “copulation effect.” We identified three layers of a neural circuit underlying this phenomenon. Abdominal neurons expressing the mechanosensory channel Piezo convey the signal of copulation to female-specific ascending neurons, LSANs, in the ventral nerve cord. LSANs relay this information to neurons expressing myoinhibitory peptides in the brain. We hereby provide a neural mechanism by which the experience of copulation facilitates females encoding their mating status, thus adjusting behavior to optimize reproduction.
  • Activity-Dependent Secretion of Synaptic Organizer Cbln1 from Lysosomes in
           Granule Cell Axons
    • Abstract: Publication date: Available online 6 May 2019Source: NeuronAuthor(s): Keiji Ibata, Maya Kono, Sakae Narumi, Junko Motohashi, Wataru Kakegawa, Kazuhisa Kohda, Michisuke YuzakiSummarySynapse formation is achieved by various synaptic organizers. Although this process is highly regulated by neuronal activity, the underlying molecular mechanisms remain largely unclear. Here we show that Cbln1, a synaptic organizer of the C1q family, is released from lysosomes in axons but not dendrites of cerebellar granule cells in an activity- and Ca2+-dependent manner. Exocytosed Cbln1 was retained on axonal surfaces by binding to its presynaptic receptor neurexin. Cbln1 further diffused laterally along the axonal surface and accumulated at boutons by binding postsynaptic δ2 glutamate receptors. Cbln1 exocytosis was insensitive to tetanus neurotoxin, accompanied by cathepsin B release, and decreased by disrupting lysosomes. Furthermore, overexpression of lysosomal sialidase Neu1 not only inhibited Cbln1 and cathepsin B exocytosis in vitro but also reduced axonal bouton formation in vivo. Our findings imply that co-release of Cbln1 and cathepsin B from lysosomes serves as a new mechanism of activity-dependent coordinated synapse modification.
  • Light-Driven Regeneration of Cone Visual Pigments through a Mechanism
           Involving RGR Opsin in Müller Glial Cells
    • Abstract: Publication date: Available online 2 May 2019Source: NeuronAuthor(s): Ala Morshedian, Joanna J. Kaylor, Sze Yin Ng, Avian Tsan, Rikard Frederiksen, Tongzhou Xu, Lily Yuan, Alapakkam P. Sampath, Roxana A. Radu, Gordon L. Fain, Gabriel H. TravisSummaryWhile rods in the mammalian retina regenerate rhodopsin through a well-characterized pathway in cells of the retinal pigment epithelium (RPE), cone visual pigments are thought to regenerate in part through an additional pathway in Müller cells of the neural retina. The proteins comprising this intrinsic retinal visual cycle are unknown. Here, we show that RGR opsin and retinol dehydrogenase-10 (Rdh10) convert all-trans-retinol to 11-cis-retinol during exposure to visible light. Isolated retinas from Rgr+/+ and Rgr−/− mice were exposed to continuous light, and cone photoresponses were recorded. Cones in Rgr−/− retinas lost sensitivity at a faster rate than cones in Rgr+/+ retinas. A similar effect was seen in Rgr+/+ retinas following treatment with the glial cell toxin, α-aminoadipic acid. These results show that RGR opsin is a critical component of the Müller cell visual cycle and that regeneration of cone visual pigment can be driven by light.Graphical Graphical abstract for this article
  • Time Cells in the Hippocampus Are Neither Dependent on Medial Entorhinal
           Cortex Inputs nor Necessary for Spatial Working Memory
    • Abstract: Publication date: Available online 2 May 2019Source: NeuronAuthor(s): Marta Sabariego, Antonia Schönwald, Brittney L. Boublil, David T. Zimmerman, Siavash Ahmadi, Nailea Gonzalez, Christian Leibold, Robert E. Clark, Jill K. Leutgeb, Stefan LeutgebSummaryA key function of the hippocampus and entorhinal cortex is to bridge events that are discontinuous in time, and it has been proposed that medial entorhinal cortex (mEC) supports memory retention by sustaining the sequential activity of hippocampal time cells. Therefore, we recorded hippocampal neuronal activity during spatial working memory and asked whether time cells depend on mEC inputs. Working memory was impaired in rats with mEC lesions, but the occurrence of time cells and of trajectory-coding cells in the stem did not differ from controls. Rather, the main effect of mEC lesions was an extensive spatial coding deficit of CA1 cells, which included inconsistency over time and reduced firing differences between positions on the maze. Therefore, mEC is critical for providing stable and distinct spatial information to hippocampus, while working memory (WM) maintenance is likely supported either by local synaptic plasticity in hippocampus or by activity patterns elsewhere in the brain.Graphical Graphical abstract for this article
  • Boc Acts via Numb as a Shh-Dependent Endocytic Platform for Ptch1
           Internalization and Shh-Mediated Axon Guidance
    • Abstract: Publication date: Available online 1 May 2019Source: NeuronAuthor(s): Julien Ferent, Fanny Giguère, Christine Jolicoeur, Steves Morin, Jean-Francois Michaud, Shirin Makihara, Patricia T. Yam, Michel Cayouette, Frederic CharronSummaryDuring development, Shh attracts commissural axons toward the floor plate through a non-canonical, transcription-independent signaling pathway that requires the receptor Boc. Here, we find that Shh induces Boc internalization into early endosomes and that endocytosis is required for Shh-mediated growth-cone turning. Numb, an endocytic adaptor, binds to Boc and is required for Boc internalization, Shh-mediated growth-cone turning in vitro, and commissural axon guidance in vivo. Similar to Boc, Ptch1 is also internalized by Shh in a Numb-dependent manner; however, the binding of Shh to Ptch1 alone is not sufficient to induce Ptch1 internalization nor growth-cone turning. Therefore, the binding of Shh to Boc is required for Ptch1 internalization and growth-cone turning. Our data support a model where Boc endocytosis via Numb is required for Ptch1 internalization and Shh signaling in axon guidance. Thus, Boc acts as a Shh-dependent endocytic platform gating Ptch1 internalization and Shh signaling.Graphical Graphical abstract for this article
  • A Retinal Circuit Generating a Dynamic Predictive Code for Oriented
    • Abstract: Publication date: Available online 1 May 2019Source: NeuronAuthor(s): Jamie Johnston, Sofie-Helene Seibel, Léa Simone Adele Darnet, Sabine Renninger, Michael Orger, Leon LagnadoSummarySensory systems must reduce the transmission of redundant information to function efficiently. One strategy is to continuously adjust the sensitivity of neurons to suppress responses to common features of the input while enhancing responses to new ones. Here we image the excitatory synaptic inputs and outputs of retinal ganglion cells to understand how such dynamic predictive coding is implemented in the analysis of spatial patterns. Synapses of bipolar cells become tuned to orientation through presynaptic inhibition, generating lateral antagonism in the orientation domain. Individual ganglion cells receive excitatory synapses tuned to different orientations, but feedforward inhibition generates a high-pass filter that only transmits the initial activation of these inputs, removing redundancy. These results demonstrate how a dynamic predictive code can be implemented by circuit motifs common to many parts of the brain.
  • Nanoscale Mobility of the Apo State and TARP Stoichiometry Dictate the
           Gating Behavior of Alternatively Spliced AMPA Receptors
    • Abstract: Publication date: Available online 30 April 2019Source: NeuronAuthor(s): G. Brent Dawe, Md. Fahim Kadir, Raminta Venskutonytė, Amanda M. Perozzo, Yuhao Yan, Ryan P.D. Alexander, Camilo Navarrete, Eduardo A. Santander, Marika Arsenault, Christian Fuentes, Mark R.P. Aurousseau, Karla Frydenvang, Nelson P. Barrera, Jette S. Kastrup, J. Michael Edwardson, Derek BowieSummaryNeurotransmitter-gated ion channels are allosteric proteins that switch on and off in response to agonist binding. Most studies have focused on the agonist-bound, activated channel while assigning a lesser role to the apo or resting state. Here, we show that nanoscale mobility of resting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors (AMPA receptors) predetermines responsiveness to neurotransmitter, allosteric anions and TARP auxiliary subunits. Mobility at rest is regulated by alternative splicing of the flip/flop cassette of the ligand-binding domain, which controls motions in the distant AMPA receptor N-terminal domain (NTD). Flip variants promote moderate NTD movement, which establishes slower channel desensitization and robust regulation by anions and auxiliary subunits. In contrast, greater NTD mobility imparted by the flop cassette acts as a master switch to override allosteric regulation. In AMPA receptor heteromers, TARP stoichiometry further modifies these actions of the flip/flop cassette generating two functionally distinct classes of partially and fully TARPed receptors typical of cerebellar stellate and Purkinje cells.Graphical Graphical abstract for this article
  • VIP Interneurons Contribute to Avoidance Behavior by Regulating
           Information Flow across Hippocampal-Prefrontal Networks
    • Abstract: Publication date: Available online 30 April 2019Source: NeuronAuthor(s): Anthony T. Lee, Margaret M. Cunniff, Jermyn Z. See, Scott A. Wilke, Francisco J. Luongo, Ian T. Ellwood, Srimadh Ponnavolu, Vikaas S. SohalSummaryInhibitory interneurons expressing vasoactive intestinal polypeptide (VIP) are known to disinhibit cortical neurons. However, it is unclear how disinhibition, occurring at the single-cell level, interacts with network-level patterns of activity to shape complex behaviors. To address this, we examined the role of prefrontal VIP interneurons in a widely studied mouse behavior: deciding whether to explore or avoid the open arms of an elevated plus maze. VIP interneuron activity increases in the open arms and disinhibits prefrontal responses to hippocampal inputs, which are known to transmit signals related to open arm avoidance. Indeed, inhibiting VIP interneurons disrupts network-level representations of the open arms and decreases open arm avoidance specifically when hippocampal-prefrontal theta synchrony is strong. Thus, VIP interneurons effectively gate the ability of hippocampal input to generate prefrontal representations, which drive avoidance behavior. This shows how VIP interneurons enable cortical circuits to integrate specific inputs into network-level representations that guide complex behaviors.Graphical Graphical abstract for this article
  • Mitochondrial Regulation of the Hippocampal Firing Rate Set Point and
           Seizure Susceptibility
    • Abstract: Publication date: Available online 29 April 2019Source: NeuronAuthor(s): Boaz Styr, Nir Gonen, Daniel Zarhin, Antonella Ruggiero, Refaela Atsmon, Neta Gazit, Gabriella Braun, Samuel Frere, Irena Vertkin, Ilana Shapira, Michal Harel, Leore R. Heim, Maxim Katsenelson, Ohad Rechnitz, Saja Fadila, Dori Derdikman, Moran Rubinstein, Tamar Geiger, Eytan Ruppin, Inna SlutskySummaryMaintaining average activity within a set-point range constitutes a fundamental property of central neural circuits. However, whether and how activity set points are regulated remains unknown. Integrating genome-scale metabolic modeling and experimental study of neuronal homeostasis, we identified mitochondrial dihydroorotate dehydrogenase (DHODH) as a regulator of activity set points in hippocampal networks. The DHODH inhibitor teriflunomide stably suppressed mean firing rates via synaptic and intrinsic excitability mechanisms by modulating mitochondrial Ca2+ buffering and spare respiratory capacity. Bi-directional activity perturbations under DHODH blockade triggered firing rate compensation, while stabilizing firing to the lower level, indicating a change in the firing rate set point. In vivo, teriflunomide decreased CA3-CA1 synaptic transmission and CA1 mean firing rate and attenuated susceptibility to seizures, even in the intractable Dravet syndrome epilepsy model. Our results uncover mitochondria as a key regulator of activity set points, demonstrate the differential regulation of set points and compensatory mechanisms, and propose a new strategy to treat epilepsy.Graphical Graphical abstract for this article
  • Causal Inference in the Multisensory Brain
    • Abstract: Publication date: Available online 29 April 2019Source: NeuronAuthor(s): Yinan Cao, Christopher Summerfield, Hame Park, Bruno Lucio Giordano, Christoph KayserSummaryWhen combining information across different senses, humans need to flexibly select cues of a common origin while avoiding distraction from irrelevant inputs. The brain could solve this challenge using a hierarchical principle by deriving rapidly a fused sensory estimate for computational expediency and, later and if required, filtering out irrelevant signals based on the inferred sensory cause(s). Analyzing time- and source-resolved human magnetoencephalographic data, we unveil a systematic spatiotemporal cascade of the relevant computations, starting with early segregated unisensory representations, continuing with sensory fusion in parietal-temporal regions, and culminating as causal inference in the frontal lobe. Our results reconcile previous computational accounts of multisensory perception by showing that prefrontal cortex guides flexible integrative behavior based on candidate representations established in sensory and association cortices, thereby framing multisensory integration in the generalized context of adaptive behavior.
  • Microcircuit Mechanisms through which Mediodorsal Thalamic Input to
           Anterior Cingulate Cortex Exacerbates Pain-Related Aversion
    • Abstract: Publication date: Available online 25 April 2019Source: NeuronAuthor(s): Karuna S. Meda, Tosha Patel, Joao M. Braz, Ruchi Malik, Marc L. Turner, Helia Seifikar, Allan I. Basbaum, Vikaas S. SohalSummaryHyperexcitability of the anterior cingulate cortex (ACC) is thought to drive aversion associated with chronic neuropathic pain. Here, we studied the contribution of input from the mediodorsal thalamus (MD) to ACC, using sciatic nerve injury and chemotherapy-induced mouse models of neuropathic pain. Activating MD inputs elicited pain-related aversion in both models. Unexpectedly, excitatory responses of layer V ACC neurons to MD inputs were significantly weaker in pain models compared to controls. This caused the ratio between excitation and feedforward inhibition elicited by MD input to shift toward inhibition, specifically for subcortically projecting (SC) layer V neurons. Furthermore, direct inhibition of SC neurons reproduced the pain-related aversion elicited by activating MD inputs. Finally, both the ability to elicit pain-related aversion and the decrease in excitation were specific to MD inputs; activating basolateral amygdala inputs produced opposite effects. Thus, chronic pain-related aversion may reflect activity changes in specific pathways, rather than generalized ACC hyperactivity.Graphical Graphical abstract for this article
  • Central Amygdala Prepronociceptin-Expressing Neurons Mediate Palatable
           Food Consumption and Reward
    • Abstract: Publication date: Available online 24 April 2019Source: NeuronAuthor(s): J. Andrew Hardaway, Lindsay R. Halladay, Christopher M. Mazzone, Dipanwita Pati, Daniel W. Bloodgood, Michelle Kim, Jennifer Jensen, Jeffrey F. DiBerto, Kristen M. Boyt, Ami Shiddapur, Ava Erfani, Olivia J. Hon, Sofia Neira, Christina M. Stanhope, Jonathan A. Sugam, Michael P. Saddoris, Greg Tipton, Zoe McElligott, Thomas C. Jhou, Garret D. StuberSummaryFood palatability is one of many factors that drives food consumption, and the hedonic drive to feed is a key contributor to obesity and binge eating. In this study, we identified a population of prepronociceptin-expressing cells in the central amygdala (PnocCeA) that are activated by palatable food consumption. Ablation or chemogenetic inhibition of these cells reduces palatable food consumption. Additionally, ablation of PnocCeA cells reduces high-fat-diet-driven increases in bodyweight and adiposity. PnocCeA neurons project to the ventral bed nucleus of the stria terminalis (vBNST), parabrachial nucleus (PBN), and nucleus of the solitary tract (NTS), and activation of cell bodies in the central amygdala (CeA) or axons in the vBNST, PBN, and NTS produces reward behavior but did not promote feeding of palatable food. These data suggest that the PnocCeA network is necessary for promoting the reinforcing and rewarding properties of palatable food, but activation of this network itself is not sufficient to promote feeding.Graphical Graphical abstract for this article
  • Neocortical Projection Neurons Instruct Inhibitory Interneuron Circuit
           Development in a Lineage-Dependent Manner
    • Abstract: Publication date: Available online 23 April 2019Source: NeuronAuthor(s): Jason C. Wester, Vivek Mahadevan, Christopher T. Rhodes, Daniela Calvigioni, Sanan Venkatesh, Dragan Maric, Steven Hunt, Xiaoqing Yuan, Yajun Zhang, Timothy J. Petros, Chris J. McBainSummaryNeocortical circuits consist of stereotypical motifs that must self-assemble during development. Recent evidence suggests that the subtype identity of both excitatory projection neurons (PNs) and inhibitory interneurons (INs) is important for this process. We knocked out the transcription factor Satb2 in PNs to induce those of the intratelencephalic (IT) type to adopt a pyramidal tract (PT)-type identity. Loss of IT-type PNs selectively disrupted the lamination and circuit integration of INs derived from the caudal ganglionic eminence (CGE). Strikingly, reprogrammed PNs demonstrated reduced synaptic targeting of CGE-derived INs relative to controls. In control mice, IT-type PNs targeted neighboring CGE INs, while PT-type PNs did not in deep layers, confirming this lineage-dependent motif. Finally, single-cell RNA sequencing revealed that major CGE IN subtypes were conserved after loss of IT PNs, but with differential transcription of synaptic proteins and signaling molecules. Thus, IT-type PNs influence CGE-derived INs in a non-cell-autonomous manner during cortical development.
  • Grid-like Neural Representations Support Olfactory Navigation of a
           Two-Dimensional Odor Space
    • Abstract: Publication date: Available online 22 April 2019Source: NeuronAuthor(s): Xiaojun Bao, Eva Gjorgieva, Laura K. Shanahan, James D. Howard, Thorsten Kahnt, Jay A. GottfriedSummarySearching for food, friends, and mates often begins with an airborne scent. Importantly, odor concentration rises with physical proximity to an odorous source, suggesting a framework for orienting within olfactory landscapes to optimize behavior. Here, we created a two-dimensional odor space composed purely of odor stimuli to model how a navigator encounters smells in a natural environment. We show that human subjects can learn to navigate in olfactory space and form predictions of to-be-encountered smells. During navigation, fMRI responses in entorhinal cortex and ventromedial prefrontal cortex take the form of grid-like representations with hexagonal periodicity and entorhinal grid strength scaled with behavioral performance across subjects. The identification of olfactory grid-like codes with 6-fold symmetry highlights a unique neural mechanism by which odor information can be assembled into spatially navigable cognitive maps, optimizing orientation, and path finding toward an odor source.
  • A Common Neuroendocrine Substrate for Diverse General Anesthetics and
    • Abstract: Publication date: Available online 18 April 2019Source: NeuronAuthor(s): Li-Feng Jiang-Xie, Luping Yin, Shengli Zhao, Vincent Prevosto, Bao-Xia Han, Kafui Dzirasa, Fan WangSummaryHow general anesthesia (GA) induces loss of consciousness remains unclear, and whether diverse anesthetic drugs and sleep share a common neural pathway is unknown. Previous studies have revealed that many GA drugs inhibit neural activity through targeting GABA receptors. Here, using Fos staining, ex vivo brain slice recording, and in vivo multi-channel electrophysiology, we discovered a core ensemble of hypothalamic neurons in and near the supraoptic nucleus, consisting primarily of neuroendocrine cells, which are persistently and commonly activated by multiple classes of GA drugs. Remarkably, chemogenetic or brief optogenetic activations of these anesthesia-activated neurons (AANs) strongly promote slow-wave sleep and potentiates GA, whereas conditional ablation or inhibition of AANs led to diminished slow-wave oscillation, significant loss of sleep, and shortened durations of GA. These findings identify a common neural substrate underlying diverse GA drugs and natural sleep and reveal a crucial role of the neuroendocrine system in regulating global brain states.
  • Alternative Splicing of Presynaptic Neurexins Differentially Controls
           Postsynaptic NMDA and AMPA Receptor Responses
    • Abstract: Publication date: Available online 17 April 2019Source: NeuronAuthor(s): Jinye Dai, Jason Aoto, Thomas C. SüdhofSummaryAMPA- and NMDA-type glutamate receptors mediate distinct postsynaptic signals that differ characteristically among synapses. How postsynaptic AMPA- and NMDA-receptor levels are regulated, however, remains unclear. Using newly generated conditional knockin mice that enable genetic control of neurexin alternative splicing, we show that in hippocampal synapses, alternative splicing of presynaptic neurexin-1 at splice site 4 (SS4) dramatically enhanced postsynaptic NMDA-receptor-mediated, but not AMPA-receptor-mediated, synaptic responses without altering synapse density. In contrast, alternative splicing of neurexin-3 at SS4 suppressed AMPA-receptor-mediated, but not NMDA-receptor-mediated, synaptic responses, while alternative splicing of neurexin-2 at SS4 had no effect on NMDA- or AMPA-receptor-mediated responses. Presynaptic overexpression of the neurexin-1β and neurexin-3β SS4+ splice variants, but not of their SS4− splice variants, replicated the respective SS4+ knockin phenotypes. Thus, different neurexins perform distinct nonoverlapping functions at hippocampal synapses that are independently regulated by alternative splicing. These functions transsynaptically control NMDA and AMPA receptors, thereby mediating presynaptic control of postsynaptic responses.
  • Synaptic Vesicle Recycling Pathway Determines Neurotransmitter Content and
           Release Properties
    • Abstract: Publication date: Available online 16 April 2019Source: NeuronAuthor(s): Kätlin Silm, Jing Yang, Pamela F. Marcott, Cedric S. Asensio, Jacob Eriksen, Daryl A. Guthrie, Amy H. Newman, Christopher P. Ford, Robert H. EdwardsSummaryIn contrast to temporal coding by synaptically acting neurotransmitters such as glutamate, neuromodulators such as monoamines signal changes in firing rate. The two modes of signaling have been thought to reflect differences in release by different cells. We now find that midbrain dopamine neurons release glutamate and dopamine with different properties that reflect storage in different synaptic vesicles. The vesicles differ in release probability, coupling to presynaptic Ca2+ channels and frequency dependence. Although previous work has attributed variation in these properties to differences in location or cytoskeletal association of synaptic vesicles, the release of different transmitters shows that intrinsic differences in vesicle identity drive different modes of release. Indeed, dopamine but not glutamate vesicles depend on the adaptor protein AP-3, revealing an unrecognized linkage between the pathway of synaptic vesicle recycling and the properties of exocytosis. Storage of the two transmitters in different vesicles enables the transmission of distinct signals.
  • Central Processing of Itch in the Midbrain Reward Center
    • Abstract: Publication date: Available online 15 April 2019Source: NeuronAuthor(s): Xin-Yu Su, Ming Chen, Yuan Yuan, Ying Li, Su-Shan Guo, Huo-Qing Luo, Chen Huang, Wenzhi Sun, Yong Li, Michael X. Zhu, Ming-Gang Liu, Ji Hu, Tian-Le XuSummaryItch is an aversive sensation that evokes a desire to scratch. Paradoxically, scratching the itch also produces a hedonic experience. The specific brain circuits processing these different aspects of itch, however, remain elusive. Here, we report that GABAergic (GABA) and dopaminergic (DA) neurons in the ventral tegmental area (VTA) are activated with different temporal patterns during acute and chronic itch. DA neuron activation lags behind GABA neurons and is dependent on scratching of the itchy site. Optogenetic manipulations of VTA GABA neurons rapidly modulated scratching behaviors through encoding itch-associated aversion. In contrast, optogenetic manipulations of VTA DA neurons revealed their roles in sustaining recurrent scratching episodes through signaling scratching-induced reward. A similar dichotomy exists for the role of VTA in chronic itch. These findings advance understanding of circuit mechanisms of the unstoppable itch-scratch cycles and shed important insights into chronic itch therapy.
  • Glutamate-Releasing SWELL1 Channel in Astrocytes Modulates Synaptic
           Transmission and Promotes Brain Damage in Stroke
    • Abstract: Publication date: Available online 11 April 2019Source: NeuronAuthor(s): Junhua Yang, Maria del Carmen Vitery, Jianan Chen, James Osei-Owusu, Jiachen Chu, Zhaozhu QiuSummaryBy releasing glutamate, astrocytes actively regulate synaptic transmission and contribute to excitotoxicity in neurological diseases. However, the mechanisms of astrocytic glutamate release have been debated. Here, we report non-vesicular release of glutamate through the glutamate-permeable volume-regulated anion channel (VRAC). Both cell swelling and receptor stimulation activated astrocytic VRAC, which requires its only obligatory subunit, Swell1. Astrocyte-specific Swell1 knockout mice exhibited impaired glutamatergic transmission due to the decreases in presynaptic release probability and ambient glutamate level. Consistently, the mutant mice displayed hippocampal-dependent learning and memory deficits. During pathological cell swelling, deletion of astrocytic Swell1 attenuated glutamate-dependent neuronal excitability and protected mice from brain damage after ischemic stroke. Our identification of a new molecular mechanism for channel-mediated glutamate release establishes a role for astrocyte-neuron interactions in both synaptic transmission and brain ischemia. It provides a rationale for targeting VRAC for the treatment of stroke and other neurological diseases associated with excitotoxicity.Graphical Graphical abstract for this article
  • Morning and Evening Circadian Pacemakers Independently Drive Premotor
           Centers via a Specific Dopamine Relay
    • Abstract: Publication date: Available online 10 April 2019Source: NeuronAuthor(s): Xitong Liang, Margaret C.W. Ho, Yajun Zhang, Yulong Li, Mark N. Wu, Timothy E. Holy, Paul H. TaghertSummaryMany animals exhibit morning and evening peaks of locomotor behavior. In Drosophila, two corresponding circadian neural oscillators—M (morning) cells and E (evening) cells—exhibit a corresponding morning or evening neural activity peak. Yet we know little of the neural circuitry by which distinct circadian oscillators produce specific outputs to precisely control behavioral episodes. Here, we show that ring neurons of the ellipsoid body (EB-RNs) display spontaneous morning and evening neural activity peaks in vivo: these peaks coincide with the bouts of locomotor activity and result from independent activation by M and E pacemakers. Further, M and E cells regulate EB-RNs via identified PPM3 dopaminergic neurons, which project to the EB and are normally co-active with EB-RNs. These in vivo findings establish the fundamental elements of a circadian neuronal output pathway: distinct circadian oscillators independently drive a common pre-motor center through the agency of specific dopaminergic interneurons.
  • Multiplexing of Theta and Alpha Rhythms in the Amygdala-Hippocampal
           Circuit Supports Pattern Separation of Emotional Information
    • Abstract: Publication date: Available online 9 April 2019Source: NeuronAuthor(s): Jie Zheng, Rebecca F. Stevenson, Bryce A. Mander, Lilit Mnatsakanyan, Frank P.K. Hsu, Sumeet Vadera, Robert T. Knight, Michael A. Yassa, Jack J. LinSummaryHow do we remember emotional events' While emotion often leads to vivid recollection, the precision of emotional memories can be degraded, especially when discriminating among overlapping experiences in memory (i.e., pattern separation). Communication between the amygdala and the hippocampus has been proposed to support emotional memory, but the exact neural mechanisms remain unclear. Here, we used intracranial recordings in pre-surgical epilepsy patients to show that successful pattern separation of emotional stimuli is associated with theta band (3–7 Hz)-coordinated bidirectional interactions between the amygdala and the hippocampus. In contrast, discrimination errors (i.e., failure to discriminate similar stimuli) were associated with alpha band (7–13 Hz)-coordinated unidirectional influence from the amygdala to the hippocampus. These findings imply that alpha band synchrony may impair discrimination of similar emotional events via the amygdala-hippocampal directional coupling, which suggests a target for treatments of psychiatric conditions such as post-traumatic stress disorder, in which aversive experiences are often overgeneralized.
  • Encoding of Wind Direction by Central Neurons in Drosophila
    • Abstract: Publication date: Available online 1 April 2019Source: NeuronAuthor(s): Marie P. Suver, Andrew M.M. Matheson, Sinekdha Sarkar, Matthew Damiata, David Schoppik, Katherine I. NagelSummaryWind is a major navigational cue for insects, but how wind direction is decoded by central neurons in the insect brain is unknown. Here we find that walking flies combine signals from both antennae to orient to wind during olfactory search behavior. Movements of single antennae are ambiguous with respect to wind direction, but the difference between left and right antennal displacements yields a linear code for wind direction in azimuth. Second-order mechanosensory neurons share the ambiguous responses of a single antenna and receive input primarily from the ipsilateral antenna. Finally, we identify novel “wedge projection neurons” that integrate signals across the two antennae and receive input from at least three classes of second-order neurons to produce a more linear representation of wind direction. This study establishes how a feature of the sensory environment—wind direction—is decoded by neurons that compare information across two sensors.Graphical Graphical abstract for this article
  • A Role of Drd2 Hippocampal Neurons in Context-Dependent Food Intake
    • Abstract: Publication date: Available online 28 March 2019Source: NeuronAuthor(s): Estefania P. Azevedo, Lisa Pomeranz, Jia Cheng, Marc Schneeberger, Roger Vaughan, Sarah A. Stern, Bowen Tan, Katherine Doerig, Paul Greengard, Jeffrey M. FriedmanSummaryAssociative learning of food cues that link location in space to food availability guides feeding behavior in mammals. However, the function of specific neurons that are elements of the higher-order, cognitive circuitry controlling feeding behavior is largely unexplored. Here, we report that hippocampal dopamine 2 receptor (hD2R) neurons are specifically activated by food and that both acute and chronic modulation of their activity reduces food intake in mice. Upstream projections from the lateral entorhinal cortex (LEC) to the hippocampus activate hD2R cells and can also decrease food intake. Finally, activation of hD2R neurons interferes with the encoding of a spatial memory linking food to a specific location via projections from the hippocampus to the septal area. Altogether these data describe a previously unidentified LEC> hippocampus> septal higher-order circuit that regulates feeding behavior.Graphical Graphical abstract for this article
  • Conversion of Graded Presynaptic Climbing Fiber Activity into Graded
           Postsynaptic Ca2+ Signals by Purkinje Cell Dendrites
    • Abstract: Publication date: Available online 27 March 2019Source: NeuronAuthor(s): Michael A. Gaffield, Audrey Bonnan, Jason M. ChristieSummaryThe brain must make sense of external stimuli to generate relevant behavior. We used a combination of in vivo approaches to investigate how the cerebellum processes sensory-related information. We found that the inferior olive encodes contexts of sensory-associated external cues in a graded manner, apparent in the presynaptic activity of their axonal projections (climbing fibers) in the cerebellar cortex. Individual climbing fibers were broadly responsive to different sensory modalities but relayed sensory-related information to the cortex in a lobule-dependent manner. Purkinje cell dendrites faithfully transformed this climbing fiber activity into dendrite-wide Ca2+ signals without a direct contribution from the mossy fiber pathway. These results demonstrate that the size of climbing-fiber-evoked Ca2+ signals in Purkinje cell dendrites is largely determined by the firing level of climbing fibers. This coding scheme emphasizes the overwhelming role of the inferior olive in generating salient signals useful for instructing plasticity and learning.
  • Location and Plasticity of the Sodium Spike Initiation Zone in Nociceptive
           Terminals In Vivo
    • Abstract: Publication date: Available online 26 March 2019Source: NeuronAuthor(s): Robert H. Goldstein, Omer Barkai, Almudena Íñigo-Portugués, Ben Katz, Shaya Lev, Alexander M. BinshtokSummaryNociceptive terminals possess the elements for detecting, transmitting, and modulating noxious signals, thus being pivotal for pain sensation. Despite this, a functional description of the transduction process by the terminals, in physiological conditions, has not been fully achieved. Here, we studied how nociceptive terminals in vivo convert noxious stimuli into propagating signals. By monitoring noxious-stimulus-induced Ca2+ dynamics from mouse corneal terminals, we found that initiation of Na+ channel (Nav)-dependent propagating signals takes place away from the terminal and that the starting point for Nav-mediated propagation depends on Nav functional availability. Acute treatment with the proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) resulted in a shift of the location of Nav involvement toward the terminal, thus increasing nociceptive excitability. Moreover, a shift of Nav involvement toward the terminal occurs in corneal hyperalgesia resulting from acute photokeratitis. This dynamic change in the location of Nav-mediated propagation initiation could underlie pathological pain hypersensitivity.
  • A Genetically Encoded Fluorescent Sensor for Rapid and Specific In Vivo
           Detection of Norepinephrine
    • Abstract: Publication date: Available online 25 March 2019Source: NeuronAuthor(s): Jiesi Feng, Changmei Zhang, Julieta E. Lischinsky, Miao Jing, Jingheng Zhou, Huan Wang, Yajun Zhang, Ao Dong, Zhaofa Wu, Hao Wu, Weiyu Chen, Peng Zhang, Jing Zou, S. Andrew Hires, J. Julius Zhu, Guohong Cui, Dayu Lin, Jiulin Du, Yulong LiSummaryNorepinephrine (NE) is a key biogenic monoamine neurotransmitter involved in a wide range of physiological processes. However, its precise dynamics and regulation remain poorly characterized, in part due to limitations of available techniques for measuring NE in vivo. Here, we developed a family of GPCR activation-based NE (GRABNE) sensors with a 230% peak ΔF/F0 response to NE, good photostability, nanomolar-to-micromolar sensitivities, sub-second kinetics, and high specificity. Viral- or transgenic-mediated expression of GRABNE sensors was able to detect electrical-stimulation-evoked NE release in the locus coeruleus (LC) of mouse brain slices, looming-evoked NE release in the midbrain of live zebrafish, as well as optogenetically and behaviorally triggered NE release in the LC and hypothalamus of freely moving mice. Thus, GRABNE sensors are robust tools for rapid and specific monitoring of in vivo NE transmission in both physiological and pathological processes.Graphical Graphical abstract for this article
  • α1ACT Is Essential for Survival and Early Cerebellar Programming in a
           Critical Neonatal Window
    • Abstract: Publication date: Available online 25 March 2019Source: NeuronAuthor(s): Xiaofei Du, Cenfu Wei, Daniel Parviz Hejazi Pastor, Eshaan R. Rao, Yan Li, Giorgio Grasselli, Jack Godfrey, Ann C. Palmenberg, Jorge Andrade, Christian Hansel, Christopher M. GomezSummaryPostnatal cerebellar development is a precisely regulated process involving well-orchestrated expression of neural genes. Neurological phenotypes associated with CACNA1A gene defects have been increasingly recognized, yet the molecular principles underlying this association remain elusive. By characterizing a dose-dependent CACNA1A gene deficiency mouse model, we discovered that α1ACT, as a transcription factor and secondary protein of CACNA1A mRNA, drives dynamic gene expression networks within cerebellar Purkinje cells and is indispensable for neonatal survival. Perinatal loss of α1ACT leads to motor dysfunction through disruption of neurogenesis and synaptic regulatory networks. However, its elimination in adulthood has minimal effect on the cerebellum. These findings shed light on the critical role of α1ACT in facilitating neuronal development in both mice and humans and support a rationale for gene therapies for calcium-channel-associated cerebellar disorders. Finally, we show that bicistronic expression may be common to the voltage-gated calcium channel (VGCC) gene family and may help explain complex genetic syndromes.Graphical Graphical abstract for this article
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