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Jinye Dai, Jason Aoto, Thomas C Südhof
AMPA- 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...
April 9, 2019: Neuron
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 Xu
Itch 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...
April 8, 2019: Neuron
Junhua Yang, Maria Del Carmen Vitery, Jianan Chen, James Osei-Owusu, Jiachen Chu, Zhaozhu Qiu
By 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...
April 8, 2019: Neuron
Xitong Liang, Margaret C W Ho, Yajun Zhang, Yulong Li, Mark N Wu, Timothy E Holy, Paul H Taghert
Many 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...
April 8, 2019: Neuron
Li-Feng Jiang-Xie, Luping Yin, Shengli Zhao, Vincent Prevosto, Bao-Xia Han, Kafui Dzirasa, Fan Wang
How 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...
April 5, 2019: Neuron
Kätlin Silm, Jing Yang, Pamela F Marcott, Cedric S Asensio, Jacob Eriksen, Daryl A Guthrie, Amy H Newman, Christopher P Ford, Robert H Edwards
In 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...
April 4, 2019: Neuron
Jie Zheng, Rebecca F Stevenson, Bryce A Mander, Lilit Mnatsakanyan, Frank P K Hsu, Sumeet Vadera, Robert T Knight, Michael A Yassa, Jack J Lin
How 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...
April 2, 2019: Neuron
Estefania P Azevedo, Lisa Pomeranz, Jia Cheng, Marc Schneeberger, Roger Vaughan, Sarah A Stern, Bowen Tan, Katherine Doerig, Paul Greengard, Jeffrey M Friedman
Associative 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...
March 26, 2019: Neuron
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 Li
Norepinephrine (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...
March 25, 2019: Neuron
Marie P Suver, Andrew M M Matheson, Sinekdha Sarkar, Matthew Damiata, David Schoppik, Katherine I Nagel
Wind 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...
March 22, 2019: Neuron
Gil Mandelbaum, Julian Taranda, Trevor M Haynes, Daniel R Hochbaum, Kee Wui Huang, Minsuk Hyun, Kannan Umadevi Venkataraju, Christoph Straub, Wengang Wang, Keiramarie Robertson, Pavel Osten, Bernardo L Sabatini
The thalamic parafascicular nucleus (PF), an excitatory input to the basal ganglia, is targeted with deep-brain stimulation to alleviate a range of neuropsychiatric symptoms. Furthermore, PF lesions disrupt the execution of correct motor actions in uncertain environments. Nevertheless, the circuitry of the PF and its contribution to action selection are poorly understood. We find that, in mice, PF has the highest density of striatum-projecting neurons among all sub-cortical structures. This projection arises from transcriptionally and physiologically distinct classes of PF neurons that are also reciprocally connected with functionally distinct cortical regions, differentially innervate striatal neurons, and are not synaptically connected in PF...
March 19, 2019: Neuron
Dario Bonanomi, Fabiola Valenza, Onanong Chivatakarn, Matthew J Sternfeld, Shawn P Driscoll, Aaron Aslanian, Karen Lettieri, Miriam Gullo, Aurora Badaloni, Joseph W Lewcock, Tony Hunter, Samuel L Pfaff
The rich functional diversity of the nervous system is founded in the specific connectivity of the underlying neural circuitry. Neurons are often preprogrammed to respond to multiple axon guidance signals because they use sequential guideposts along their pathways, but this necessitates a strict spatiotemporal regulation of intracellular signaling to ensure the cues are detected in the correct order. We performed a mouse mutagenesis screen and identified the Rho GTPase antagonist p190RhoGAP as a critical regulator of motor axon guidance...
March 15, 2019: Neuron
Michael A Gaffield, Audrey Bonnan, Jason M Christie
The 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...
March 14, 2019: Neuron
Robert H Goldstein, Omer Barkai, Almudena Íñigo-Portugués, Ben Katz, Shaya Lev, Alexander M Binshtok
Nociceptive 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...
March 14, 2019: Neuron
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 Gomez
Postnatal 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...
March 13, 2019: Neuron
Rishi Rajalingham, James J DiCarlo
Extensive research suggests that the inferior temporal (IT) population supports visual object recognition behavior. However, causal evidence for this hypothesis has been equivocal, particularly beyond the specific case of face-selective subregions of IT. Here, we directly tested this hypothesis by pharmacologically inactivating individual, millimeter-scale subregions of IT while monkeys performed several core object recognition subtasks, interleaved trial-by trial. First, we observed that IT inactivation resulted in reliable contralateral-biased subtask-selective behavioral deficits...
March 11, 2019: Neuron
Haifeng Xu, Ling Liu, Yuanyuan Tian, Jun Wang, Jie Li, Junqiang Zheng, Hongfei Zhao, Miao He, Tian-Le Xu, Shumin Duan, Han Xu
Fear behavior is under tight control of the prefrontal cortex, but the underlying microcircuit mechanism remains elusive. In particular, it is unclear how distinct subtypes of inhibitory interneurons (INs) within prefrontal cortex interact and contribute to fear expression. We employed a social fear conditioning paradigm and induced robust social fear in mice. We found that social fear is characterized by activation of dorsal medial prefrontal cortex (dmPFC) and is largely diminished by dmPFC inactivation. With a combination of in vivo electrophysiological recordings and fiber photometry together with cell-type-specific pharmacogenetics, we further demonstrated that somatostatin (SST) INs suppressed parvalbumin (PV) INs and disinhibited pyramidal cells and consequently enhanced dmPFC output to mediate social fear responses...
March 8, 2019: Neuron
Monica M Li, Joseph C Madara, Jennifer S Steger, Michael J Krashes, Nina Balthasar, John N Campbell, Jon M Resch, Nicholas J Conley, Alastair S Garfield, Bradford B Lowell
SIM1-expressing paraventricular hypothalamus (PVH) neurons are key regulators of energy balance. Within the PVHSIM1 population, melanocortin-4 receptor-expressing (PVHMC4R ) neurons are known to regulate satiety and bodyweight, yet they account for only half of PVHSIM1 neuron-mediated regulation. Here we report that PVH prodynorphin-expressing (PVHPDYN ) neurons, which notably lack MC4Rs, function independently and additively with PVHMC4R neurons to account for the totality of PVHSIM1 neuron-mediated satiety...
March 8, 2019: Neuron
Michael Telias, Bristol Denlinger, Zachary Helft, Casey Thornton, Billie Beckwith-Cohen, Richard H Kramer
Light responses are initiated in photoreceptors, processed by interneurons, and synaptically transmitted to retinal ganglion cells (RGCs), which send information to the brain. Retinitis pigmentosa (RP) is a blinding disease caused by photoreceptor degeneration, depriving downstream neurons of light-sensitive input. Photoreceptor degeneration also triggers hyperactive firing of RGCs, obscuring light responses initiated by surviving photoreceptors. Here we show that retinoic acid (RA), signaling through its receptor (RAR), is the trigger for hyperactivity...
March 8, 2019: Neuron
Oliver M Vikbladh, Michael R Meager, John King, Karen Blackmon, Orrin Devinsky, Daphna Shohamy, Neil Burgess, Nathaniel D Daw
Little is known about the neural mechanisms that allow humans and animals to plan actions using knowledge of task contingencies. Emerging theories hypothesize that it involves the same hippocampal mechanisms that support self-localization and memory for locations. Yet limited direct evidence supports the link between planning and the hippocampal place map. We addressed this by investigating model-based planning and place memory in healthy controls and epilepsy patients treated using unilateral anterior temporal lobectomy with hippocampal resection...
March 8, 2019: Neuron
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