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      Slow-wave sleep is controlled by a subset of nucleus accumbens core neurons in mice

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          Abstract

          Sleep control is ascribed to a two-process model, a widely accepted concept that posits homoeostatic drive and a circadian process as the major sleep-regulating factors. Cognitive and emotional factors also influence sleep–wake behaviour; however, the precise circuit mechanisms underlying their effects on sleep control are unknown. Previous studies suggest that adenosine has a role affecting behavioural arousal in the nucleus accumbens (NAc), a brain area critical for reinforcement and reward. Here, we show that chemogenetic or optogenetic activation of excitatory adenosine A 2A receptor-expressing indirect pathway neurons in the core region of the NAc strongly induces slow-wave sleep. Chemogenetic inhibition of the NAc indirect pathway neurons prevents the sleep induction, but does not affect the homoeostatic sleep rebound. In addition, motivational stimuli inhibit the activity of ventral pallidum-projecting NAc indirect pathway neurons and suppress sleep. Our findings reveal a prominent contribution of this indirect pathway to sleep control associated with motivation.

          Abstract

          In addition to circadian and homoeostatic drives, motivational levels influence sleep−wake cycles. Here the authors demonstrate that adenosine receptor-expressing neurons in the nucleus accumbens core that project to the ventral pallidum are inhibited by motivational stimuli and are causally involved in the control of slow-wave sleep.

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          Most cited references37

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          A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex.

          A key obstacle to understanding neural circuits in the cerebral cortex is that of unraveling the diversity of GABAergic interneurons. This diversity poses general questions for neural circuit analysis: how are these interneuron cell types generated and assembled into stereotyped local circuits and how do they differentially contribute to circuit operations that underlie cortical functions ranging from perception to cognition? Using genetic engineering in mice, we have generated and characterized approximately 20 Cre and inducible CreER knockin driver lines that reliably target major classes and lineages of GABAergic neurons. More select populations are captured by intersection of Cre and Flp drivers. Genetic targeting allows reliable identification, monitoring, and manipulation of cortical GABAergic neurons, thereby enabling a systematic and comprehensive analysis from cell fate specification, migration, and connectivity, to their functions in network dynamics and behavior. As such, this approach will accelerate the study of GABAergic circuits throughout the mammalian brain. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness.

            Both subjective and electroencephalographic arousal diminish as a function of the duration of prior wakefulness. Data reported here suggest that the major criteria for a neural sleep factor mediating the somnogenic effects of prolonged wakefulness are satisfied by adenosine, a neuromodulator whose extracellular concentration increases with brain metabolism and which, in vitro, inhibits basal forebrain cholinergic neurons. In vivo microdialysis measurements in freely behaving cats showed that adenosine extracellular concentrations in the basal forebrain cholinergic region increased during spontaneous wakefulness as contrasted with slow wave sleep; exhibited progressive increases during sustained, prolonged wakefulness; and declined slowly during recovery sleep. Furthermore, the sleep-wakefulness profile occurring after prolonged wakefulness was mimicked by increased extracellular adenosine induced by microdialysis perfusion of an adenosine transport inhibitor in the cholinergic basal forebrain but not by perfusion in a control noncholinergic region.
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              VTA dopaminergic neurons regulate ethologically relevant sleep-wake behaviors.

              Dopaminergic ventral tegmental area (VTA) neurons are critically involved in a variety of behaviors that rely on heightened arousal, but whether they directly and causally control the generation and maintenance of wakefulness is unknown. We recorded calcium activity using fiber photometry in freely behaving mice and found arousal-state-dependent alterations in VTA dopaminergic neurons. We used chemogenetic and optogenetic manipulations together with polysomnographic recordings to demonstrate that VTA dopaminergic neurons are necessary for arousal and that their inhibition suppresses wakefulness, even in the face of ethologically relevant salient stimuli. Nevertheless, before inducing sleep, inhibition of VTA dopaminergic neurons promoted goal-directed and sleep-related nesting behavior. Optogenetic stimulation, in contrast, initiated and maintained wakefulness and suppressed sleep and sleep-related nesting behavior. We further found that different projections of VTA dopaminergic neurons differentially modulate arousal. Collectively, our findings uncover a fundamental role for VTA dopaminergic circuitry in the maintenance of the awake state and ethologically relevant sleep-related behaviors.
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                Author and article information

                Contributors
                huangzl@fudan.edu.cn
                lazarus.michael.ka@u.tsukuba.ac.jp
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                29 September 2017
                29 September 2017
                2017
                : 8
                Affiliations
                [1 ]ISNI 0000 0001 2369 4728, GRID grid.20515.33, International Institute for Integrative Sleep Medicine (WPI-IIIS), , University of Tsukuba, ; 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
                [2 ]ISNI 0000 0004 0619 8943, GRID grid.11841.3d, Department of Pharmacology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, , Shanghai Medical College of Fudan University, ; Shanghai, 200032 China
                [3 ]ISNI 0000 0000 9490 772X, GRID grid.186775.a, Department of Physiology, School of Basic Medical Sciences, , Anhui Medical University, ; Hefei, 230032 China
                [4 ]ISNI 0000 0001 2348 0746, GRID grid.4989.c, Laboratory of Neurophysiology, ULB-Neuroscience Institute, , Université Libre de Bruxelles (ULB), ; 808 Route de Lennik, Brussels, 1070 Belgium
                Article
                781
                10.1038/s41467-017-00781-4
                5622037
                28963505
                9d07dc9c-9672-4eab-a093-55977618e51f
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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