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      Striatal adenosine A 2A receptor neurons control active-period sleep via parvalbumin neurons in external globus pallidus

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          Abstract

          Dysfunction of the striatum is frequently associated with sleep disturbances. However, its role in sleep-wake regulation has been paid little attention even though the striatum densely expresses adenosine A 2A receptors (A 2ARs), which are essential for adenosine-induced sleep. Here we showed that chemogenetic activation of A 2AR neurons in specific subregions of the striatum induced a remarkable increase in non-rapid eye movement (NREM) sleep. Anatomical mapping and immunoelectron microscopy revealed that striatal A 2AR neurons innervated the external globus pallidus (GPe) in a topographically organized manner and preferentially formed inhibitory synapses with GPe parvalbumin (PV) neurons. Moreover, lesions of GPe PV neurons abolished the sleep-promoting effect of striatal A 2AR neurons. In addition, chemogenetic inhibition of striatal A 2AR neurons led to a significant decrease of NREM sleep at active period, but not inactive period of mice. These findings reveal a prominent contribution of striatal A 2AR neuron/GPe PV neuron circuit in sleep control.

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          Most cited references 54

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          Adenosine receptors as drug targets--what are the challenges?

          Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors--either directly or indirectly--have now entered the clinic. However, only one adenosine receptor-specific agent--the adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma)--has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges.
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            Physiology and pharmacology of striatal neurons.

            The basal ganglia occupy the core of the forebrain and consist of evolutionarily conserved motor nuclei that form recurrent circuits critical for motivation and motor planning. The striatum is the main input nucleus of the basal ganglia and a key neural substrate for procedural learning and memory. The vast majority of striatal neurons are spiny GABAergic projection neurons, which exhibit slow but temporally precise spiking in vivo. Contributing to this precision are several different types of interneurons that constitute only a small fraction of total neuron number but play a critical role in regulating striatal output. This review examines the cellular physiology and modulation of striatal neurons that give rise to their unique properties and function.
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              Adenosine and sleep-wake regulation.

              This review addresses three principal questions about adenosine and sleep-wake regulation: (1) Is adenosine an endogenous sleep factor? (2) Are there specific brain regions/neuroanatomical targets and receptor subtypes through which adenosine mediates sleepiness? (3) What are the molecular mechanisms by which adenosine may mediate the long-term effects of sleep loss? Data suggest that adenosine is indeed an important endogenous, homeostatic sleep factor, likely mediating the sleepiness that follows prolonged wakefulness. The cholinergic basal forebrain is reviewed in detail as an essential area for mediating the sleep-inducing effects of adenosine by inhibition of wake-promoting neurons via the A1 receptor. The A2A receptor in the subarachnoid space below the rostral forebrain may play a role in the prostaglandin D2-mediated somnogenic effects of adenosine. Recent evidence indicates that a cascade of signal transduction induced by basal forebrain adenosine A1 receptor activation in cholinergic neurons leads to increased transcription of the A1 receptor; this may play a role in mediating the longer-term effects of sleep deprivation, often called sleep debt.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                12 October 2017
                2017
                : 6
                Affiliations
                [1 ]deptDepartment of Pharmacology, School of Basic Medical Science Fudan University ShanghaiChina
                [2 ]deptState Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science Fudan University ShanghaiChina
                [3 ]deptDepartment of Anatomy, Histology and Embryology, School of Basic Medical Science Fudan University ShanghaiChina
                [4 ]deptInternational Institute for Integrative Sleep Medicine University of Tsukuba TsukubaJapan
                [5 ]deptLaboratory of Neurophysiology, ULB Neuroscience Institute Université Libre de Bruxelles BrusselsBelgium
                University of California, San Francisco United States
                University of California, San Francisco United States
                Author notes
                [†]

                These authors contributed equally to this work.

                Article
                29055
                10.7554/eLife.29055
                5655138
                29022877
                © 2017, Yuan et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                Product
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81420108015
                Award Recipient :
                Funded by: National Basic Research Program of China;
                Award ID: 2015CB856401
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31571103
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31671099
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81271466
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31471064
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31530035
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81571296
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Neuroscience
                Custom metadata
                Rostral and central striatum controls slow-wave sleep during active phase in mice.

                Life sciences

                mouse, optogenetics, chemogenetics, sleep, a2a receptor, striatum

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