title: Adenosine A2Areceptors in the olfactory bulb suppress rapid eye movement sleep in rodents.
abstract: Rapid eye movement (REM) sleep behavior disorder in humans is often accompanied by a reduced ability to smell and detect odors, and olfactory bulbectomized rats exhibit increased REM sleep, suggesting that the olfactory bulb (OB) is involved in REM-sleep regulation. However, the molecular mechanism of REM-sleep regulation by the OB is unknown. Adenosine promotes sleep and its A2Areceptors (A2AR) are expressed in the OB. We hypothesized that A2AR in the OB regulate REM sleep. Bilateral microinjections of the A2AR antagonist SCH58261 into the rat OB increased REM sleep, whereas microinjections of the A2AR agonist CGS21680 decreased REM sleep. Similar to the A2AR antagonist, selective A2AR knockdown by adeno-associated virus carrying short-hairpin RNA for A2AR in the rat OB increased REM sleep. Using chemogenetics on the basis of designer receptors exclusively activated by designer drugs, we demonstrated that the inhibition of A2AR neurons increased REM sleep, whereas the activation of these neurons decreased REM sleep. Moreover, using a conditional anterograde axonal tract-tracing approach, we found that OB A2AR neurons innervate the piriform cortex and olfactory tubercle. These novel findings indicate that adenosine suppresses REM sleep via A2AR in the OB of rodents.
authors.affiliation: Department of Pharmacology and Shanghai Key Laboratory of Bioactive Small Molecules, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China.
authors.forename: Yi-Qun
authors.initials: YQ
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Shanghai Key Laboratory of Bioactive Small Molecules, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Shanghai Key Laboratory of Bioactive Small Molecules, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China.
authors.forename: Dian-Ru
authors.initials: DR
authors.lastname: Wang
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.
authors.forename: Yoan
authors.initials: Y
authors.lastname: Cherasse
authors.affiliation: Department of Pharmacology and Shanghai Key Laboratory of Bioactive Small Molecules, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China.
authors.forename: Ze
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Shanghai Key Laboratory of Bioactive Small Molecules, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China.
authors.forename: Meng-Qi
authors.initials: MQ
authors.lastname: Zhang
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.
authors.forename: Oriana
authors.initials: O
authors.lastname: Lavielle
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.
authors.forename: Kristopher
authors.initials: K
authors.lastname: McEown
authors.affiliation: Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles, 1070, Brussels, Belgium.
authors.forename: Serge N
authors.initials: SN
authors.lastname: Schiffmann
authors.affiliation: Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles, 1070, Brussels, Belgium.
authors.forename: Alban
authors.initials: A
authors.lastname: de Kerchove d'Exaerde
authors.affiliation: Department of Pharmacology and Shanghai Key Laboratory of Bioactive Small Molecules, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China. quweimin@fudan.edu.cn.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Qu
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan. lazarus.michael.ka@u.tsukuba.ac.jp.
authors.forename: Michael
authors.initials: M
authors.lastname: Lazarus
authors.affiliation: Department of Pharmacology and Shanghai Key Laboratory of Bioactive Small Molecules, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China. huangzl@fudan.edu.cn.
authors.forename: Zhi-Li
authors.initials: ZL
authors.lastname: Huang
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004576:Electromyography; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics; D009830:Olfactory Bulb / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D012895:Sleep, REM / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic; D014230:Triazoles / Q000494:pharmacology
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D008164:Luminescent Proteins; D010627:Phenethylamines; D016760:Proto-Oncogene Proteins c-fos; D011743:Pyrimidines; D034741:RNA, Small Interfering; D043705:Receptor, Adenosine A2A; D014230:Triazoles; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine
keywords: A2AR-Cre mice; Chemogenetics; REM-sleep behavior disorder; Short-hairpin RNA