title: Impact of circadian nuclear receptor REV-ERBα on midbrain dopamine production and mood regulation.
abstract: The circadian nature of mood and its dysfunction in affective disorders is well recognized, but the underlying molecular mechanisms are still unclear. Here, we show that the circadian nuclear receptor REV-ERBα, which is associated with bipolar disorder, impacts midbrain dopamine production and mood-related behavior in mice. Genetic deletion of the Rev-erbα gene or pharmacological inhibition of REV-ERBα activity in the ventral midbrain induced mania-like behavior in association with a central hyperdopaminergic state. Also, REV-ERBα repressed tyrosine hydroxylase (TH) gene transcription via competition with nuclear receptor-related 1 protein (NURR1), another nuclear receptor crucial for dopaminergic neuronal function, thereby driving circadian TH expression through a target-dependent antagonistic mechanism. In conclusion, we identified a molecular connection between the circadian timing system and mood regulation, suggesting that REV-ERBα could be targeting in the treatment of circadian rhythm-related affective disorders.
authors.affiliation: Department of Biological Sciences and Brain Research Center for 21st Frontier Program in Neuroscience, Seoul National University, Seoul 151-742, Korea.
authors.forename: Sooyoung
authors.initials: S
authors.lastname: Chung
authors.affiliation: Department of Biological Sciences and Brain Research Center for 21st Frontier Program in Neuroscience, Seoul National University, Seoul 151-742, Korea.
authors.forename: Eun Jeong
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences and Brain Research Center for 21st Frontier Program in Neuroscience, Seoul National University, Seoul 151-742, Korea.
authors.forename: Seongsik
authors.initials: S
authors.lastname: Yun
authors.affiliation: Department of Biological Sciences and Brain Research Center for 21st Frontier Program in Neuroscience, Seoul National University, Seoul 151-742, Korea.
authors.forename: Han Kyoung
authors.initials: HK
authors.lastname: Choe
authors.affiliation: Department of Brain and Cognitive Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Seong-Beom
authors.initials: SB
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Son
authors.affiliation: Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, Harvard Stem Cell Institute, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
authors.forename: Kwang-Soo
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Neurobiology, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, USA.
authors.forename: Dean E
authors.initials: DE
authors.lastname: Dluzen
authors.affiliation: Department of Brain and Cognitive Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Inah
authors.initials: I
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors.forename: Onyou
authors.initials: O
authors.lastname: Hwang
authors.affiliation: Department of Legal Medicine, College of Medicine, Korea University, Seoul 136-705, Korea. Electronic address: songh@korea.ac.kr.
authors.forename: Gi Hoon
authors.initials: GH
authors.lastname: Son
authors.affiliation: Department of Biological Sciences and Brain Research Center for 21st Frontier Program in Neuroscience, Seoul National University, Seoul 151-742, Korea; Department of Brain and Cognitive Sciences, Seoul National University, Seoul 151-742, Korea. Electronic address: kyungjin@snu.ac.kr.
authors.forename: Kyungjin
authors.initials: K
authors.lastname: Kim
mesh_terms: D000339:Affect; D000818:Animals; D001714:Bipolar Disorder / Q000235:genetics; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm; D004298:Dopamine / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019964:Mood Disorders / Q000235:genetics / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
chemical_list: D006657:Histones; C499650:Nr1d2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D014446:Tyrosine 3-Monooxygenase; D056926:CLOCK Proteins; D004298:Dopamine