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Cell. 2014 May 8;157(4):858-68. doi: 10.1016/j.cell.2014.03.039.

Impact of circadian nuclear receptor REV-ERBα on midbrain dopamine production and mood regulation.

Author information

1
Department of Biological Sciences and Brain Research Center for 21st Frontier Program in Neuroscience, Seoul National University, Seoul 151-742, Korea.
2
Department of Brain and Cognitive Sciences, Seoul National University, Seoul 151-742, Korea.
3
Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138-736, Korea.
4
Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, Harvard Stem Cell Institute, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
5
Department of Anatomy and Neurobiology, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, USA.
6
Department of Legal Medicine, College of Medicine, Korea University, Seoul 136-705, Korea. Electronic address: songh@korea.ac.kr.
7
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.

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.

PMID:
24813609
DOI:
10.1016/j.cell.2014.03.039
[Indexed for MEDLINE]
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