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

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

Chung Sooyoung; Lee Eun Jeong; Yun Seongsik; Choe Han Kyoung; Park Seong-Beom; Son Hyo Jin; Kim Kwang-Soo; Dluzen Dean E; Lee Inah; Hwang Onyou; Son Gi Hoon; Kim Kyungjin

Cell

2014

2014-05

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-ERBalpha, which is associated with bipolar disorder, impacts midbrain dopamine production and mood-related behavior in mice. Genetic deletion of the Rev-erbalpha gene or pharmacological inhibition of REV-ERBalpha activity in the ventral midbrain induced mania-like behavior in association with a central hyperdopaminergic state. Also, REV-ERBalpha 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-ERBalpha could be targeting in the treatment of circadian rhythm-related affective disorders.

*Affect; *Circadian Rhythm; Animals; Bipolar Disorder/genetics; CLOCK Proteins/genetics/metabolism; Cytoplasmic and Nuclear/genetics/*metabolism; Dopamine/*metabolism; Genetic; Group A; Histones/metabolism; Humans; Inbred C57BL; Knockout; Male; Member 2/metabolism; Mesencephalon/*metabolism; Mice; Mood Disorders/genetics/metabolism; Nuclear Receptor Subfamily 4; Rats; Receptors; Repressor Proteins/genetics/*metabolism; Transcription; Tyrosine 3-Monooxygenase/genetics

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