Impact of Circadian Nuclear Receptor REV-ERBα on Midbrain Dopamine Production and Mood Regulation

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. [Display omitted] •Altered midbrain REV-ERBα induces mania-like behavior and a hyperdopaminergic state•Tyrosine hydroxylase (TH) gene transcription is directly repressed by REV-ERBα•REV-ERBα and NURR1 antagonistically regulate cyclic TH gene transcription•REV-ERBα controls circadian histone modification of the TH promoter The circadian nuclear receptor REV-ERBα drives midbrain dopamine production and release and thereby regulates mood control.