Impact of Circadian Nuclear Receptor REV-ERB alpha 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-ERB alpha, which is associated with bipolar disorder, impacts midbrain dopamine production and mood-related behavior in mice. Genetic deletion of the Rev-erb alpha gene or pharmacological inhibition of REV-ERB alpha activity in the ventral midbrain induced mania-like behavior in association with a central hyperdopaminergic state. Also, REV-ERB alpha repressed tyrosine hydroxylase (TH) gene transcription via competition with nuclear receptor-related 1 protein (NURR1), another nuclear receptor crucial for dopa-minergic 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 REVERBa could be targeting in the treatment of circadian rhythm-related affective disorders.