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.
Bibliographical noteFunding Information:
We thank Dr. U. Schibler (University of Geneva) for providing Rev-erbα mutant mice, Dr. T.P. Burris (Scripps Institute) for providing SR8278, Dr. H. Kim (Korea University) for help with microarray experiments, Dr. T. Chun (Korea University) for assistance with FACS experiments, and S. Lee (Seoul National University) for constructing hyperdrives. This work was supported by the Brain Research Center of the 21 st Century Frontier Research Program (2009K001287), the Neural Technology Development and Service for Neuroscience Research (2013056731), and the National Research Foundation of Korea (2010-0025112, 2011-0019232, 2012M3A9C7050135). BioScience Writers edited the manuscript.