Circadian Mood Regulation through REV-ERBα
  • Kyungjin Kim
  • SLS Colloquia / 04.13.2017. 04:00pm / Room N104, Bldg 110
Abstract

Circadian rhythm regulates a variety of physiological and behavioral consequences in mammals. The mammalian circadian timing system is hierarchically organized: The central circadian pacemaker residing in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus orchestrates numerous extra-SCN local oscillators in several regions of the brain and peripheral tissues. The circadian nature of mood and its dysfunction in affective disorders is well recognized, but the underlying molecular mechanism remains unclear. We found that REV-ERBα, one of the potent transcription repressor, impacts midbrain dopamine (DA) production and mood-related behaviors in mice. Genetic abrogation of Rev-erbα or pharmacological inhibition of REV-ERBα activity in the ventral midbrain induced mania-like and depressive behaviors in association of hyper-dopaminergic state. REV-ERBα represses tyrosine hydroxylase (TH, a rate-limiting step of DA synthesis) gene transcription by competition with NURR1 (a nuclear receptor for DA neuronal development and maintenance) and functions driving circadian expression of DA system. Furthermore REV-ERBα represses TH gene transcription by recruiting histone deacetylase 3(HDAC3) to the promoter region resulting in suppressive histone deacetylation. In summary, the present study demonstrates the novel functional link between circadian timing system and DA-controlling mood regulation through REV-ERBα.