Impact of Circadian Nuclear Receptor REV-ERBα 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-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.

Tyrosine hydroxylase down-regulation after loss of Abelson helper integration site 1 (AHI1) promotes depression via the circadian clock pathway in mice

“…1K, TH protein levels are higher at subjective dawn (circadian time 00, CT00) than at subjective dusk (CT12) in both of Fig. S2), consistent with the study by other investigators (23). We next cloned a mutant TH promoter that lacks Rev-Erbα binding site and investigated the effect of AHI1 on its activity (Fig.…”

“…Many studies indicated that expression of TH is a time-of-day circadian oscillating pattern and its expression is lowered at daytime and raised at night in mouse brain (23,28,30). So, we tested that whether AHI1 affects TH expression at different times of the day.…”

“…Circadian gene products regulate daily oscillation of monoamine neurotransmitters, either by controlling their biosynthesis or metabolism (19,20,22). Tyrosine hydroxylase (TH), a rate-limiting enzyme for DA biosynthesis, is directly repressed by circadian nuclear receptor Rev-Erbα (23,24). Rev-Erbα binds to RRE (REV-ERBs/retinoic acid receptor-related orphan nuclear receptor response element (RORE))/NBRE (NGFI-B response element) elements in TH promoter to repress TH expression via competing with nuclear receptor-related protein 1 (NURR1), a major transcriptional factor of TH (23,25).…”

“…Tyrosine hydroxylase (TH), a rate-limiting enzyme for DA biosynthesis, is directly repressed by circadian nuclear receptor Rev-Erbα (23,24). Rev-Erbα binds to RRE (REV-ERBs/retinoic acid receptor-related orphan nuclear receptor response element (RORE))/NBRE (NGFI-B response element) elements in TH promoter to repress TH expression via competing with nuclear receptor-related protein 1 (NURR1), a major transcriptional factor of TH (23,25). TH expression is also negatively regulated by circadian locomotor output cycle kaput (CLOCK) that is heterodimerized with brain and muscle arnt-like protein 1 (BMAL1) (26)(27)(28).…”

Serotonin buffers hippocampal neuroplasticity and emotional behavior

“…2G). Altogether, behavioral testing revealed reduced depression-and anxiety-like behaviors, increased risk-taking, unusual aggression as well as slower locomotor habituation to novelty in KO mice, which together are considered mania-like behavioral phenotypes in rodents (Chung et al, 2014;Logan and McClung, 2016), modeling traits occurring during the manic phase of Bipolar Disorder (BD).…”