Behavioral Changes and Dopaminergic Dysregulation in Mice Lacking the Nuclear Receptor Rev-erbα

The regulation of behavior by the molecular components of the circadian clock is not well understood. Here we report that mice lacking the nuclear receptor Rev-erb alpha, a potent transcriptional repressor and core clock component, displayed marked hyperactivity and impaired response habituation in novel environments. In addition, Rev-erb alpha knockout (KO) mice were deficient in short-term, long-term, and contextual memories and also showed impairment in nest-building ability. Together, these results suggest that Rev-erb alpha KO mice manifest defective hippocampal function. Interestingly, the changes in novelty-induced locomotor activity of Rev-erb alpha KO mice were comparable at multiple times of day, potentially due to the muted amplitude of Rev-erb alpha oscillation in the hippocampus of wild-type mice. Hippocampal dopamine turnover was increased in Rev-erb alpha KO mice, due to up-regulation of tyrosine hydroxylase, the rate-limiting enzyme in dopamine production, and pharmacologic inhibition of tyrosine hydroxylase activity partially rescued locomotor hyperactivity. These findings reveal a novel, nonredundant function for Rev-erb alpha that links a core component of the circadian gene-regulatory network to the control of dopaminergic and hippocampus-dependent behaviors.