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Mol Endocrinol. 2014 Apr;28(4):490-8. doi: 10.1210/me.2013-1351. Epub 2014 Feb 19.

Behavioral changes and dopaminergic dysregulation in mice lacking the nuclear receptor Rev-erbα.

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  • 1Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism (J.J., B.F., Z.G-H., M.A.L.), Department of Neurosciences (W.T.O., J.M.), and Division of Hematology-Oncology, Department of Medicine (P.S.K.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104; and Children's Hospital of Philadelphia Research Institute (E.N.K., M.B.R.), Departments of Pediatrics and Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104.


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-erbα, a potent transcriptional repressor and core clock component, displayed marked hyperactivity and impaired response habituation in novel environments. In addition, Rev-erbα 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-erbα KO mice manifest defective hippocampal function. Interestingly, the changes in novelty-induced locomotor activity of Rev-erbα KO mice were comparable at multiple times of day, potentially due to the muted amplitude of Rev-erbα oscillation in the hippocampus of wild-type mice. Hippocampal dopamine turnover was increased in Rev-erbα 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-erbα that links a core component of the circadian gene-regulatory network to the control of dopaminergic and hippocampus-dependent behaviors.

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