title: Behavioral changes and dopaminergic dysregulation in mice lacking the nuclear receptor Rev-erbα.
abstract: 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.
authors.affiliation: Division 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.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jager
authors.forename: W Timothy
authors.initials: WT
authors.lastname: O'Brien
authors.forename: Jessica
authors.initials: J
authors.lastname: Manlove
authors.forename: Elizabeth N
authors.initials: EN
authors.lastname: Krizman
authors.forename: Bin
authors.initials: B
authors.lastname: Fang
authors.forename: Zachary
authors.initials: Z
authors.lastname: Gerhart-Hines
authors.forename: Michael B
authors.initials: MB
authors.lastname: Robinson
authors.forename: Peter S
authors.initials: PS
authors.lastname: Klein
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002940:Circadian Rhythm / Q000235:genetics; D003071:Cognition; D004298:Dopamine / Q000378:metabolism*; D005106:Exploratory Behavior; D006185:Habituation, Psychophysiologic / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000172:deficiency* / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine