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

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

SUBMITTER: Jager J

PROVIDER: S-EPMC3968406 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Jager Jennifer J O'Brien W Timothy WT Manlove Jessica J Krizman Elizabeth N EN Fang Bin B Gerhart-Hines Zachary Z Robinson Michael B MB Klein Peter S PS Lazar Mitchell A MA

Molecular endocrinology (Baltimore, Md.) 20140219 4

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 su ...[more]

PMID: 24552589

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Project description:AimsAdverse cardiovascular events have day/night patterns with peaks in the morning, potentially related to endogenous circadian clock control of platelet activation. Circadian nuclear receptor Rev-erbα is an essential and negative component of the circadian clock. To date, the expression profile and biological function of Rev-erbα in platelets have never been reported.Methods and resultsHere, we report the presence and functions of circadian nuclear receptor Rev-erbα in human and mouse platelets. Both human and mouse platelet Rev-erbα showed a circadian rhythm that positively correlated with platelet aggregation. Global Rev-erbα knockout and platelet-specific Rev-erbα knockout mice exhibited defective in haemostasis as assessed by prolonged tail-bleeding times. Rev-erbα deletion also reduced ferric chloride-induced carotid arterial occlusive thrombosis, prevented collagen/epinephrine-induced pulmonary thromboembolism, and protected against microvascular microthrombi obstruction and infarct expansion in an acute myocardial infarction model. In vitro thrombus formation assessed by CD41-labelled platelet fluorescence intensity was significantly reduced in Rev-erbα knockout mouse blood. Platelets from Rev-erbα knockout mice exhibited impaired agonist-induced aggregation responses, integrin αIIbβ3 activation, and α-granule release. Consistently, pharmacological inhibition of Rev-erbα by specific antagonists decreased platelet activation markers in both mouse and human platelets. Mechanistically, mass spectrometry and co-immunoprecipitation analyses revealed that Rev-erbα potentiated platelet activation via oligophrenin-1-mediated RhoA/ERM (ezrin/radixin/moesin) pathway.ConclusionWe provided the first evidence that circadian protein Rev-erbα is functionally expressed in platelets and potentiates platelet activation and thrombus formation. Rev-erbα may serve as a novel therapeutic target for managing thrombosis-based cardiovascular disease.

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

Publications

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

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