REV-ERBβ is required to maintain normal wakefulness and the wake-inducing effect of dual REV-ERB agonist SR9009

Abstract

Circadian signaling regulates and synchronizes physiological and behavioral processes, such as feeding, metabolism, and sleep cycles. The endogenous molecular machinery that regulates circadian activities is located in the suprachiasmatic nucleus of the hypothalamus. The REV-ERBs are transcription factors that play key roles in the regulation of the circadian clock and metabolism. Using pharmacological methods, we recently demonstrated the involvement of the REV-ERBs in sleep architecture. Another group reported a delayed response to sleep deprivation and altered sleep cycles in REV-ERBα null mice, indicating a role of REV-ERBα in sleep. Given that REV-ERBβ is structurally and functionally similar to REV-ERBα, we investigated the role of REV-ERBβ in sleep and wakefulness by assessing electroencephalographic recordings in REV-ERBβ deficient mice and the mechanism underlying effects of loss of REV-ERBβ on sleep. Our data suggest that REV-ERBβ is involved in the maintenance of wakefulness during the activity period. In addition, REV-ERBβ-deficient mice administered with dual REV-ERB agonist SR9009, failed to show drug-induced wake increase. Finally, the expression of a number of genes known to mediate sleep and wakefulness were altered in REV-ERBβ null mice.