Behavioral and Genetic Dissection of a Mouse Model for Advanced Sleep Phase Syndrome

Abstract

Vasoactive intestinal polypeptide (VIP) has been implicated in sleep regulation as a promoter of rapid eye movement (REM) sleep. Previous work has shown that the amount of time spent in REM sleep is increased by intracerebroventricular administration of VIP, and reduced by treatment with VIP antagonists or antibodies against VIP. A variety of evidence suggests that VIP is critical for normal expression of circadian rhythmicity of diverse physiological and behavioral parameters. In the present study, we investigated the role of this peptide in sleep regulation using VIP-deficient (VIP-/-) mice. EEG/EMG sleep-wake patterns were recorded in VIP-/- mice and their wild-type littermate controls under normal light-dark (LD), constant darkness (DD) and sleep deprivation conditions. VIP-/- mice exhibited reduced REM sleep time over the 24-h cycle while total daily amounts of NREM sleep and wakefulness were not altered significantly. The reduced REM sleep time in VIP-/- mice occurred entirely during the day due to a reduction in the duration, but not the frequency, of REM sleep bouts. In response to sleep deprivation, compensatory rebounds in NREM sleep and REM sleep were also attenuated in VIP-/- mice. Finally, the loss of VIP altered the temporal distribution of sleep in that the VIP -/- mice exhibited smaller amplitude rhythms in total sleep, NREM sleep, and REM sleep under both LD and DD. These results indicate that VIP regulates the duration of REM sleep, sleep homeostatic mechanisms as well as the temporal patterning of sleep.