Sleep rhythmicity and homeostasis in mice with targeted disruption of mPeriod genes

1 West Roxbury Veterans Affairs Medical Center and Harvard Medical School, West Roxbury 02132; and 2 Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 Submitted 1 March 2004 ; accepted in final form 15 March 2004 In mammals, sleep is regulated by circadian and homeostatic mechanisms. The circadian component, residing in the suprachiasmatic nucleus (SCN), regulates the timing of sleep, whereas homeostatic factors determine the amount of sleep. It is believed that these two processes regulating sleep are independent because sleep amount is unchanged after SCN lesions. However, because such lesions necessarily damage neuronal connectivity, it is preferable to investigate this question in a genetic model that overcomes the confounding influence of circadian rhythmicity. Mice with disruption of both mouse Period genes ( mPer ) 1 and mPer2 have a robust diurnal sleep-wake rhythm in an entrained light-dark cycle but lose rhythmicity in a free-run condition. Here, we examine the role of the mPer genes on the rhythmic and homeostatic regulation of sleep. In entrained conditions, when averaged over the 24-h period, there were no significant differences in waking, slow-wave sleep (SWS), or rapid eye movement (REM) sleep between mPer1 , mPer2 , mPer3 , mPer1-mPer2 double-mutant, and wild-type mice. The mice were then kept awake for 6 h (light period 6–12), and the mPer mutants exhibited increased sleep drive, indicating an intact sleep homeostatic response in the absence of the mPer genes. In free-run conditions (constant darkness), the mPer1-mPer2 double mutants became arrhythmic, but they continued to maintain their sleep levels even after 36 days in free-running conditions. Although mPer1 and mPer2 represent key elements of the molecular clock in the SCN, they are not required for homeostatic regulation of the daily amounts of waking, SWS, or REM sleep. circadian rhythmicity; rapid eye movement sleep Address for reprint requests and other correspondence: P. J. Shiromani, West Roxbury VA Medical Center, 1400 VFW Parkway, West Roxbury, MA 02132 (E-mail: pshiromani{at}hms.harvard.edu ).