Bmal1: a potential homeostatic regulator of the sleep-wake cycle

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Sleep disorders and environmental challenges that reduce daily sleep amount act upon systems that drive the daily reciprocal relationship between sleep and wakefulness. Unfortunately, the physiological, neural, and genetic composition of these systems remains largely undetermined. The identification of the genes and molecules that drive and respond to changes in daily sleep-wake amount will provide new therapeutic targets for the treament of sleep disorders and co-morbid disease states. Since the reciprocal relationship between sleep and wakefulness is driven by 1) the circadian timing system and 2) a homeostatic system that allots sleep amount as a function of prior wake duration, it stands to reason that the two systems share common molecular elements. The experiments described in this proposal will take advantage of recently generated lines of conditional transgenic mice to test the hypothesis that Bmall, a core component of the circadian timing system, facilitates wakefulness and bolsters the homeostatic response to sleep loss. Specific aim 1 will determine whether amplication of Bmall expression enhances wakefulness or modifies the homeostatic response to sleep loss by polysomnographically analyzing sleep-wake states in a transgenic mouse line that over-expresses Bmall but conserves circadian function. Specific aim 2 will determine where the influences of Bmall on the sleep-wake cycle are mediated by examining sleep-wake states in transgenic mouse lines that exclusively express Bmall in the brain or periphery. Specific aim 3 will determine whether influences of Bmall on sleep-wake states are driven directly or induced through developmental influences of the mutation. This will be accomplished by examining sleep-wake states in transgenic mice whose expression of Bmall in brain tissue will be conditionally activated and deactivated by doxycycline administration. The goal of these studies is to establish and characterize a molecular link between the circadian timing system and the processes that drive sleep and/or wakefulness. Through the use of new trangenic technology this study will allow the analysis of sleep during the temporal and spatial manipulation of gene expression to examine potential therapeutic targets for treatment of sleep disroders.