The overall question that motivates this SCOR in Neurobiology of Sleep and Sleep Apnea is the question of differential sleepiness in patients with obstructive sleep apnea. There is a marked disparity in the degree of sleepiness between patients with similar degrees of respiratory disturbance during sleep. Individuals are found with severe sleep apnea who are not excessively sleepy during the day and have limited benefit from therapy. Differential sleepiness is more marked in those with mild to moderate sleep apnea, a condition which affects millions of Americans. This issue is, hence, of fundamental import to the major clinical questions--who will benefit from treatment of sleep apnea, and how can such individuals be identified? To address this question, we propose a comprehensive, coordinated set of projects. Project by Weaver addresses differential susceptibility in patients with sleep apnea. We consider whether differential sleepiness is the result of the following: co-morbidities, in particular obesity; variations in sleep duration; night-to-night variability in respiratory disturbance during sleep. Fundamental is the concept that differential susceptibility reflects biological differences between individuals with respect to the robustness of their sleep promoting system (sleep homeostasis) in a similar way to trait differences between normal individuals in the response to sleep deprivation. Our hypothesis is that sleep homeostatic differences will be, in large part, genetically determined, based on recent observations of the genetic determination of sleep homeostasis in mice. Hence, we propose a study evaluating the heritability of sleep homeostasis in humans using a design based on monozygotic and dizygotic twins (Project by Kuna). These human projects are complemented by two projects in mice to evaluate the genes involved in determining sleepiness and sleep homeostasis, that will provide candidate genes for likely future studies of the mechanisms of differential sleepiness in humans. Project by Pack addresses whether there is coordinated regulation of genes involved in ATP production, in part mediated by cyclic-AMP response element binding protein (CREB), with wakefulness and sleep and whether the dynamic nature of this regulation is likely part of the signaling mechanisms for sleepiness. Complimentary studies are proposed at the mRNA, protein and enzyme activity levels, and the issue of site-specific regulation in brain is addressed. The final project Abel more directly examines the role of CREB and determines, using immunohistochemical and mutant mice with reporter genes, the time course and spatial distribution of CREB activation in relationship to sleep/wake, the role of noradrenaline in this process, and likely CREB target genes using both microarray approaches and hypothesis-driven investigation. These four closely interconnected projects are supported by three Cores.
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