IMPACT OF SLEEP LOSS AND CIRCADIAN DISRUPTION ON NEURAL REGULATION OF METABOLISM

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Seeinstructions): The long-term goal of this project is to dissect the molecular basis for accelerated metabolic aging induced by circadian disruption and sleep loss in mice. Consistent with the overall goals of this program project, our focus will be to exploit mouse genetic tools to uncover the effect of circadian disruption at distinct time points in life on the progression of sleep impairment, and metabolic phenotypes. Our focus stems from work that has established that (1) circadian Clock mutant mice develop sleep loss and severe cardiometabolic disease during aging and (2) that high-fat diet itself leads to altered behavioral and molecular circadian rhythms in mice. We hypothesize that a 'vicious cycle' interconnects sleep and circadian disruption with cardiometabolic diisease. Moreover, we propose that there circadian disruption during critical windows in life effect the severity of cardiometabolic disease. We propose to exploit a genetic rescue strategy in which we have engineered clock mice harboring tetracycline-inducible wild-type alleles of the clock gene that can be selectively turned on or off within brain at distinct time points throughout life. Clock brain rescue mice have normal locomotor activity rhythms, but we do not know whether they also have normalized sleep and/or normalized metabolic profiles. Here we propose to test they hypothesis that clock gene rescue in brain at distinct ages either in early life or adulthood has different effects on sleep and the progression of cardiometabolic disease. In Aim 1, we propose to rescue clock function in brain throughout life; in Aim 2 we propose to rescue only in early life; and in Aim 3 we propose to rescue clock function in brain in adult life. We will then analyze sleep (REM/NREM/delta power) and metabolic endpoints (feeding rhythms, body composition, hormonal/biochemical markers and tissue metabolic gene networks). Results of these studies will establish the cause-and-effect relationship between disruption of circadian systems, sleep, and metabolic homeostasis and pinpoint the most vulnerable periods in life that set in motion an irreversible course of accelerated aging. RELEVANCE (See instructions): The goal of this proposal is to dissect the molecular basis for accelerated metabolic aging induced by circadian disruption and sleep loss in mice. Insight gained from these studies will advance our knowledge of the interdependence of circadian disruption, sleep impairment, and cardiometabolic disease. We will establish the age-dependence of altered behavior on metabolic aging and create new insight for both prevention and rational theranies that will avert diabetes and ohfisitv durinn aninn.