Bmal1 as a Central and Peripheral Regulator of Sleep Homeostasis

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DESCRIPTION (provided by applicant): Insufficient sleep is a widespread public health problem that increases metabolic demands and subsequent related risks of morbidity and mortality. To better understand the mechanisms of recovery from insufficient sleep and the consequences of insufficient sleep, this training plan aims to examine central and peripheral molecular (BMAL1) regulation of sleep and metabolism at neurochemical, physiological, and cellular levels. BMAL1 is a central focus because it is a circadian transcription factor that is thought to influence daily sleep amount and recovery from sleep loss. The specific aims of this research proposal will be addressed by the use of transgenic mice that have amplification or rescue of BMAL1 expression specific to the brain or skeletal muscle. Use of the tetracycline transactivator system in these mice also permits for temporal knockdown or rescue of tissue-specific BMAL1 expression in order to delineate between developmental versus direct effects. The central hypothesis is that the extent of increases in central and peripheral metabolic demands during sleep loss, determined from levels of extracellular adenosine in the basal forebrain and glucose and oxygen utilization in skeletal muscle, and the extent of dissipations of these parameters during recovery sleep is dependent on tissue-specific BMAL1 expression. This information will advance our scientific understanding and resolve critical barriers of how and where BMAL1 influences sleep and metabolic processes during sleep loss. The execution of this central hypothesis requires a synthesis of past, present, and proposed research methods training and effective communication with my sponsors, who are experts in areas of sleep, circadian rhythms, and skeletal muscle physiology. The specific aims will also be supplemented with collaborative research projects, continued education, and teaching, which will provide additional training in metabolic, neurophysiological, and molecular research methods and professional development.