Regulation of Sleep and Circadian Behaviors by TGF-alpha Signaling

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DESCRIPTION (provided by applicant): More than 30 million Americans suffer from chronic sleep disorders such as narcolepsy and insomnia. Yet, despite the medical impact of sleep disorders, relatively little is known of the genetic and neural circuits that underlie sleep and wakefulness. Sleep is a conserved behavior across the animal kingdom, and is regulated by homeostatic processes that respond to internal cues of sleep need, as well as a circadian process that responds to environmental cues. A caveat to most vertebrate sleep studies, however, is that they rely on nocturnal mammals such as mice and rats to model sleep behavior. These animals are good models for homeostatic sleep regulation, but it is unclear whether circadian aspects of sleep regulation are conserved with diurnal mammals such as humans. I will exploit the relatively simple yet conserved neural circuits of the zebrafish, a diurnal vertebrate, to test several hypotheses regarding the role of transforming growth factor alpha (TGF-alpha) in regulating sleep and circadian behaviors. First, I will test the hypothesis that TGF-alpha acts as a circadian signal to inhibit locomotor activity by performing gain and loss of function genetic experiments using high throughput locomotor activity and arousal threshold assays. Second, I will exploit the amenability of zebrafish larvae to high-throughput pharmacological administration and behavioral assays to determine the molecular mechanisms that mediate TGF-alpha-dependent behaviors in zebrafish. Third, I will characterize the cells that produce and respond to TGF-alpha signaling, and test the hypothesis that TGF-alpha signaling activates sleep-promoting neural populations and silences wake- promoting neural populations. These experiments will help to illuminate the genetic and neural mechanisms through which TGF-alpha mediates circadian cues that regulate wake/sleep states in diurnal animals. These studies will improve our understanding of how sleep is regulated and may lead to novel treatments for sleep and circadian rhythm disorders.