The ins and outs of sleep: How internal metabolic and external environmental signals affect the sleep process

The behavioral pattern of activity followed by rest (activity:rest) is an evolutionarily conserved trait. A prominent manifestation of rest in vertebrates consists of sleep, which is adaptive because a disruption of sleep by internal or external influences results in severe health outcomes such as obesity, mood disorders, cognitive impairment, and so forth. Despite the clinical imperative to understand how these cues influence sleep, the mechanisms by which they do so are still unclear. Internally, metabolic cues interact with biochemical pathways that regulate sleep amount and quality. Externally, numerous environmental cues such as light, temperature, and chemicals affect the timing of sleep behavior. The goal of this thesis is to understand the mechanisms by which one internal (the \u27ins\u27) and one external (the \u27outs\u27) cue regulates sleep behavior using Drosophila melanogaster. This work consists of two independent projects that evaluate the \u27ins and outs\u27 of sleep. We begin with the \u27ins\u27 by addressing how one metabolic enzyme GABA Transaminase (GABAT) controls energy and sleep homeostasis. GABAT is a mitochondrial enzyme found in GABAergic neurons and glial cells where it breaks down the sleep-promoting neurotransmitter, GABA, into glutamate and succinic semialdehyde, both of which can also be used for energy via the TCA cycle. In this study, we determine the mechanism by which GABAT regulates metabolic and sleep homeostasis. In our second project, we evaluate the \u27outs\u27 of sleep by examining an uncharacterized phenomenon whereby organisms lose their ability to maintain the circadian timing of sleep cycles in the presence of cold-temperature stress. In this project, we use wild-derived flies to evaluate the evolutionary significance of maintaining circadian cycles in some strains regardless of temperature variance, and then determine the cellular and molecular mechanism by which other strains lose their ability to drive circadian rhythms of behavior at low temperature. Overall, the work accomplished in this thesis puts us one step closer towards understanding the \u27ins and outs\u27 of sleep