Proposal Summary Neural regulation of sleep, appetite and energy homeostasis is critical to an animal’s survival and under stringent evolutionary pressure. Despite the prevalence of disorders associated with metabolism and sleep, the neural and genetic processes that regulate interactions between these two systems is unclear. This proposal will investigate how genes and neurons modulate sleep in response to changes in metabolism. Flies, like mammals, potently modulate rest/activity cycles in accordance with their nutritional needs. Specifically, flies and mammals suppress sleep in response to food deprivation, presumably to initiate food-seeking behavior. Powerful genetics in the fruit fly allow for precise characterization of genes regulating behavioral and metabolic processes. We recently identified a single pair of neurons that express the neuropeptide Leucokinin and are required for sleep- metabolism interactions. This proposal will examine the neural signatures of food deprivation within these neurons, and how they are regulated by intrinsic and extrinsic cues associated with feeding state. We will combine single cell physiology and sequencing to define the molecular changes within these neurons associated with sleep and food deprivation. Finally, we will examine how the peripheral adipose tissue communicates energy stores to neurons in the brain that regulate sleep-metabolism interactions. Functional investigation of genes regulating sleep-metabolism interactions will provide the groundwork for understanding metabolic regulation of behavior and further our understanding of obesity, sleep disorders and diabetes.