Project Summary Neural regulation of sleep and metabolic homeostasis are critical to many aspects of human health. Despite extensive epidemiological evidence linking sleep dysregulation with obesity, diabetes, and metabolic syndrome, little is known about the neural and molecular basis for the integration of sleep and metabolic state. The genetic and functional basis of sleep is highly conserved from fruit flies to mammals. While the application of genetic approaches in flies have been used to identify novel genes and neural circuit mechanisms regulating sleep, the field has predominantly focused on sleep duration, rather than the physiological effects of sleep. This proposal employs a novel assay for simultaneously measuring sleep and metabolic rate in single flies. Preliminary data reveals that mutation of Neurofibromin 1 (Nf1), a gene that has been linked to sleep and metabolic dysregulation in humans, abolishes sleep-dependent modulation of metabolic rate in flies. The proposed experiments seek to identify the neurons required for sleep-metabolism interactions and determine the effects of Nf1 on the activity of neural circuits regulating sleep and metabolic function. Further, genetic experiments will be performed to identify the protein domains within NF1, and downstream signaling pathways, that are required for sleep-metabolism interactions. The completion of this work will yield insights into the cellular and neural circuit basis for the integration of sleep and metabolic rate, and establish flies as a model for investigating these interactions. Given the robust conservation of sleep and metabolism between flies and mammals, these results will provide a platform for investigation of how these processes are regulated, with the potential to provide insight into the association between sleep loss and metabolism-related disease.