The Molecular and Cellular Basis of the Sleep Homeostat

Project Summary Understanding why we sleep remains one of the most enduring mysteries in science. Nearly every organism examined, even jellyfish that lack a centralized nervous system, exhibits a restorative sleep-like state. While asleep, we cannot eat, mate, defend ourselves from predators or care for our young. Inadequate sleep contributes to brain disease such as Alzheimer's and depression, and even diseases outside of the brain, such as diabetes and obesity. Sleep is homeostatically regulated, i.e., sleep is driven by the duration and intensity of prior waking experience. However, the mechanistic basis of the sleep homeostat remains unclear. How does wakefulness tax the brain? How does the homeostat sense those effects? How does the homeostat trigger sleep? How does sleep restore the brain? Almost uniquely among brain functions, sleep requires the coordinated activity of widespread brain regions. We aim to reveal the molecular and circuit basis of the sleep homeostat using a simple animal model Drosophila. We will apply innovative genetically targeted transcriptomic and proteomic approaches such as single-cell RNA sequencing and enzymatic proximity labeling in the compact Drosophila brain to provide insights into sleep-dependent genomic and proteomic changes at single gene, single protein, and single cell resolution. We will then exploit the power of Drosophila genetics to assess the functional impact of sleep/wake dependent neurons and genes by examining effects on sleep including sleep-dependent functions including memory consolidation and lifespan. Based on our discovery that neural mechanisms controlling the circadian regulation of sleep are widely conserved, we predict that core homeostatic mechanisms will similarly be widely conserved. The integration of these experimental approaches will produce mechanistic insights that link gene to neuron to behavior and should reveal transformative insights into the components, logic, and function of the sleep homeostat.