Sleep circuitry: linking homeostasis, sedation and stress

This proposal aims to understand: 1) What circuitries sense the inexorable drive to sleep when we are sleep-deprived? We will investigate if sleep need is sensed locally in the brain by a distributed circuit network that feeds into a central hub, the lateral hypothalamus, providing global restorative sleep. We have identified neurons in the mouse prefrontal cortex, preoptic hypothalamus, and ventral tegmental area (VTA) that sense sleep need and contribute to inducing sleep after sleep deprivation. Learning how responses to sleep deprivation are embedded in distributed sleep circuitry would explain how sleep homeostasis works at the circuit level. 2) Do sedative drugs promote these restorative sleep pathways? How do two important drugs, propofol and dexmedetomidine, intervene in the sleep-homeostasis circuitry? We will search for cells that respond to sedatives to induce restorative sleep without deleterious effects (hypothermia). Understanding this circuitry may identify new drug targets. 3) What is the significance of sleep-promoting circuitry we have discovered in the basal ganglia and midbrain (globus pallidus to lateral habenula to VTA to lateral hypothalamus), which overlaps with circuitry that responds to aversive outcomes and stress? We will investigate if this basal ganglia-triggered sleep helps offline processing of negative experience.