PROJECT SUMMARY/ABSTRACT The neural circuits that induce and maintain anesthetic-induced unconsciousness remain incompletely understood. Given that anesthesia and sleep are both forms of reversible unconsciousness, anesthesia research has investigated whether sleep circuits in the brain regulate anesthetic-induced unconsciousness. However, studies of the preoptic area, which contains the main sleep centers in the brain, do not explain all aspects of anesthetic-induced unconsciousness, leading researchers to look for new brain circuits. A newly discovered midbrain nucleus, the rostromedial tegmental nucleus (RMTg), sends major GABAergic projections to the ventral tegmental area (VTA). Altering the activity of dopaminergic neurons in the VTA has been previously shown to induce emergence from continuous inhaled anesthesia, suggesting a role of midbrain circuits in regulating anesthetic-induced unconsciousness. To date, only one paper has begun studying the role of the RMTg in sleep, and no papers have yet looked at its role in anesthesia. This proposal will fill this gap and provide new information about a midbrain nucleus that may regulate different states of consciousness. The central hypothesis of this proposal is that altering the activity of the GABAergic RMTg neurons will impact the brain’s sensitivity to anesthetics. We will use transgenic rats expressing Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to specifically activate or inhibit GABAergic neurons of the RMTg. Aim 1 will investigate the impact of altering the RMTg’s activity on NREM sleep using electroencephalogram (EEG) recordings. Aim 2 will use rodent behavioral assays and in vivo EEG and local field potential (LFP) recordings to determine the extent to which the RMTg’s activity influences anesthetic sensitivity. The results from this proposal will characterize a new circuit that may modulate reversible unconsciousness in the brain. Understanding novel circuits involved in regulating different states of consciousness will generate new knowledge that could help develop new treatments for various disorders of consciousness, including neurological sleep disorders and minimally consciousness patients. Understanding the neural circuits involved in producing anesthesia could also help scientists design more specific anesthetics that have fewer physiological side effects on systems like the respiratory and cardiovascular systems.