PROJECT SUMMARY/ABSTRACT Every day approximately 100,000 people undergo general anesthesia in the United States, and by the age of 70, almost all of us will experience general anesthesia. Yet it remains unknown how anesthetics produce unconsciousness, and how consciousness is restored after general anesthesia. The broad, long- term objectives of this project are to: (1) make general anesthesia safer by developing new ways to restore consciousness and cognition in anesthetized patients, and (2) aid the development of safer anesthetics by elucidating the mechanisms of anesthetic-induced unconsciousness. In our application we show that midbrain GABA neurons in the rostromedial tegmental nucleus (RMTg) are involved in anesthetic-induced unconsciousness, while midbrain dopamine neurons in the ventral tegmental area (VTA) are involved in emergence and cognitive recovery from general anesthesia. The Specific Aims are to: (1) characterize the role of the RMTg-VTA circuit in anesthetic-induced unconsciousness, (2) characterize the role of VTA dopamine neurons and their projections in anesthetic emergence, and (3) identify the VTA dopaminergic projections that promote cognitive recovery from the anesthetized state, using a touchscreen-based visual discrimination task. Using genetically modified rodents that allow for selective targeting of dopamine and GABA neurons, we will employ a combination of optogenetics, chemogenetics, neurophysiological recordings, and touchscreen cognitive testing to elucidate the anesthetic circuitry of the midbrain. This project will shed light on fundamental mechanisms of anesthesia and consciousness, which will allow us to improve patient care by developing new techniques to help the brain recover from general anesthesia. In addition, this work will facilitate the development of new anesthetics with fewer side effects.