PROJECT SUMMARY/ABSTRACT General anesthetics are essential in medicine, providing unconsciousness, amnesia and analgesia for otherwise intolerable surgical procedures. Although general anesthetics are widely used, little is known about how the brain recovers consciousness after general anesthesia. Consequently, there are no available treatments for common clinical problems associated with recovery from general anesthesia, such as emergence delirium and delayed emergence. Recent studies demonstrate that subcortical arousal nuclei are important for recovery of arousal, but mechanisms underlying recovery of cognition have not been explored. There are important knowledge gaps that this research program intends to fill over the next five years. First, the trajectory of cognitive recovery during anesthetic emergence is unknown. Specifically, it is unclear how discrete cognitive domains recover, and how the recovery trajectory differs among commonly used anesthetic drugs with different mechanisms of action. Second, it is unknown whether there are sex differences in cognitive recovery from general anesthesia, and whether different stages of the estrous cycle alter the cognitive recovery profile in female rodents. Finally, it its unknown if activating neural circuits involved in arousal, attention, and memory facilitate cognitive recovery from general anesthesia. The broad, long-term objectives of this R35 (MIRA) grant are to elucidate how cognition recovers after general anesthesia, and to develop novel approaches to accelerate recovery. First, we will use touchscreen-based cognitive testing of rats to establish how specific cognitive domains recover after general anesthesia. Second, we will determine whether the female estrous cycle influences cognitive recovery. Finally, we will use chemogenetic manipulations to activate neural circuits involved in arousal, attention, and memory to test for acceleration of cognitive recovery. These studies will inform and guide novel approaches to accelerate recovery of consciousness after general anesthesia and treat common clinical problems associated with anesthetic emergence. They will also provide new insights into fundamental mechanisms of consciousness and cognition.