OVERALL ABSTRACT General anesthesia is a fascinating man-made, neurophysiological phenomenon that has been developed empirically over many years to enable safe and humane performance of surgical and non-surgical procedures. Specifically it is a drug-induced condition consisting of unconsciousness, amnesia, analgesia and immobility, along with physiological stability. General anesthesia is administered daily to 60,000 patients in the United States, the mechanisms for how anesthetics act in the brain to create the states of anesthesia are not well understood. Significant progress has been made recently in characterizing the molecular sites that anesthetics target. However, how actions at specific molecular targets lead to the behavioral states is less well understood. Addressing this issue requires a systems neuroscience approach to define how actions of the drugs at specific molecular targets and neural circuits lead to a behavioral state of general anesthesia. In this program project entitled, Integrated Systems Neuroscience Studies of Anesthesia, we will develop an integrated systems neuroscience program consisting of human, non-human primate, rodent and modeling studies of four anesthetics: the GABAA agents, propofol and sevoflurane; the alpha-2 adrenergic agonist, dexmedetomidine; and the NMDA receptor antagonist, ketamine. The program project will also include a DATA ANALYSIS CORE, which will provide assistance with data analysis and conduct research on statistical methods. The Specific Aims are to understand how the actions of the anesthetics at specific molecular targets and neural circuits produce the oscillatory dynamics (EEG rhythms, changes in LFPs and neural spiking activity) that are likely a primary common mechanism through which anesthetics create altered states of arousal (sedation, hallucination, unconsciousness). The research will develop new, fundamental knowledge about the neurophysiological mechanisms of anesthetic actions that will have broad impact. This new knowledge will offer a new approach to real-time monitoring and control of brain states of patients receiving general anesthesia and sedation. Anesthesia caregivers will be able to relate the prominent oscillatory dynamics induced by anesthetics to their altered states of arousal through their actions at specific molecular targets and in specific neural circuits. Improved neurophysiologically-based monitoring and drug delivery strategies offer the promise of reducing the undesirable anesthetic side effects such as nausea, vomiting, neurotoxicity and post-operative cognitive dysfunction. This research will provide new, fundamental quantitative insights into the workings of the brain's arousal and cognitive systems that may translate into new approaches to creating the states of general anesthesia along with ways to treat disorders of arousal such as sleep, depression, coma and pain.