PROJECT 3: RODENT STUDIES OF ANESTHETIC ACTION 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 assistant 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). In our rodent studies we will use multi-electrode arrays to record multiple single unit activity and local field potentials from two or more sites in the frontal cortex, thalamus, parietal cortex, while unconsciousness is induced by systematically controlling anesthetic dosing. The dosing will be systematically decreased to allow the animal to recover consciousness. The animals will be trained to execute a continually administered cognitive visual task so we track the changes in its arousal state. We will characterize the altered states of arousal induced by each anesthetic by relating the dynamics of the neurophysiological changes to the changes in behavior. The rodent studies will allow simultaneous recording from multiple brain areas to gain a detailed description of how anesthetics alter brain circuit dynamics to produce a specific behavioral state. We will also conduct neural modulation experiments using optogenetics and local pharmacology to understand how changes in specific circuits alter network dynamic and lead to changes in arousal state. These studies will also provide fundamental new knowledge about the neurophysiology of the brain's arousal circuits that will be relevant to problems such as coma, sleep disorders, pain and depression.