Objective: The objective of this proposal is to train Dr. Aubrey Chan, MD/PhD, dual-boarded in internal medicine and psychiatry, to become an independent VA physician-scientist. He will be mentored in state-of- the-art neuroscience research techniques in recording neural signals by his mentors Drs. Rainbo Hultman and Nandakumar Narayanan, and he will be mentored in the cutting-edge analytical techniques applied to these signals by Dr. Matthew Howard. Dr. John Wemmie will serve as the career development mentor, providing guidance in Dr. Chan’s development as a principal investigator, managing lab personnel, mentoring graduate students, scientific communication, and grantsmanship. These research techniques will be applied to a novel, circuit-wide analysis of defensive responses by recording from and analyzing signals of multiple brain regions simultaneously. Defensive responses are physiological, emotional, and behavioral changes that occur when an organism is faced with a threat. Excessively active or exaggerated defensive responses underlie psychiatric illnesses like post-traumatic stress disorder, an illness that is highly prevalent in the veteran population, and which causes tremendous distress, disability, and suicide in veterans. Defensive responses will be studied in mice in response to carbon dioxide (CO2), a naturalistic stimulus which represents the interoceptive (internal) threat of suffocation. This threat will be compared and contrasted with exposure to trimethylthiazoline (TMT), a component of fox odor, representing the naturalistic but exteroceptive (external) threat of a predator. Responses will be analyzed both in a naïve state and after animals are exposed to a traumatic, chronic social defeat stress (CSDS). Dr. Chan will also dedicate time to the clinical care of veterans. Being dual-trained in internal medicine and psychiatry, he is particularly suited to treating the complex comorbid conditions often seen in veterans. He will work on the inpatient psychiatric unit and the psychiatric consult-liaison service at the Iowa City VA Medical Center. Methods: Custom electrodes will be constructed and stereotactically implanted into multiple mouse brain sites. After recovery from surgery, awake, behaving mice will be exposed to threatening stimuli while neural recordings are performed. Aim 1 will study the effects of CO2 and TMT in naïve animals, with follow-up exposures after animals have undergone CSDS. Behaviors will be matched against neural signals. Neural signals will be evaluated for local field potential (LFP) power, firing rates of individual neurons, and for functional connectivity measures between brain sites. In addition, the bispectral & electome methods will be used to detect salient neurophysiological features that predict behaviors. Aim 2 will use optogenetic manipulation of neural signals to modify defensive behaviors. To facilitate these studies, Dr. Chan will take coursework in automated behavioral scoring and stati...