Title: Mitochondrial Regulation of Brain Network Dynamics in Stress Project Summary Stress-related neuropsychiatric disorders, such as bipolar disorder, schizophrenia, major depressive disorder (MDD), and post-traumatic stress disorder (PTSD), often exhibit mitochondrial dysfunction. Mitochondria play a critical role in responding to environmental stressors and influencing brain health throughout an individual's life. However, the specific impact of mitochondrial dysfunction on brain network activity under stress conditions and its subsequent effect on cognitive and behavioral changes remain poorly understood. The proposed research will use a multi-method approach that combines molecular, cellular, and circuit-level analyses to understand how mitochondrial bioenergetics and quality control mechanisms contribute to the synchronized brain network activity underlying cognition in normal and pathological states. The research strategy will focus on understanding basic mechanisms that regulate mitochondrial functions and how these processes impact brain networks in stress conditions. A comprehensive understanding of how key mitochondrial processes regulate the spatiotemporal dynamics of neural activity will provide fundamental insights into how these critical cellular processes contribute to brain function. In the present proposal, Dr. Quigley will test the hypothesis that the properties of mitochondria in distinct brain regions confer vulnerability to cellular stress that can be detected at the network level, contributing to behavioral outcomes. To do so, Aim 1 aims to investigate region and cell type specific mitochondrial phenotypes throughout the brain associated with stress. The approach will use a combination of imaging techniques, biochemistry, and physiological assays to examine subcellular differences in mitochondrial dynamics and protein expression under conditions of stress. Aim 2 aims to identify joint molecular and electrophysiological markers for changes in allostatic load induced by mitochondrial dysfunction. This will be achieved by first examining the relationship between in vivo mitochondrial functions, brain circuit activity, and stress by characterizing a method of light-activated induction of oxidative stress, followed by measurements of electrical activity and the use of statistical methods to make comparisons to behavioral stress. Subsequently, candidate markers will be identified from proteomic experiments to inform the measuring of joint neurophysiological and molecular biomarkers associated with stress and the application of advanced statistical methods to identify associated patterns that correlate with behavioral states. The proposed research will pave the way for further independent studies and may aid in developing new therapeutic avenues that span diagnostic categories. Combined with the applicant’s prior graduate training in acquiring and analyzing in vivo electrophysiology data, this work will facilitate Dr. Quigley’s...