Central nervous system (CNS) metabolism and neuronal excitability are interdependent, and so CNS metabolism is the biochemical basis of cognition, memory, and behavior. Dysregulation of CNS is implicated in numerous disorders, including Alzheimer’s Disease, epilepsy, Parkinson’s disease, and brain injury, but the mechanistic connections between CNS metabolism and disease are poorly understood. The University of Kentucky (UK) College of Medicine has made significant investments over the last few years in investigators with metabolic and metabolomics expertise and instrumentation to support their research efforts, which has enhanced existing strengths in neuroscience, cancer, cardiovascular, and diabetes and obesity research. Thus, UK proposes to establish a unique multidisciplinary Center of Biomedical Research Excellence (COBRE) on CNS Metabolism (CNS-Met) as a strategically designed, sustainable framework that promotes leading-edge research focused on the role of metabolic mediators of brain function and disease. The proposed interdisciplinary center leverages highly specialized expertise in glucose biology, neuronal signaling, mitochondrial metabolism, systems neuroscience, and data sciences as well as the presence of advanced metabolomics and imaging capabilities to create an integrated research framework focused on CNS metabolism. The overarching goals are to strengthen UK’s neuroscience research enterprise by providing a thematically focused and sustainable multidisciplinary infrastructure dedicated to defining the contribution of metabolism to CNS function and neurological diseases and to use this novel platform to develop promising and highly-skilled, early-stage investigators in an exciting and impactful area of CNS research. To accomplish these goals, we will meet four specific aims: (1) Develop a critical mass of funded investigators with research programs directly related to the COBRE’s unifying theme; (2) provide strong team-based mentoring combining basic and clinical expertise; (3) recruit new investigators to the COBRE in multidisciplinary areas of neurologic dysfunction through pilot project grant and recruitment of junior Research Project Leaders; and (4) create synergy among research projects via critical links to strong research centers and core facilities at UK, including existing COBREs. Emerging synergies will be developed through three research projects, an Administrative Core, a critical research core in Metabolomics, all linked by strong biostatistics/bioinformatics support, all of which are critical to the proposed studies and will contribute to the development of institutional resources. The scientific focus of the three research projects are brain metabolism interactions with neurological disease, spanning basic and translational perspectives. This concentration of multidisciplinary expertise focused on widely recognized yet understudied metabolic mechanisms of neurological diseases promises significant new understandi...