Project Grant F30ES036896

LIPID-BASED INTERVENTIONS TO MITIGATE THE IMPACT OF ARSENIC ON MICROGLIAL FUNCTION AND NEUROBEHAVIOR - PROJECT SUMMARY/ABSTRACT ANXIETY AND DEPRESSION AFFLICT MORE THAN 548 MILLION PEOPLE WORLDWIDE. FURTHERMORE, >20% OF INDIVIDUALS ARE REFRACTORY TO CONVENTIONAL TREATMENT, LEADING TO A 2.2-FOLD INCREASE IN MORTALITY RISK. IMPORTANTLY, INDIVIDUALS WITH EARLY-LIFE ANXIETY/DEPRESSION ALSO SHOW A 1.24 TO 2-FOLD HIGHER RISK OF DEMENTIA IN LATER LIFE, SUGGESTING CONVERGING PATHOGENIC MECHANISMS. AN INCOMPLETE UNDERSTANDING OF THESE CONDITIONS IS A SIGNIFICANT BARRIER TO IMPROVING PATIENT NEUROPSYCHIATRIC/NEUROCOGNITIVE HEALTH. UNTIL RECENTLY, EFFORTS TO CLARIFY DISEASE ETIOLOGY HAVE CENTERED AROUND GENETIC AND SOCIAL FACTORS, OFTEN NEGLECTING ENVIRONMENTAL DRIVERS THAT ARE INCREASINGLY LINKED TO NEUROBEHAVIORAL DYSFUNCTION. AMONG THE WHO'S TOP CHEMICALS OF PUBLIC HEALTH CONCERN, ARSENIC (AS) IS A TOXIC METALLOID STRONGLY ASSOCIATED WITH ANXIETY, DEPRESSION, AND DEMENTIA. IMPORTANTLY, DATA INDICATE THAT THESE DISORDERS HAVE NEUROINFLAMMATORY ORIGINS, WITH MICROGLIA SERVING AS CAUSAL MEDIATORS. ARSENIC IS KNOWN TO ACCUMULATE IN THE BRAIN AND ACTIVATE MICROGLIA. HOWEVER, THE MECHANISMS BY WHICH IT CONTRIBUTES TO NEUROBEHAVIORAL DYSFUNCTION REMAINS INCOMPLETELY UNDERSTOOD. OUR LAB HAS SHOWN THAT ARSENIC DEPLETES THE BRAIN OF THE ESSENTIAL FATTY ACID DOCOSAHEXAENOIC ACID (DHA). THIS IS SIGNIFICANT BECAUSE DHA PLAYS MULTIPLE HOMEOSTATIC ROLES IN THE BRAIN, INCLUDING EFFECTS ON NEUROTRANSMISSION AND MICROGLIAL CLASS-SWITCHING FROM PRO- INFLAMMATORY (M1) TO ANTI-INFLAMMATORY (M2) STATES. THIS PROPOSAL WILL USE A COMPLEMENTARY ARRAY OF IN VIVO MOUSE STUDIES AND EX VIVO EXPERIMENTS IN PRIMARY MICROGLIA TO INTERROGATE OUR CENTRAL HYPOTHESIS THAT DHA IS ESSENTIAL FOR PROTECTING NEUROBEHAVIORAL HEALTH FROM ARSENIC TOXICITY, AND THAT TARGETED BRAIN DHA ENRICHMENT MITIGATES ENVIRONMENTAL THREATS LINKED TO ANXIETY, DEPRESSION, AND DEMENTIA. THE RESEARCH COMPONENT OF THIS TRAINING GRANT WILL PROVIDE THE FELLOW WITH A RIGOROUS DEPTH AND BREADTH OF TRAINING IN A COMPLEMENTARY ARRAY OF STATE-OF-THE-ART TECHNIQUES, INCLUDING ADVANCED BEHAVIORAL ASSESSMENTS, ELECTROPHYSIOLOGY, MASS SPECTROMETRY IMAGING, AND VARIOUS ASSAYS TO CHARACTERIZE MICROGLIAL BIOLOGY. THESE TECHNICAL SKILLS WILL BE SUPPLEMENTED WITH HIGHLY ENGAGED MULTIDISCIPLINARY MENTORSHIP AND EDUCATIONAL ACTIVITIES ACROSS THE FIELDS OF NEUROSCIENCE, ENVIRONMENTAL HEALTH, AND CLINICAL MEDICINE. A CENTRAL GOAL OF THIS INTEGRATED TRAINING PLAN IS TO EMPOWER THE FELLOW WITH SKILLS TO CRITICALLY APPRAISE, USE, AND ANALYZE VARIOUS MODELS, METHODS, AND DATA. COLLECTIVELY, THIS PROPOSAL WILL LAUNCH THE FELLOW'S LONG-TERM SUCCESS AS A PHYSICIAN-SCIENTIST AT THE CUTTING-EDGE OF ENVIRONMENTAL NEUROSCIENCE WITH THE KNOWLEDGE AND SKILLS TO UNLOCK THE MECHANISMS OF ENVIRONMENTALLY-DRIVEN NEUROBEHAVIORAL DYSFUNCTION IN ORDER TO IMPROVE HUMAN HEALTH AND PROMOTE HEALTH EQUITY.