Lipid-Based Interventions to Mitigate the Impact of Arsenic on Microglial Function and Neurobehavior - PROJECT SUMMARY/ABSTRACT Anxiety afflicts more than 359 million people worldwide. Furthermore, >40% of individuals are refractory to conventional first-line treatments, leading to a 2.2-fold increase in mortality risk. An incomplete understanding of these conditions is a significant barrier to improving patient neuropsychiatric health. Until recently, efforts to clarify disease etiology and develop therapeutic interventions have centered around genetic and social factors, often neglecting environmental drivers that are increasingly linked to neurobehavioral dysfunction. However, a growing body of evidence suggests toxic metal/metalloid exposures contribute to adverse neuropsychiatric outcomes. For example, inorganic arsenic (iAs), a widespread environmental toxicant, increases anxiety/anxiety-like phenotypes in various epidemiological and experimental studies. Thus, environmental exposures to iAs may significantly contribute to the risk of anxiety across populations. Importantly, data indicate that anxiety 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 that are crucial for cognitive function, 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 in vitro experiments in SIM-A9 microglia to interrogate our central hypothesis that DHA is essential for protecting neurobehavioral health from arsenic toxicity, and that targeted brain DHA enrichment via use of a novel lysophosphatidylcholine DHA (LPC-DHA) therapy mitigates environmental threats linked to anxiety. Unlike traditional triglyceride DHA that accumulates peripherally, LPC-DHA is preferentially shuttled across the blood-brain barrier by a unique transporter called MFSD2A. Thus, 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 with a focus on translational therapeutic development. 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 develop new therapeutic approaches to improve human health.
