Omega-3 supplementation as a therapeutic agent in PAE-induced neuroinflammation

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Abstract An estimated 10% of pregnant women in the US report consuming alcohol within the past 30 days, and 3% report binge drinking. Prenatal alcohol exposure (PAE) causes significant cognitive impairment in humans and in animal models, and persistent PAE-induced neuroinflammation may contribute to these impairments, although underlying mechanisms are not well understood. Understanding these mechanisms will inform strategies that may improve outcomes for these individuals. Neuroinflammation is induced through a complex and dynamic network of lipid mediators, cytokines, and chemokines produced from various neuroimmune cells, including microglia which are the resident macrophage-like innate immune cells of the brain. They are the first line of innate immunity and mediate immune regulation and resolution of inflammation. Polyunsaturated fatty acids (PUFAs) provide critical structural and functional components in the brain and in resident immune cells. Long-chain PUFAs can elicit immunomodulatory effects via their metabolites; these lipid mediators can alter the intensity and/or duration of inflammation. Omega-3 PUFAs are well known for their anti-inflammatory and pro-resolving properties; relevant lipid metabolites include E-series resolvins derived from eicosapentaenoic acid (EPA) that elicit their anti-inflammatory effects by binding to the chemerin receptor (ChemR23). Microglia have high levels of EPA and ChemR23. Activation of ChemR23 suppresses neuroinflammation, while its removal increases inflammation. Alcohol consumption during pregnancy is associated with decreased PUFA accumulation in the developing brain which may disrupt the ability of microglia to resolve neuroinflammation. The long-term goal of the proposed research is to evaluate the role of resolvins in PAE-induced neuroinflammation. Specifically, this study will utilize a ChemR23 knockout (KO) mouse strain. Pregnant mice will be exposed to alcohol and provided an EPA-enriched diet. Offspring will be assessed for lipid and resolvin concentrations in the brain (Aim 1) and neuroinflammation (Aim 2) at weaning. Experiments will be done in KO and background (C57BL/B6J) mice to functionally test the role of EPA-derived resolvins in PAE-induced neuroinflammation. The Nutrition Research Institute of UNC Chapel Hill (NRI) is located on the North Carolina Research Campus (NCRC). The campus maintains a collaborative atmosphere among multiple universities, companies and community partners and provides state-of-the-art lab and animal facilities housing all necessary equipment for the proposed research. My mentor Dr. Sandra Mooney sustains a strong scholarship in PAE, neurodevelopment, behavioral studies, grantsmanship, and academic collaboration. Taken together, Dr. Mooney’s mentorship and the NRI will help me to achieve my goals of; strengthening my background in PAE, nutrition, neurodevelopment and neuroimmunology research, build a strong neurodevelopment and neuroimmunology assessment skill set, and strengthen my scientific writing and grantsmanship skills.