Role of n-3 polyunsaturated fatty acids in myelinationduring development

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PROJECT SUMMARY Maternal nutrition plays an indispensable role in fetal and infant brain development. Accordingly, nutritional deficiencies during this critical window can cause neurodevelopmental disorders. Yet, exactly how nutrients contribute to the cellular and molecular mechanisms governing neurodevelopment is largely unknown. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (n-3 PUFA) consumed from fatty fish, accumulates in the phospholipids of cell membranes and is required for brain growth and maturation. Although DHA can be biosynthesized, offspring primarily rely on maternal DHA to meet their needs. Importantly, a global shift to Western-style diets has also led to decreased DHA intakes, raising concerns about the neurodevelopmental consequences for offspring. Humans with low DHA status display white matter defects and cognitive and behavioral deficits. Furthermore, DHA-deficient animals exhibit pro-inflammatory responses from microglia, the brain’s resident immune cells. Microglia also regulate the development and elimination of myelin, the axon insulator that increases the speed of nerve impulses and gives white matter its color. Indeed, novel work from our lab has shown that microglia phagocytose excess myelin during normal development. However, it is not known whether the neuroinflammatory and microglial consequences of low DHA status culminate in the abnormal regulation of myelination. Using a zebrafish model, I will generate DHA-depleted offspring via genetic and maternal diet strategies. By employing powerful single-cell transcriptomic and in vivo imaging techniques, I will investigate whether low DHA status alters: Inflammatory signaling and phagocytosis-related gene expression in microglia (Aim 1); myelin development and morphology (Aim 2); and the microglial phagocytosis of myelin sheaths (Aim 3). This work could reveal a cellular mechanism by which low DHA status leads to white matter defects and provide insight into nutritional strategies that optimize infant health and prevent neurodevelopmental disorders. Through my proposed training at the University of Colorado Anschutz Medical Campus, I will gain the conceptual, technical, and professional skills necessary to establish my independent research niche at the intersection of nutrition and developmental neurobiology.