Impact of Nutritional Status on Mechanisms Guiding Brain Development - Perinatal nutritional deficiencies are associated with a higher risk of cognitive and psychiatric disorders, but the cellular and molecular mechanisms explaining this link remain unclear and understudied. Docosahexaenoic acid (DHA), an omega-3 fatty acid found in fatty fish, is an essential building block of brain cell membranes during embryonic development. Importantly, the fetus relies on DHA from the maternal diet to meet the demands of brain growth. Yet, most Americans consume Western-style diets containing very low DHA, raising concerns about the neurodevelopmental consequences for offspring. Low DHA status leads to grey and white matter defects and early-life cognitive impairments. At a cellular and molecular level, perinatal rodent models with DHA deficiency display elevated pro-inflammatory cytokines and activated microglia, the brain’s resident immune cells. Microglia play a key role in the brain’s response to injury and disease. However, during development, microglia also actively sculpt neural circuits through their interactions with neurons and oligodendrocytes. Does DHA deficiency disrupt neuroimmune signaling and critical microglial functions, leading to the observed neurodevelopmental abnormalities? To advance our understanding of how DHA status impacts the developing brain, we will need powerful tools and animal models. Zebrafish are an ideal model system for studying neurodevelopmental mechanisms, as embryos are transparent, enabling direct observation of dynamic cell-cell interactions in the brain at single- cell resolution. To leverage the strengths of the zebrafish model system, I generated DHA-deficient offspring via gene-editing and dietary strategies. With my new model, I am now poised to investigate whether DHA deficiency disrupts neuroimmune gene signatures and cell-cell communication (Aim 1) and the microglia-mediated processes that shape neural circuits (Aim 2). I will also test the extent to which the offspring behavioral phenotype is explained by microglial responses, neuroimmune pathways, and the maternal diet (Aim 3). This project will reveal unparalleled insights into DHA’s role in the brain, potentially informing nutritional strategies that enhance cognitive health. Through my proposed training, I will carve out a research niche at the crossroads of nutrition and developmental neurobiology and lay the foundations for my competitive independent research program.
