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Abstract
Brain development and health are influenced by nutrients, which can modulate neurochemical pathways, functional connectivity, and recovery mechanisms. Nutritional interventions, such as functional foods rich in essential nutrients and bioactive compounds, play important roles in supporting neurodevelopment, mitigating oxidative stress, and enhancing brain resilience during development and restoring its function. This dissertation explores how interventions through nutrients and pharmacotherapeutics modified from naturally occurring compounds can influence brain outcomes through a series of studies using a translational pig model. In study #1, the effects of perinatal supplementation of docosahexaenoic acid (DHA) on specialized pro-resolving lipid mediators (SPMs) in the brain of offspring were investigated using a sow and piglet dyad model to provide insights into potential mechanisms linking maternal DHA intake with improved neurodevelopmental and cognitive outcomes. Perinatal DHA status has previously been associated with enhanced cognitive performance in offspring, potentially mediated by its anti-inflammatory properties. SPMs, derived from DHA, play a crucial role in resolving inflammation and have recently been identified as modulators of cognitive function. Levels of SPMs were higher in the brains of piglets from DHA-fed sows, particularly in the prefrontal cortex and cerebellum, compared to control piglets. Additionally, a distinct association of several prefrontal SPMs with activation of the cerebellar functional network was marked in the piglet offspring. The findings from this study support the importance of maternal DHA supplementation in promoting neurodevelopmental health through the modulation of brain SPM levels in offspring. In study #2, shifting from a single bioactive compound approach in study #1 to a functional whole-food approach, the impact of perinatal egg yolk supplementation on functional outcomes in offspring was explored using the same model as study #1. Egg yolk is a complex nutrient matrix, including various nutrients such as amino acids, fatty acids, vitamins, minerals and bioactive food compounds, which have individually demonstrated benefits for infant neurodevelopmental outcomes. However, investigations into the neurodevelopmental impact of perinatal supplementation with whole egg yolk as a functional food are limited. Perinatal egg yolk supplementation increased the executive and cerebellar functional activity in the brain of offspring. Maternal egg yolk supplementation also enhanced hippocampal and cerebellar fiber lengths and altered behavioral outcomes in piglets, suggesting that consuming a nutritious whole food during the perinatal period may benefit neurodevelopmental outcomes in offspring. While studies #1 and #2 emphasized nutrition during healthy brain formation during early stages of development, study #3 addressed the impact of an antioxidant therapeutic intervention on recovery and restoration of brain injury in a traumatic brain injury (TBI) model. In study #3, the effects of a novel antioxidant therapeutic, CMX-2043, were evaluated by assessing the activities of antioxidant enzymes in a pig model of TBI. Treatment with CMX-2043 led to distinct alterations in antioxidant enzyme activities, with intravenous administration enhancing liver catalase and brain SOD activity, while subcutaneous administration primarily elevated brain catalase activity. Notably, increased brain catalase activity correlated with improved MRI markers of recovery, including reduced brain lesion volume, midline shift, and brain swelling and atrophy. These findings highlight the potential of both functional foods and therapeutic interventions in shaping brain development, enhancing functional outcomes, and promoting recovery from brain injury, underscoring their significance in advancing strategies for optimizing brain health across early life and injury contexts. Ultimately, the findings from this dissertation provide evidence-based insights that may guide public health recommendations for dietary and therapeutic interventions aimed at improving neurodevelopmental and neurological outcomes across the lifespan.