Our novel hypothesis is that a high maternal fat intake is a heretofore un-appreciated risk factor for adverse neurodevelopmental outcome after acute neonatal brain injury. This is supported by our preliminary experiments and new epidemiologic evidence. We now propose to extend our findings and to investigate underlying mechanisms in the systemic and brain myeloid cell lineage. The typical US diet is high in fat (about 34% of calories from fat), with abundant saturated and n6 polyunsaturated fatty acids but limited n3 fatty acids. Obesity induces chronic, low-grade inflammation during pregnancy and increases risk for adverse neonatal outcomes, yet maternal weight and dietary fat intake have not been evaluated as risk factors for neonatal hypoxic-ischemic brain injury. Furthermore a pervasive limitation among experimental models of neonatal brain injury is that animals are typically fed a low-fat chow, with 14% of calories from fat that does not reflect the typical US diet. In preliminary studies we compared outcome, after unilateral cerebral hypoxia-ischemia, in progeny of dams fed low-fat chow vs. a diet with 34% of calories from fat. The high-fat diet progeny had reduced serum and brain n3 fatty acids, and a marked increase in proportion of circulating monocytes. On postnatal day 7 (P7) pups from both diet groups concurrently underwent hypoxic-ischemic lesioning. In the high fat diet group, we found increased mortality, and worse sensorimotor function after a 1 or 4-week recovery. The goal of this proposal is to confirm these trends and to test the hypotheses that a pro-inflammatory switch in brain myeloid cell phenotype and function is the mechanism that underlies these effects, and that a high fat diet disproportionately increases white matter injury. Studies will be conducted in a well-characterized model of neonatal hypoxic-ischemic brain injury elicited by unilateral carotid artery ligation and exposure to 8% oxygen in 7-day-old rats. Strengths of the model include the ability to titrate severity of injury by varying the duration of hypoxia and the feasibility of incorporatig multiple complementary quantifiable functional and pathological outcome measures. The Aims of the proposal are (i) In a neonatal rodent model of HI brain injury, to compare sensorimotor function and neuropathology outcomes in offspring of dams who are fed low (17%) or high (34%) fat diets during pregnancy and lactation. To determine if reversion of maternal high fat to low fat diet on P7 influences these outcomes; (ii) To determine if maternal high fat diet during pregnancy and lactation induces a pro- inflammatory myeloid cell phenotype and function in blood and brain of their progeny. This line of research will provide essential building blocks for future preclinical and clinical research to translate our novel preliminary results into public heath measures, human maternal dietary interventions or neonatal treatment regimens that are relevant to the modern U.S. population.