PROJECT SUMMARY In the United States, one in three women of reproductive age is obese. In large epidemiologic studies, maternal obesity is associated with cognitive deficits in children, including reduced and low IQ (<70), and lower reading and math scores. Underlying mechanisms remain unclear. What is known is that maternal obesity is a state of chronic low-level immune activation, and both placental and brain inflammation have been reported in fetuses and offspring of obese women. Microglia, the resident immune cells of the brain, have been implicated in the pathogenesis of many of the neurodevelopmental morbidities noted with increased frequency in offspring of obese women. Despite this, there is a gap in knowledge about if/how placental inflammation affects fetal brain development in the setting of maternal obesity. We have demonstrated sex-specific fetal brain transcriptomes in the setting of maternal obesity, with dysregulated immune and inflammatory signaling highlighted as key effects of maternal obesity on both the male and female embryonic brain. We subsequently demonstrated a significant and sexually dimorphic effect of maternal obesity on microglial antigen (Iba-1) density in the embryonic hippocampus, and hippocampal learning deficits in obesity-exposed offspring, with male offspring more significantly affected. These data support the hypothesis that aberrant brain immune activation in embryonic life is one mechanism underlying enduring cognitive deficits. Inappropriate fetal microglial priming may therefore have lifelong neurodevelopmental consequences, but direct evaluation of microglial function in a living human fetus or neonate is impossible. Fortunately, placental macrophages (Hofbauer cells) and microglia have a common origin in the fetal yolk sac. Yolk-sac-derived macrophages comprise the permanent pool of brain microglia throughout an individual’s lifetime. Therefore, placental Hofbauer cells represent a potentially novel biologic sentinel that may mirror microglial immunoreactivity. Here, we seek to test the following hypotheses: (1a) maternal obesity will prime both Hofbauer cells and fetal brain microglia to overrespond to an immune challenge (1b) Maternal obesity will induce key alterations in the fetal microglial single cell transcriptome which will be recapitulated in the Hofbauer cell transcriptome (2) Selective ablation of pro-inflammatory macrophage signaling in the fetal brain and placenta using an innovative transgenic mouse will rescue maternal obesity-associated hippocampal learning deficits. The proposed experiments will fill a knowledge gap by ascertaining whether increased pro-inflammatory macrophage signaling in the placenta and fetal brain is a mechanism underlying offspring hippocampal learning deficits in maternal obesity. Demonstrating a causal link between fetal placental and brain macrophage-mediated inflammation and neurodevelopmental morbidity has potential therapeutic applications. If Hofbauer cells...