Impact of Maternal Stress and Poly(I:C)-Stimulated Viral Activation on Placental Immune Dynamics and Offspring Neurobehavioral Development

PROJECT SUMMARY The etiology of neurodevelopmental psychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia remains elusive, hindering the innovation of novel treatments. These disorders are thought to have an overlap in their pathophysiology due to a shared association with in utero exposure to maternal infection, stress, and cytokine levels. These hypothesized immune programming mechanisms have begun to be investigated by using mouse models of prenatal stress and maternal immune activation which cause a similar offspring behavioral phenotype as these disorders. Our lab has established prenatal stress to increase fetal microglia inflammatory cytokine expression, which continues into adulthood in the cortex, suggesting their function is dysregulated throughout life. Further, preliminary data from our lab has shown prenatal stress to reduce the presence of maternal macrophages relative to fetal-derived macrophages in the placenta with an overall decrease in immune cells. This imbalance is paralleled by a diminished interferon response and a stressed-induced suppression in the maternal plasma cytokine response to exposure of the viral mimetic poly(I:C). Given this preliminary data, we hypothesize that prenatal stress impairs the placental immune response to maternal viral stimulation with a subsequent potentiation of the effects of maternal immune activation on fetal neuroimmune and behavioral development. To delineate the specific effects on maternal and fetal placental immune cells we will apply our established prenatal stress and poly(I:C) exposure model to a transgenic mouse line that specifically expresses TdTomato in fetal macrophages. In Aim 1, we will investigate changes in the placental immune response using flow cytometry, immunohistochemistry, and RNA-sequencing of FACS sorted maternal and fetal macrophages. In Aim 2, we will assess the changes in fetal microglia using RNA-sequencing and evaluate their long-term programming by isolating microglia from adult wild type offspring to evaluate their reactivity in vitro. Further, we will characterize changes to offspring communicative output, social behavior, anxiety-like behavior, and repetitive behaviors to determine whether the interaction between prenatal stress and maternal viral stimulation potentiate the deleterious behavioral consequences on the offspring. Our approach is innovative and significant, as it will be the first project to define the maternal and fetal specific effects on placental immune function in both prenatal stress and poly(I:C) stimulation and how these common maternal environmental disruptions interact to impact offspring neuroimmune and behavioral development. The outlined aims are coupled with a rigorous training plan integrating advanced technical skill development in in vivo analyses, high-parameter flow cytometry, and bioinformatics with essential non-technical skill development in scientific communication, mentorship, and scientific writing. This comprehensive training plan will provide the unique and necessary skills to develop into an independent physician-scientist innovating novel therapies for neurodevelopmental disorders.