Project Summary The materno-fetal interface is a crucial environment for a healthy fetal development during pregnancy and delivery. A decrease in maternal trophic factors, such as maternal thyroid hormones or a maternal inflammation/maternal immune activation (MIA) have been linked to an increased risk for neurodevelopmental disorders, such as autism or preterm births. However, there has been no study to date to directly evaluate their impact on human developing brain. To fill this gap of knowledge, we propose to experimentally study the consequences of inflammatory factors on human neurodevelopment using the cerebral organoids co-cultured with microglial cells, a 3D model that mimics the early stages of the human brain development. Microglial cells are immune cells of the central nervous system that are generated in the yolk sac and penetrating the brain parenchyma during a critical time of the embryogenesis coinciding with synaptogenesis and gliogenesis. Given that microglial cells are generated in the periphery, we hypothesized that microglial cells are an important component of the human brain development and most likely the first brain cell type to be exposed and respond to an environmental factor/toxin that can potentially contribute to neurodevelopmental disorders prenatally. Here, we will investigate the impact of maternal inflammation due to bacterial or viral infections on human microglial cells and how that can impact the human developing brain. In addition, given that a person could be exposed to more toxic factors simultaneously or sequentially during that individual’s lifespan or during pregnancy, we will also aim to closely replicate the human experience, by testing the impact of co-exposures to infectious agents and study their synergistic impact on human microglial function and human neurodevelopment. Current studies using iPSCs has been limited sample size and the lack of diversity in the samples that are often derived from donors from a single race/ethnical group. Thus, to have a more inclusive approach, in this proposal, we will use a large cohort of samples from healthy individuals (>50), representative of different races, ethnicities and genders closely mimicking the proportions found in the United States’ population that will provide a better understanding of the health disparities and interventions both in populations and in specific subgroups. Ultimately, our goal is to provide a better understanding of the disease mechanisms involved in maternal inflammation and better targeted therapies from which the majority of the population in the US could benefit from.