Project 3: Neurodevelopment in an NHP MIA model

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PROJECT SUMMARY – PROJECT 3 Epidemiological studies have implicated maternal infection in the etiology of psychiatric and neurodevelopmen- tal disorders, such as schizophrenia (SZ). Animal models of maternal immune activation (MIA) further support the link by demonstrating that experimental activation of the maternal immune system induces changes in offspring brain and behavioral development in domains relevant to human neurodevelopmental disease. However, critical gaps in knowledge persist related to two of the most important aspects of this risk factor for human disease: (i) most pregnancies are resilient to maternal infection and (ii) susceptible pregnancies lead to multiple distinct disorders in offspring. We have recently extended the results of the rodent MIA model into a species more closely related to humans – the rhesus monkey. Compared with rodents, nonhuman primate (NHPs) are more similar to humans in placental structure and physiology, gestational timelines, brain develop- ment, immune ontogeny, neuroanatomical organization, and behavioral complexity. The NHP thus provides a translationally relevant model system to systematically examine issues related to MIA risk, resilience and phenotypic heterogeneity. Results to date indicate that MIA-exposed male monkeys exhibit immune alterations in the early postnatal period, followed by reductions in frontal grey matter as early as 6 months of age and sub- tle impairments in social behavior and cognitive processing that emerge prior to 18 months of age. These early developmental changes in MIA-exposed NHPs provide an opportunity to identify translationally relevant factors that predict susceptibility or resilience to prenatal immune challenge, and to explore for the first time the impact of MIA in female NHP offspring. In this project we will (i) quantify the acute maternal-placental-fetal response to prenatal immune challenge and determine the relationship with subsequent changes in NHP neurobehavioral development; (ii) determine the impact of MIA on species-typical social and cognitive developmental milestones in male and female NHP offspring; and (iii) characterize long-lasting changes in dynamic cellular immune function, peripheral inflammatory markers, and brain cytokines in NHP offspring. Our project directly addresses the central hypothesis and all 3 aims of this Conte Center and leverages the unique features of the NHP model to bridge the gap between rodent MIA models and patient populations. Results from this project will provide unprecedented insight into MIA-induced changes in the primate maternal-placental-fetal environment in collaboration with Project 1. Our comprehensive assessment of NHP behavior is translationally aligned with Project 2 rodent studies and Project 5 human studies, resulting in an overarching computational framework that will bridge the species. The same NHPs that undergo behavioral phenotyping will participate in longitudinal neuroimaging (Project 5) followed by characterization of brain cytokines and changes in gene expression (Project 4). If successful, our project will identify translational biomarkers to predict which pregnan- cies are most vulnerable, thus providing a means to mitigate the deleterious effects of MIA during pregnancy.