Project 3: Neurodevelopment in an NHP MIA model

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.

Grant Number: 5P50MH106438-10
NIH Institute/Center: NIH
Principal Investigator: Melissa Bauman