A lack of understanding of causal etiology is a major barrier to diagnosis and treatment of neurodevelopmental disorders (NDD) such as autism and schizophrenia. This is especially true for the connection between maternal infection and brain disorders, where epidemiological studies have shown that a variety of immune challenges during pregnancy are associated with increased rates of NDD in exposed offspring. Rodent models of maternal infection recapitulate behavioral abnormalities, enabling investigation of the mechanisms underlying pathology. Studies using compounds such as poly(I:C), which mimics viral dsRNA, have shown that maternal immune activation (MIA) alone can produce parallel behavioral, anatomical, and synaptic pathology in exposed offspring even without pathogen exposure. These findings suggest that maternal immune signaling factors directly or indirectly impact fetal brain development. Identifying the root causal pathways activated by MIA and the downstream impact of these acute changes on early brain development will provide insight into prevention or intervention of root causes to ameliorate downstream pathology and lifelong decreases in quality of life. We hypothesized that these root changes would be evident in the transcriptomes of the fetal cerebral cortex after MIA exposure. In preliminary studies, we generated a time course map of neurodevelopmental gene expression changes in a mouse model of poly(I:C) challenge in mid-gestation. These preliminary systems-level transcriptomics data reveal a sequence of neurodevelopmental pathology following MIA, including novel findings indicating that an initial stress response mediates changes in neural progenitor cell behavior and brain structure. We identified a strong acute signature present by 6hrs after MIA that persists over the initial days after exposure. These acute changes are followed by changes in genes associated with proliferative dynamics and neuronal differentiation and, finally, with changes in the level of known cell-identity markers. Here we propose to validate and define how the observed gene expression signatures are associated with anatomical, structural, and cellular changes in the developing and postnatal mouse brain after MIA exposure. We will use the same poly(I:C) model and examine the same time points profiled via transcriptomics, using a combination of histology, functional and structural assays, and cell-specific analysis towards the objectives of 1) identifying the cell-specific and anatomical roots of the acute response to MIA, 2) characterizing changes in identity and proliferative behavior in neuronal progenitors and differentiating neurons, and 3) linking developmental expression signatures to neuroanatomical changes in postnatal brain. These experiments will generate significant insights into generalized pathological mechanisms of MIA and will provide the basis for future in-depth study of the specific causal pathways activated in MIA- exposed fetal brain that we will validate in this work. The results from our studies will additionally seed future translational work focused on developing novel targeted pharmacological interventions.
Epidemiology studies have revealed a strong link between maternal immune infections and brain disorders such as autism and schizophrenia. However, root biological causes arising from exposure during brain development remain unidentified. We will study changes to the embryonic brain after maternal immune challenge in the mouse towards the goal of improving diagnosis, reducing risk, and developing new treatments.
