Project 4: Refining transcriptional networks in MIA

PROJECT SUMMARY – PROJECT 4 Despite substantial advances in genetics, there is a lack of understanding of how environmental or fetal- maternal factors influence neuropsychiatric disease susceptibility. Over the last 4 years we have shown that maternal immune activation (MIA), a risk factor for neurodevelopmental disorders, results in long lasting regional changes in gene expression in the brain of mice and non-human primates (NHP). One set of key observations has been that variability in the maternal immune response, driven by baseline differences in immunoreactivity (BIR), likely contributes to the variability in offspring outcomes. These observations provide us with the opportunity to mechanistically connect maternal immune factors with subsequent resilience or sus- ceptibility in changes in brain and behavior in offspring. By transcriptomic profiling of immune cells from the mothers before and during pregnancy following MIA, as well as brain cells from MIA and control offspring, at the bulk tissue and single cell level, this project provides a molecular and cellular framework for understanding the basis for differential outcomes in offspring caused by MIA across species. Specifically, we will distinguish how differential cortico-striatal gene expression relates to BIR before pregnancy and to changes in maternal immune responses during MIA. First, in collaboration with Project 3 we will characterize changes in gene expression in specific cell types in dorsolateral prefrontal cortex (PFC) and striatum in NHP MIA off- spring using bulk RNAseq and nucSeq to measure transcriptome changes in cortical neurons, striatal neurons, and glial populations, including males and females (controls and MIA) from mothers with a compre- hensive assessment of their immune response and fetal-placental development. Second, our team will characterize and integrate the transcriptional signature caused by MIA to identify changes in gene ex- pression in specific cell types in the PFC and striatum of susceptible and resilient mouse MIA offspring characterized in Project 2. Third, these data will be combined with transcriptomic markers in blood from susceptible and resilient female mice and NHPs before and during pregnancy from Project 1, to identify changes in gene expression in specific immune cell types associated with MIA and variability in BIR. Fourth, we will integrate molecular data with outcomes and maternal premorbid immune response to identify biomarkers and mechanistic models of susceptibility and resilience in mothers and offspring We will identify changes associated with maternal parameters including in blood immune cells (Aim 3), cytokine pro- files (Project 1) and maternal sickness (Projects 2 and 3), and associate them with offspring response (brain cytokines, behavior: Projects 1, 2, 3; imaging changes in humans: Project 5). These data will be used to inform mechanistic models that link neuroimmune responses to molecular pathways and specific cellular responses, to the emergence of altered brain structure and behavior. The single platform, cross-species design will enable us to more definitively determine the relationship of these changes to neuropsychiatric disease in humans.