Perspectives on Neuroscience and Behavior

Abstract

Maternal immune activation (MIA) from either infectious or noninfectious maternal exposure is a risk factor for a range of neurodevelopmental neuropsychiatric disorders. However, most individuals exposed to MIA do not have a developmental disorder (exposure to maternal respiratory tract infections can be as high as 50%). This raises the question of what factors determine the resilience or susceptibility to MIA. Now, some of the behavioral, molecular, and neuroanatomical correlates of resilience or susceptibility to MIA have been described. Isogenic C57BL.6N mice mothers were administered the viral mimetic, poly(IC), on day 12 of gestation. Behavioral testing was done on offspring at 12 weeks of age, using tests of locomotion, anxiety-like behavior, working memory, social interaction, and prepulse inhibition of the acoustic startle reflex. A two-step cluster analysis of the behavioral data resulted in two groups (about equal incidence) with susceptible mice having impaired behavioral performance compared to control or resilient mice. Next-generation RNA sequencing in the medial prefrontal cortex (mPFC) and amygdala (Amy) using differentially expressed genes (DEGs) compared to controls disclosed that susceptible mice had more DEGs in mPFC, but less DEGs in Amy than resilient mice, and resilient mice had more changes in DEGs in the Amy than control mice, suggesting allostatic adaptations in resilient mice. Interestingly, susceptible mice had more downregulated DEGs annotated with oxidative phosphorylation in the mPFC, but less DEGs in the Amy pertaining to DARP-32 and G protein-coupled receptor signaling than resilient mice. Ex vivo structural magnetic resonance imaging revealed that susceptible mice had reduced covariance for the same regions than control and resilient mice had positive correlations for. When a second group of MIA-exposed mice were studied in adulthood, those with higher levels of plasma inflammatory cytokines (about 40%) had impaired social approach behavior and sensorimotor gating, demonstrating the relationship between increased inflammatory cytokines and impaired behavior (Mueller and others 2021). Since there were little sex differences and the findings were driven by within-litter variability, other factors such as utero placement or postweaning social hierarchies could be involved. Although this study does not isolate a robust factor producing susceptibility to MIA, it does provide evidence, even in isogenic mice, that DEGs are involved. This is a good advance because using this model, future studies can focus on the regulation of DEGs to better understand the mechanisms producing susceptibility or resilience to MIA.