Maternal immune activation and early postnatal resource deprivation stress induce sex-biased behavioral and proteomic alterations in mice

“Maternal infection during pregnancy increases the risk of neuropsychiatric disease in exposed offspring. Rodent models of maternal immune activation (MIA) typically involve in utero immune activation using infectious agents such as bacteria or double-stranded RNA. Two of the most common models stimulate toll-like receptor 4 (TLR4) using the bacterial endotoxin lipopolysaccharide or TLR3 using the mimetic poly(I:C). However, some of the prenatal infectious agents that are most strongly linked to risk for neurodevelopmental disorders are single-stranded viruses such as rubella or influenza. Single-stranded mimetics that stimulate TLR7 are relatively underutilized in rodent MIA models.
Despite the risk, the majority of maternal infections do not result in offspring neurodevelopmental disorders. MIA appears to act as a ‘priming event’, increasing susceptibility to other risk factors. In humans, early-life adversity increases the risk for stress-related emotional and cognitive disorders later in life and many neuropsychiatric disorders are exacerbated by stressful perinatal experiences such as early-life maltreatment or neglect. Here, we studied the impact of a two-hit model of MIA activation in combination with early-life stress on offspring neurodevelopment.

Here, we studied the impact on offspring neurodevelopment of MIA by TLR7 stimulation. To model resource deprivation stress, we used a limited bedding and nesting (LBN) paradigm to induce neural and behavioral alterations. We assessed communicative, social, perseverative, and anxiety-like behaviors in both male and female offspring. Total and phospho-proteomic analyses of midbrains were performed.

In this study, we demonstrate that a two-hit model of maternal TLR7 activation and early postnatal stress induces sex-biased alterations in offspring communicative, social, and perseverative behaviors as well as proteomic/phospho-proteomic alterations. Intriguingly, female behavioral alterations were correlated with proteomic differences, whereas male behavioral changes were strongly correlated only with phospho-proteomic differences, suggesting differential mechanisms through which the dual-hit paradigm alters offspring behaviors.”