Intrauterine position effects in a mouse model of maternal immune activation

Jun 19, 2024Brain, behavior, and immunity

Effects of fetal position in the womb on immune-related changes from maternal illness in mice

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Abstract

Mice exposed to maternal immune activation (MIA) in different intrauterine positions show significant variability in sociability and sensorimotor gating deficits.

MIA-exposed offspring developing between only female fetuses (0M-MIA) exhibited significant deficits in sociability and sensorimotor gating.
In contrast, MIA-exposed offspring developing between one or two male fetuses (1/2M-MIA) did not display these same behavioral deficits.
Both male and female offspring showed similar intrauterine position effects regarding these behavioral outcomes.
MIA increased fetal brain levels of pro- and anti-inflammatory cytokines, but TNF-α levels remained elevated in 0M-MIA offspring into late gestation.
1/2M-MIA offspring had higher testosterone levels in the fetal brain during late gestation compared to 0M-MIA offspring.
These findings suggest that intrauterine positioning may contribute to variability in outcomes related to MIA exposure.

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Rodent models of maternal immune activation (MIA) are increasingly used as experimental tools in preclinical research of immune-mediated neurodevelopmental disorders and mental illnesses. Using a viral-like MIA model that is based on prenatal poly(I:C) exposure in mice, we have recently identified the existence of subgroups of MIA-exposed offspring that show dissociable behavioral, transcriptional, brain network and inflammatory profiles even under conditions of genetic homogeneity and identical MIA. Here, we tested the hypothesis that the intrauterine positions of fetuses, which are known to shape individual variability in litter-bearing mammals through variations in fetal hormone exposure, may contribute to the variable outcomes of MIA in mice. MIA was induced by maternal administration of poly(I:C) on gestation day 12 in C57BL/6N mice. Determining intrauterine positions using delivery by Cesarean section (C-section), we found that MIA-exposed offspring developing between female fetuses only (0M-MIA offspring) displayed significant deficits in sociability and sensorimotor gating at adult age, whereas MIA-exposed offspring developing between one or two males in utero (1/2M-MIA offspring) did not show the same deficits. These intrauterine position effects similarly emerged in male and female offspring. Furthermore, while MIA elevated fetal brain levels of pro- and anti-inflammatory cytokines independently of the precise intrauterine position and sex of adjacent fetuses during the acute phase, fetal brain levels of TNF-α remained elevated in 0M-MIA but not 1/2M-MIA offspring until the post-acute phase in late gestation. As expected, 1/2M offspring generally showed higher testosterone levels in the fetal brain during late gestation as compared to 0M offspring, confirming the transfer of testosterone from male fetuses to adjacent male or female fetuses. Taken together, our findings identify a novel source of within-litter variability contributing to heterogeneous outcomes of short- and long-term effects in a mouse model of MIA. In broader context, our findings highlight that individual differences in fetal exposure to hormonal and inflammatory signals may be a perinatal factor that shapes risk and resilience to MIA.

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Intrauterine position effects in a mouse model of maternal immune activation

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