Abstract：
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.
摘要：
母体免疫激活（MIA）的啮齿动物模型越来越多地用作免疫介导的神经发育障碍和精神疾病的临床前研究的实验工具。使用基于小鼠产前聚（I：C）暴露的病毒样MIA模型，我们最近确定了MIA暴露后代的亚组的存在，这些亚组表现出可分离的行为，转录，即使在遗传同质性和相同的MIA条件下，大脑网络和炎症谱也是如此。这里,我们检验了胎儿宫内位置的假设，已知它们通过胎儿激素暴露的变化来塑造产仔哺乳动物的个体差异，可能有助于小鼠MIA的可变结果。在C57BL/6N小鼠中,通过在妊娠第12天母体施用聚(I:C)诱导MIA。通过剖腹产（剖腹产）确定宫内位置，我们发现，仅在雌性胎儿之间发育的MIA暴露的后代（0M-MIA后代）在成年时的社交能力和感觉运动门控方面表现出明显的缺陷，而子宫内一个或两个雄性之间发育的MIA暴露的后代（1/2M-MIA后代）没有显示出相同的缺陷。这些宫内位置效应同样出现在雄性和雌性后代中。此外，而在急性期，MIA升高了胎儿大脑中促炎和抗炎细胞因子的水平，而与宫内位置和相邻胎儿的性别无关，0M-MIA但1/2M-MIA后代的胎儿脑TNF-α水平保持升高，直到妊娠晚期急性期。不出所料,与0M后代相比，1/2M后代在妊娠后期通常在胎儿大脑中显示出更高的睾丸激素水平，确认睾丸激素从男性胎儿转移到相邻的男性或女性胎儿。一起来看,我们的研究发现发现了一种新的产仔内变异性来源,该来源导致了MIA小鼠模型短期和长期效应的异质性结果.在更广泛的背景下，我们的研究结果强调,胎儿暴露于激素和炎症信号的个体差异可能是影响MIA风险和恢复力的围产期因素.
