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Abstract：
Exposure to maternal immune activation (MIA) in utero is a risk factor for neurodevelopmental disorders later in life. The impact of the gestational timing of MIA exposure on downstream development remains unclear.
We characterized neurodevelopmental trajectories of mice exposed to the viral mimetic poly I:C (polyinosinic:polycytidylic acid) either on gestational day 9 (early) or on day 17 (late) using longitudinal structural magnetic resonance imaging from weaning to adulthood. Using multivariate methods, we related neuroimaging and behavioral variables for the time of greatest alteration (adolescence/early adulthood) and identified regions for further investigation using RNA sequencing.
Early MIA exposure was associated with accelerated brain volume increases in adolescence/early adulthood that normalized in later adulthood in the striatum, hippocampus, and cingulate cortex. Similarly, alterations in anxiety-like, stereotypic, and sensorimotor gating behaviors observed in adolescence normalized in adulthood. MIA exposure in late gestation had less impact on anatomical and behavioral profiles. Multivariate maps associated anxiety-like, social, and sensorimotor gating deficits with volume of the dorsal and ventral hippocampus and anterior cingulate cortex, among others. The most transcriptional changes were observed in the dorsal hippocampus, with genes enriched for fibroblast growth factor regulation, autistic behaviors, inflammatory pathways, and microRNA regulation.
Leveraging an integrated hypothesis- and data-driven approach linking brain-behavior alterations to the transcriptome, we found that MIA timing differentially affects offspring development. Exposure in late gestation leads to subthreshold deficits, whereas exposure in early gestation perturbs brain development mechanisms implicated in neurodevelopmental disorders.
We characterized neurodevelopmental trajectories of mice exposed to the viral mimetic poly I:C (polyinosinic:polycytidylic acid) either on gestational day 9 (early) or on day 17 (late) using longitudinal structural magnetic resonance imaging from weaning to adulthood. Using multivariate methods, we related neuroimaging and behavioral variables for the time of greatest alteration (adolescence/early adulthood) and identified regions for further investigation using RNA sequencing.
Early MIA exposure was associated with accelerated brain volume increases in adolescence/early adulthood that normalized in later adulthood in the striatum, hippocampus, and cingulate cortex. Similarly, alterations in anxiety-like, stereotypic, and sensorimotor gating behaviors observed in adolescence normalized in adulthood. MIA exposure in late gestation had less impact on anatomical and behavioral profiles. Multivariate maps associated anxiety-like, social, and sensorimotor gating deficits with volume of the dorsal and ventral hippocampus and anterior cingulate cortex, among others. The most transcriptional changes were observed in the dorsal hippocampus, with genes enriched for fibroblast growth factor regulation, autistic behaviors, inflammatory pathways, and microRNA regulation.
Leveraging an integrated hypothesis- and data-driven approach linking brain-behavior alterations to the transcriptome, we found that MIA timing differentially affects offspring development. Exposure in late gestation leads to subthreshold deficits, whereas exposure in early gestation perturbs brain development mechanisms implicated in neurodevelopmental disorders.
摘要：
子宫内暴露于母体免疫激活（MIA）是生命后期神经发育障碍的危险因素。MIA暴露的妊娠时间对下游发育的影响尚不清楚。
我们使用纵向结构磁共振成像从断奶到成年，在妊娠第9天（早期）或第17天（晚期）描述了暴露于病毒模拟物polyI：C（聚肌苷酸：聚胞苷酸）的小鼠的神经发育轨迹。使用多变量方法，我们将神经影像学和行为变量与最大改变时间(青春期/成年早期)相关,并使用RNA测序确定了进一步研究的区域.
早期MIA暴露与青春期/成年期早期脑容量加速增加相关，在成年后期在纹状体恢复正常。海马体,和扣带皮质.同样，焦虑的改变，刻板印象，青春期观察到的感觉运动门控行为在成年期正常化。妊娠晚期MIA暴露对解剖和行为特征的影响较小。多变量地图与焦虑相关，社会,和感觉运动门控缺陷与背侧和腹侧海马以及前扣带皮质的体积有关，在其他人中。在背侧海马中观察到最多的转录变化，富含成纤维细胞生长因子调节的基因，自闭症行为，炎症途径，和microRNA调控。
利用综合假设和数据驱动的方法，将大脑行为改变与转录组联系起来，我们发现MIA时间差异影响后代发育。妊娠晚期暴露会导致亚阈值缺陷，而妊娠早期暴露会扰乱与神经发育障碍有关的大脑发育机制。
我们使用纵向结构磁共振成像从断奶到成年，在妊娠第9天（早期）或第17天（晚期）描述了暴露于病毒模拟物polyI：C（聚肌苷酸：聚胞苷酸）的小鼠的神经发育轨迹。使用多变量方法，我们将神经影像学和行为变量与最大改变时间(青春期/成年早期)相关,并使用RNA测序确定了进一步研究的区域.
早期MIA暴露与青春期/成年期早期脑容量加速增加相关，在成年后期在纹状体恢复正常。海马体,和扣带皮质.同样，焦虑的改变，刻板印象，青春期观察到的感觉运动门控行为在成年期正常化。妊娠晚期MIA暴露对解剖和行为特征的影响较小。多变量地图与焦虑相关，社会,和感觉运动门控缺陷与背侧和腹侧海马以及前扣带皮质的体积有关，在其他人中。在背侧海马中观察到最多的转录变化，富含成纤维细胞生长因子调节的基因，自闭症行为，炎症途径，和microRNA调控。
利用综合假设和数据驱动的方法，将大脑行为改变与转录组联系起来，我们发现MIA时间差异影响后代发育。妊娠晚期暴露会导致亚阈值缺陷，而妊娠早期暴露会扰乱与神经发育障碍有关的大脑发育机制。
