Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA; Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA; Cell and Molecular Biology Graduate Training Program, University of Virginia, Charlottesville, VA 22908, USA.
Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.
Brain Behav Immun. 2023 Feb;108:80-97. doi: 10.1016/j.bbi.2022.10.024. Epub 2022 Nov 4.
Perturbations to the in utero environment can dramatically change the trajectory of offspring neurodevelopment. Insults commonly encountered in modern human life such as infection, toxins, high-fat diet, prescription medications, and others are increasingly linked to behavioral alterations in prenatally-exposed offspring. While appreciation is expanding for the potential consequence that these triggers can have on embryo development, there is a paucity of information concerning how the crucial maternal-fetal interface (MFI) responds to these various insults and how it may relate to changes in offspring neurodevelopment. Here, we found that the MFI responds both to an inflammatory state and altered serotonergic tone in pregnant mice. Maternal immune activation (MIA) triggered an acute inflammatory response in the MFI dominated by interferon signaling that came at the expense of ordinary development-related transcriptional programs. The major MFI compartments, the decidua and the placenta, each responded in distinct manners to MIA. MFIs exposed to MIA were also found to have disrupted sex-specific gene expression and heightened serotonin levels. We found that offspring exposed to MIA had sex-biased behavioral changes and that microglia were not transcriptionally impacted. Moreover, the combination of maternal inflammation in the presence of pharmacologic inhibition of serotonin reuptake further transformed MFI physiology and offspring neurobiology, impacting immune and serotonin signaling pathways alike. In all, these findings highlight the complexities of evaluating diverse environmental impacts on placental physiology and neurodevelopment.
子宫内环境的干扰可能会极大地改变后代神经发育的轨迹。在现代人类生活中常见的感染、毒素、高脂肪饮食、处方药物等，越来越多地与产前暴露后代的行为改变有关。虽然人们越来越意识到这些诱因可能对胚胎发育产生潜在影响，但关于关键的母体-胎儿界面（MFI）如何应对这些各种干扰以及它如何与后代神经发育的变化相关的信息却很少。在这里，我们发现 MFI 对怀孕小鼠的炎症状态和 5-羟色胺能递质改变均有反应。母体免疫激活（MIA）在 MFI 中引发了以干扰素信号为主的急性炎症反应，这是以牺牲普通发育相关转录程序为代价的。主要的 MFI 隔室，即蜕膜和胎盘，对 MIA 的反应方式各不相同。暴露于 MIA 的 MFIs 也被发现具有破坏性别特异性基因表达和升高 5-羟色胺水平的特性。我们发现，暴露于 MIA 的后代表现出性别偏倚的行为改变，而小胶质细胞的转录不受影响。此外，在存在 5-羟色胺再摄取抑制剂的情况下，母体炎症的组合进一步改变了 MFI 生理学和后代神经生物学，对免疫和 5-羟色胺信号通路均有影响。总之，这些发现强调了评估不同环境因素对胎盘生理学和神经发育影响的复杂性。
