Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
Department of Psychiatry, University of Western Ontario, London, ON, Canada.
Front Immunol. 2020 Jun 9;11:1145. doi: 10.3389/fimmu.2020.01145. eCollection 2020.
Maternal immune activation (MIA) caused by exposure to pathogens or inflammation during critical periods of neurodevelopment is a major risk factor for behavioral deficits and psychiatric illness in offspring. A spectrum of behavioral abnormalities can be recapitulated in rodents by inducing MIA using the viral mimetic, PolyI:C. Many studies have focused on long-term changes in brain structure and behavioral outcomes in offspring following maternal PolyI:C exposure, but acute changes in prenatal development are not well-characterized. Using RNA-Sequencing, we profiled acute transcriptomic changes in rat conceptuses (decidua along with nascent embryo and placenta) after maternal PolyI:C exposure during early gestation, which enabled us to capture gene expression changes provoked by MIA inclusive to the embryonic milieu. We identified a robust increase in expression of genes related to antiviral inflammation following maternal PolyI:C exposure, and a corresponding decrease in transcripts associated with nervous system development. At mid-gestation, regions of the developing cortex were thicker in fetuses prenatally challenged with PolyI:C, with females displaying a thicker ventricular zone and males a thicker cortical mantle. Along these lines, neural precursor cells (NPCs) isolated from fetal brains prenatally challenged with PolyI:C exhibited a higher rate of self-renewal. Expression of Notch1 and the Notch ligand, delta-like ligand 1, which are both highly implicated in maintenance of NPCs and nervous system development, was increased following PolyI:C exposure. These results suggest that MIA elicits rapid gene expression changes within the conceptus, including repression of neurodevelopmental pathways, resulting in profound alterations in fetal brain development.
母体免疫激活（MIA）是由神经发育关键期暴露于病原体或炎症引起的，是后代行为缺陷和精神疾病的主要风险因素。通过使用病毒模拟物聚肌苷酸（PolyI:C）诱导 MIA，啮齿动物中可以重现一系列行为异常。许多研究都集中在母体 PolyI:C 暴露后后代的大脑结构和行为结果的长期变化上，但产前发育的急性变化尚未得到很好的描述。通过 RNA 测序，我们对妊娠早期母体 PolyI:C 暴露后大鼠胚胎（蜕膜以及新生胚胎和胎盘）的急性转录组变化进行了分析，这使我们能够捕获由 MIA 引起的包括胚胎环境在内的基因表达变化。我们发现，母体 PolyI:C 暴露后，与抗病毒炎症相关的基因表达显著增加，而与神经系统发育相关的转录本则相应减少。在妊娠中期，经 PolyI:C 产前挑战的胎儿发育中的皮质区域更厚，其中雌性的脑室区更厚，雄性的皮质层更厚。沿着这些思路，从经 PolyI:C 产前挑战的胎儿大脑中分离出的神经前体细胞（NPC）表现出更高的自我更新率。Notch1 和 Delta-like 配体 1（Notch 配体 1）的表达增加，Notch1 和 Notch 配体 1 都高度参与 NPC 的维持和神经系统发育。这些结果表明，MIA 会在胚胎中引起快速的基因表达变化，包括抑制神经发育途径，从而导致胎儿大脑发育的深刻改变。
