Maternal antioxidant treatment prevents behavioural and neurological changes in offspring exposed to prenatal social stress [RNA-seq]

Maternal exposure to social stress during pregnancy is associated with an increased risk of psychiatric disorders in the offspring in later life. How the effects of maternal social stress are transmitted to the developing foetus is unclear. Using a rat model of maternal social stress during pregnancy, we explored the mechanisms by which maternal stress is conveyed to the foetus and the potential for targeted treatment to prevent disease in the offspring. Maternal stress induced oxidative stress in the placenta, but not in the foetal brain, which was prevented by a single administration of nanoparticle-bound antioxidant prior to the stress exposure. Moreover, this antioxidant treatment prevented prenatal stress-induced anxiety-like behaviour in juvenile male offspring, along with neurological and gene expression changes in the offspring brain. In vitro, placental conditioned medium or foetal plasma from stressed pregnancies caused changes to cultured cortical neurons, similar to those observed in the brains of juvenile offspring exposed to prenatal stress, and were found to contain altered levels of extracellular microRNAs but not corticosterone. The present study highlights the crucial role of the placenta, and molecules secreted from the placenta, in foetal brain development and provides evidence of the potential for treatment that can prevent maternal stress-induced foetal programming of neurological disease.孕期母体暴露于社交应激，与子代成年后罹患精神障碍的风险升高密切相关。目前尚不明确母体社交应激的效应是如何传递至发育中的胎儿的。本研究采用孕期母体社交应激的大鼠模型，探究了母体应激向胎儿传递的具体机制，以及通过靶向干预预防子代患病的潜在可行性。母体应激可诱导胎盘产生氧化应激，但不会对胎儿大脑造成该类影响；该效应可通过在应激暴露前单次给予纳米颗粒结合型抗氧化剂得以阻断。此外，该抗氧化剂干预可阻断产前应激诱导的幼年雄性子代类焦虑样行为，同时改善子代大脑的神经学异常与基因表达紊乱。体外实验中，应激妊娠母体的胎盘条件培养液或胎儿血浆可使体外培养的皮层神经元发生异常改变，该改变与产前应激暴露的幼年子代大脑中观察到的变化一致；且此类样本中细胞外微RNA（microRNAs）水平出现异常，但皮质酮（corticosterone）水平无明显变化。本研究阐明了胎盘及其分泌的分子在胎儿大脑发育中的关键作用，并为通过干预手段预防母体应激诱导的胎儿神经疾病程序化提供了实验依据。