Oxytocin induced labor causes region and sex-specific transient oligodendrocyte cell death in neonatal mouse brain
Oxytocin induced labor causes region and sex-specific transient oligodendrocyte cell death in neonatal mouse brain
复制标题
DOI：
10.1111/jog.14149
复制
发表时间：
2019-11-19
影响因子：
1.6
通讯作者：
Nishimori, Katsuhiko
中科院分区：
文献类型：
--
作者：
Hirayama, Takashi;Hiraoka, Yuichi;Nishimori, Katsuhiko
目的先前的报告显示催产素诱导分娩与后代精神障碍之间存在关联。然而，这些报告在流行病学分析方面受到限制，其机制尚不清楚。在本研究中，我们假设引产直接导致新生儿脑损伤并导致精神障碍的发展。因此，我们试图用动物模型来验证这一假设。方法采用足月妊娠小鼠C57BL/6J皮下注射催产素建立引产动物模型。我们通过定量聚合酶反应和tdt介导的dUTP缺口末端标记染色来评估新生儿脑损伤的早期基因表达（c-Fos， c-Jun和JunB）。为了研究损伤的脑细胞类型，我们使用tdt介导的dUTP缺口末端标记染色和每种脑组分特异性蛋白（如Oligo2， NeuN， GFAP和Iba1）进行双重免疫染色。结果引产过程中的脑损伤导致与精神障碍有关的特定脑区细胞死亡，仅发生在P0的雄性后代中。此外，与其他细胞类型相比，少突胶质细胞前体具有选择性易感性。围产期这种少突胶质细胞特异性损伤导致P5时olig2阳性细胞数量增加。胎儿大脑中催产素和Oxtr的表达水平不受母体引产时催产素的影响。结论引产所致的少突胶质细胞死亡仅发生在雄性子代，与催产素本身无关。这可能是解释人类流行病学数据表明引产与精神障碍之间存在关联的潜在机制。
Aim Previous reports showed associations between oxytocin induced labor and mental disorders in offspring. However, those reports are restricted in epidemiological analyses and its mechanism remains unclear. In this study, we hypothesized that induced labor directly causes brain damage in newborns and results in the development of mental disorders. Therefore we aimed to investigate this hypothesis with animal model. Methods The animal model of induced labor was established by subcutaneous oxytocin administration to term-pregnant C57BL/6J mice. We investigated the neonatal brain damage with evaluating immediate early gene expression (c-Fos, c-Jun and JunB) by quantitative polymerase reaction and TdT-mediated dUTP nick end labeling staining. To investigate the injured brain cell types, we performed double-immunostaining with TdT-mediated dUTP nick end labeling staining and each brain component specific protein, such as Oligo2, NeuN, GFAP and Iba1. Results Brain damage during induced labor led to cell death in specific brain regions, which are implicated in mental disorders, in only male offspring at P0. Furthermore, oligodendrocyte precursors were selectively vulnerable compared to the other cell types. This oligodendrocyte-specific impairment during the perinatal period led to an increased numbers of Olig2-positive cells at P5. Expression levels of oxytocin and Oxtr in the fetal brain were not affected by the oxytocin administered to mothers during induced labor. Conclusion Oligodendrocyte cell death in specific brain regions, which was unrelated to the oxytocin itself, was caused by induced labor in only male offspring. This may be an underlying mechanism explaining the human epidemiological data suggesting an association between induced labor and mental disorders.