孕期心理应激对子代情志和认知发育影响的近远期效应及其胎盘调控机制

Epidemiological studies have shown an association between psychological stress during pregnancy and offspring neurobehavioral development. Presently, few clinical observations are conducted to study the long-term effects of psychological stress on the offspring, and the underlying mechanism is not clear. According to the hypothesis intrauterine programming affected by the HPA-axis and placenta, with pre-built modeling methods and evaluation system, pregnant rats are given the stimulus of fear alone, and evaluation is performed to appraise the psychological stress of the pregnant rats, so as the short- and long-term cognitive function and emotional characteristics of the offspring at different age, which provides the basis for clinical drug intervention. Placental development parameters and protein composition changes are detected by proteomic technique, to explore the mechanisms of barriers and regulation in materno-fetal transmission of placental tissue. Questionnaires, scale scores and laboratory indicators in clinical trials are used to screen pregnant women and children with emotional and cognitive impairment, and explore the short- and long-term impact of maternal psychological stress during pregnancy on offspring in emotional and cognitive development, and its underlying mechanism in placenta-regulation. This project will not only enrich and improve the theory fear impairs the kidney in traditional Chinese medicine and the fetal origin hypothesis in modern medicine, but also provide guidance to prevent mental illness during pregnancy, reduce the incidence of emotional and cognitive disorders, and ensure bearing and rearing better children.

流行病学研究证明，孕期心理应激与子代神经行为发育之间存在关联。但目前对子代影响的远后效应临床观察较少，关联的作用机制尚不清楚。课题组依据"HPA轴和胎盘共同影响宫内编程"假说，用前期构建的造模方法和评价体系，对孕鼠给予单纯恐惧心理刺激，通过评价孕鼠心理应激状态、子代不同年龄认知功能和情志特征，探讨孕期心理应激对子代情志、认知发育影响的近远期效应，为临床干预的实施提供依据；通过蛋白质组学技术检测胎盘发育参数和蛋白质成份的变化，探讨胎盘组织在母-胎心理应激信息传递中的屏障和调控机制；在临床中筛选孕产妇及情志认知障碍患儿，采用问卷调查、量表评分和实验室检测相结合，探讨孕期母体心理应激对子代情志认知发育的近远期影响及胎盘调控机制。 本项目的实施不但有利于丰富和完善传统中医"恐伤肾"理论和现代"胎源学说"；更有利于指导孕期心理疾病防治，减少情志和认知障碍性疾病的发病率，从根源上保证"优生优育"。

孕期心理应激对子代神经行为发育的影响是近年来研究的热点。本项目从临床研究和动物实验两方面探索了孕期心理应激对子代近远期情志和认知发育的影响，并利用蛋白组学技术监测孕妇和孕鼠胎盘蛋白质的整体变化。结果表明：①母代孕期心理应激对子代近期（0-1岁）和远期（1-14岁）的智力和情感发育均产生不良影响，主要表现为母代孕期心理应激与6-14岁情志、认知障碍患儿的流体智力水平负相关，而与患儿的HPA轴激活程度正相关。其可能的机制是孕期心理应激除影响孕母HPA轴功能外，还通过PP1α催化亚基、14-3-3ε蛋白、核仁素、热激蛋白等蛋白质的表达及核糖体信号通路、血管平滑肌收缩通路、催产素信号通路等多条通路对胎盘功能产生影响，进而影响子代情志和认知发育。②孕期恐伤肾对仔鼠情志和认知近远期的发育皆有影响，表现为仔鼠脑内NE、DA、HVA、GABA等水平降低、而GLU、GLY等水平升高，星形胶质细胞活化和海马细胞凋亡，海马NMDAR1、NR2B、FGF2、FGFR1和额叶FGF2、FGFR1等蛋白表达下调，海马P-tau、c-fos等蛋白表达上调。其机制为恐伤孕鼠可使胎盘组织中多种蛋白质（如Cofilin-1、14-3-3ζ、14-3-3θ、claudins、Occludin及 DJ-1等）异常表达，并通过PI3K-AKT等信号通路、物质代谢、补体途径、ECM-受体等途径影响子代发育。本项目的研究结果不但有利于传统中医“恐伤肾”理论和现代“胎源学说”的丰富和完善，还有利于指导孕期心理疾病的防治，减少情志和认知障碍性疾病的发病率，从根源上保证优生优育。