自主要求剖宫产对子代工作记忆的影响及低位GCs与海马CRH-CRHR1信号互作机制

Since the rate of caesarean delivery on maternal request (CDMR) is dramatically increasing, the negative effect of CDMR on infant cognitive development has aroused much controversies. Inverted-U effects have been observed between glucocorticoids (GCs) and hippocampus-dependent synaptic plasticity through GR in acute stress. In the hippocampus, CRH/CRF is expressed in interneurons to activate CRH receptors (CRHR1/CRFR1) in response to stress and linked with working memory. The surge of GCs release stimulated by natural delivery is necessary for infant cognitive development. Infants born via CDMR, however, typically lack the necessary release of stress hormone. Thus, this study hypothesizes that “Low level of GCs interacts with CRH-CRHR1 signal in hippocampus and bridges CDMR with infant working memory”. A population-based birth cohort will be set up to observe whether specific CRHR1 polymorphisms moderate the effect of CDMR in infants’ working memory by examining cortisol level after birth and expression level of glucocorticoids key functional genes. Taken together, caesarean delivery animal model will be established. Blood corticosterone levels, as well as CRFR1 and glucocorticoids key functional genes expression in hippocampus at different postnatal time points will be determined, and their associations with working memory and synaptic plasticity in CA1, CA3 will be analyzed. And then, findings of animal study will be confirmed in human samples. This study will offer the very direct evidence for the relationship between CDMR and infant working memory and preliminarily elucidate the underlying molecular mechanisms. The present research is also expected to provide new evidence-based conclusions helpful in controlling the rising CDMR rates in China.

产妇自主要求剖宫产（CDMR）率的上升引发了学者对其致子代认知发育不良效应的热烈争议。糖皮质激素（GCs）与突触可塑性呈“∩”型关联，应激时海马释放促肾上腺皮质激素释放激素/因子（CRH/CRF）并激活1型受体CRHR1/CRFR1影响记忆功能。CDMR作为特殊形式的急性应激，取消了正常的GCs上升过程，我们假设“低位GCs与海马CRH-CRHR1信号的交互作用联结了CDMR对子代工作记忆的影响”。本研究建立人群出生队列，分别观察携带CRHR1高风险和保护性基因型的CDMR和自然分娩儿童GCs水平及关键功能基因表达与工作记忆的关系；建立剖宫产小鼠模型，观察两种方式分娩仔鼠不同时点外周血皮质酮水平、海马CRFR1和GCs关键基因表达，及其与工作记忆和突触可塑性的关联，再经人群队列分析印证。研究将为CDMR影响子代工作记忆提供直接证据，并初步阐明其分子机制，为控制我国高CDMR率提供循证依据。

产妇自主要求剖宫产（CDMR）率的上升引发了学者对其致子代认知发育不良效应的关注和争议。项目开创性建设安徽出生队列平台，发现CDMR影响儿童早期体格发育轨迹，尤其与女童高体脂相关轨迹有关。选择性剖宫产缩短了母乳喂养持续时间，4个月纯母乳喂养介导了剖宫产与学龄前儿童孤独症样行为的病因关联；胎盘炎症和氧化应激可能以性别特异性方式介导了CDMR引发的儿童情绪和行为问题。分娩方式与促肾上腺皮质激素释放激素1型受体（CRHR1）基因多态性对儿童认知功能的影响存在交互作用，携带CRHR1高危基因型的选择性剖宫产儿童流体推理正常及高常的比例较低。同时，研究构建剖宫产动物模型，发现剖宫产与雄性子代抑郁和雌性子代焦虑有关，前额叶皮质关键神经递质的变化可能解释了剖宫产与子代情绪症状之间的关联。通过构建小动物生命早期应激范式，发现生命早期应激损伤子代学习记忆功能和海马突触相关蛋白的表达。生命早期应激暴露时阻断糖皮质激素受体（GR）和CRFR1，可在一定程度上逆转个体的学习记忆损伤；值得注意的是，应激时反复阻断CRFR1可显著改善剖宫产子代青春期学习记忆能力。未见剖宫产对儿童青少年远期生殖健康的不良作用效应。拓展研究充分评估了其他形式生命早期应激对子代神经精神发育的作用效应，妊娠相关焦虑、孕前肥胖和孕期增重异常、妊娠期甲状腺功能异常等心理、社会和内分泌代谢应激影响儿童情绪、行为和认知发育。.通过人群-动物-人群循证，验证了“低位GCs与海马CRH-CRHR1信号互作联接选择性剖宫产与子代认知功能损伤的关联”这一假说。从母婴安全的角度来看，CDMR并无临床必要性，是可干预、可控的，研究结果为产科临床分娩方式的知情选择提供了循证依据，对指导妇幼保健实践的作用彰明较著。研究也搭建起分子生物学、围生医学和预防医学的桥梁，进一步助力发育源性疾病的早期精准预防。