父母敏感性与儿童内化问题：表观遗传机制

Although mounting evidence has identified the crucial role of parental sensitivity in the development of child internalizing problems, the underlying biological mechanism is still little known. Epigenetics processes have been recently considered to play a vital role in the biological embedding of early family environmental factors and the development of psychosocial maladjustment. From this newly emerging epigenetic perspective, this project aim to explore how NR3C1 promoter methylation, the function of the HPA axis and NR3C1 genotype work together in revealing the biological mechanism regarding how parental sensitivity plays its role in child internalizing problems..Two studies will be conducted in this project. In study 1, within a sample of 300 Chinese preschoolers, using multiple research approaches (i.e., observation, questionnaire, experiment, genotyping and DNA methylation), a moderated mediation model is constructed. Within this moderated mediation model, we will firstly examine a chain mediation pathway from parental insensitivity to child internalizing problems via the hypermethylation of NR3C1 promoter and heightened function of the HPA axis, and then test the moderation effect of the Bcl1 polymorphism in NR3C1 gene in the abovementioned chain mediation pathway. Subsequently, we will select insensitive parents from study 1, and conduct a longitudinal intervention study (i.e., study 2) targeting at enhancing their parental sensitivity. By this intervention, we will examine whether or not the enhancement of parental sensitivity causally leads to the decrease of NR3C1 promoter methylation as well as child internalizing problems. Also, this invention study will bring in the application of an evidence-based intervention method to China to help Chinese parents promote their sensitivity and reduce or prevent child problem behaviors. .This project provides a deeper understanding about the epigenetic mechanism underlying how parental sensitivity in child early years of life plays its role in child internalizing problems at a molecular level. Furthermore, the evidence-based identification of epigenetic biomarkers may lead to an early identification of problem behaviors and could be helpful for its early preventive interventions.

尽管众多研究已揭示了父母敏感性在儿童内化问题中的重要作用，但我们对其内在生物学机制知之甚少。本项目拟从表观遗传学这一新兴的研究视角出发，考察压力应激相关基因NR3C1基因的甲基化、Bcl1多态性，及后继HPA轴功能如何共同作用，以揭开父母敏感性影响儿童内化问题的表观遗传机制。具体包括：1）采用横断、相关研究，考察父母敏感性相继通过NR3C1基因甲基化、HPA轴功能影响儿童内化问题的链式中介路径，以及Bcl1多态性在这一链式中介路径中的潜在调节作用；2）采用随机控制试验设计的纵向、干预研究（属于实验研究的范畴），考察父母敏感性的改善能否因果性逆转NR3C1基因甲基化的升高，进而降低儿童内化问题。本项目能够从分子水平上揭示父母敏感性作用于儿童内化问题的生物学机制，利于基于生物学标记的预防与降低儿童内化问题的干预、预防项目的开发与实施。

探讨父母教养作用于儿童青少年内化问题的内在生物学机制是当前家庭教养领域的重要前沿课题。本项目从行为表观遗传学这一新兴的研究视角出发，以我国核心家庭的学龄前儿童（3~6岁）及其父母和连续追踪两年的青少年（15~18岁）为被试，综合采用传统发展心理学的观察法、问卷调查法及DNA甲基化技术与基因分型技术，借助多变量相关设计和随机对照试验设计系统考察了压力应激相关基因NR3C1基因启动子区1F的甲基化和NR3C1基因多态性在父母敏感性、儿童期虐待及父母教养质量与儿童青少年内化问题关系中的作用机制。. 研究的主要结果如下：在学龄前儿童样本中，1）较低水平的母亲敏感性、较高水平的父亲干涉性以及儿童期躯体虐待能够显著下调学龄前儿童NR3C1基因甲基化，但NR3C1基因甲基化却与儿童内化问题的发生无显著关联；2）NR3C1基因Bcl1与TthIIII多态性均无法显著调节父母教养与儿童NR3C1基因甲基化以及内化问题间的关系。3）HPA轴压力应激性未能中介早期家庭环境与儿童内化问题相关变量执行功能间的关系，但能够以“敏感因子”的方式显著调节早期家庭环境与儿童执行功能间的关系。在青少年样本中，1）儿童期虐待能够下调青少年中期NR3C1基因甲基化，进而导致青少年晚期内化问题的增多。相似地，较差的儿童期父母教养质量亦能够下调青少年中期NR3C1基因甲基化，进而提高青少年晚期焦虑症状；2）NR3C1基因Bcl1多态性以拮抗或补偿式的方式显著调节NR3C1基因甲基化在儿童期虐待与青少年焦虑与情绪症状关系间的中介效应，但NR3C1基因TthIIII多态性以增强或促进的方式显著调节NR3C1基因甲基化在儿童期母亲教养质量与青少年抑郁症状、焦虑症状关系间的中介效应；3）相比各类早期家庭环境间的交互效应以及累加效应，儿童期虐待对青少年中期NR3C1基因甲基化的独立效应具有更大的预测力和效果量。4）在NR3C1基因甲基化与青少年内化问题的双向关系中，青少年NR3C1基因甲基化更可能是“因”、驱动其内化问题的改变。5）多位点HPA轴遗传变异比单位点遗传变异在解释内化问题的遗传与环境交互作用机制上具有更强的效果量。. 本项目研究从分子水平上揭示了父母教养作用于儿童青少年内化问题的生物学机制，有利于后续基于生物学标记的预防与降低儿童内化问题的干预、预防项目的开发与实施。