儿童期城市暴露对精神分裂症患病风险的脑成像及表观遗传机制研究

Studies have shown that stress related with city living is one of important environmental risk factors for schizophrenia, which can have lasting effects on the brain circuits and human behavior. However, the underlying neurobiological mechanisms of the city exposure increasing the risk of schizophrenia are still unclear. The epigenetic modification may be involved in the regulation process. Our previous study examined the effects on higher brain functions of starkly different degrees of rural and urban childhoods in healthy adults, and the preliminary neuroimaging findings suggested that the childhood environment had significant effects on the higher cortical functions linked with schizophrenia like working memory. Based on the preliminary findings, the current project will recruit schizophrenic patients with different childhood urban or rural upbring environment and explore the effects of childhood city exposure on brain circuits invovled in higher function like information processing of social stress, emotion and executive control and etc. This aim will be achieved by comparing the brain activation during the social competitive working memory task and emotional picture task between urban upbring patients and rural upbring patients. Because the urbanicity was believed to stand as a proxy for environment risk factors for schizophrenia we will further explore the relationship between the above neuroimaging phenotype and specific environmental risk factors associated with urban living. In the second aim, by using the epigenome-wide association study strategy, we will first screen the peripheral blood DNA methylation sites associated with childhood environment in a previous sample of healthy adults with different childhood rural or urban upbring environment, and then we will replicate the screened DNA methylation sites in two independent samples of healthy adults with different childhood environment from previous study and patients with schizophrenia from the current project. We will investigate the association between the DNA methylation and the affected brain function by the childhood city exposure and its specific environmental risk factors. The expected results of this project will enhance knowledge about how the childhood city exposure increases risk for schizophrenia and its potentially epigenetic mechanisms.

城市相关环境应激是精神分裂症(SCH)发病的重要风险因素，对大脑神经环路及行为产生持久的影响，可能与DNA甲基化等表观遗传修饰对大脑的调控有关，但其神经生物学机制尚不明确。本课题组前期探索了健康志愿者儿童期环境因素对认识功能及脑结构与功能的影响。本项目拟在前期研究基础上，纳入儿童期城市或农村成长的SCH患者，采集城市生活相关的生物、社会和心理环境因素信息，进行诊断、认知评估及脑磁共振扫描，综合上述数据，探讨儿童期城市暴露对SCH患者社会应激、情绪、执行控制等高级脑环路的影响模式及其相关的特定环境风险因素；采用表观基因组关联研究策略筛选与城市暴露相关的外周血DNA甲基化位点，并进行独立样本验证；探讨DNA甲基化修饰与儿童期环境对成人脑功能效应的关联，揭示特定环境因素影响SCH患病风险可能的表观遗传机制。预期研究结果有助于从环境-遗传协同角度阐明SCH的脑异常机制，为该病发病机理研究提供线索。

城市相关环境风险因素是精神分裂症、抑郁症等精神疾病发病的重要风险因素，对大脑神经环路及行为产生持久的影响，可能与DNA甲基化等表观遗传修饰对大脑的调控有关，但其神经生物学机制尚不明确。本课题组前期探索了健康志愿者儿童期城市化水平对脑结构与功能的影响。本项目在前期研究基础上，进一步纳入具有不同儿童期城市化水平的健康成人以及精神分裂症等精神障碍患者，采集城市生活相关的生物、社会经济以及物理环境因素信息，进行认知评估及脑磁共振扫描。通过整合多组学数据，探索环境对人类行为潜在影响的分子和神经机制，具体开展了三方面研究：1）基于精神疾病患者数据，探究遗传和环境风险相关的精神疾病脑结构和功能改变的神经影像学特征；2）探究环境效应的神经和表观遗传机制，以及环境效应与精神疾病遗传风险的交互作用；3）探究特定环境风险因素相关的脑影像学表型特征。研究主要发现包括：纹状体活动和精神分裂症多基因遗传风险参与社会竞争应激下工作记忆行为表现个体差异的神经和分子机制；城市出生和成长与个体更快的信息处理速度有关，这一过程受到特定基因DNA甲基化水平和特定脑区(颞上回似乎起到重要作用)静息态局部脑功能活动整合调节；近期及儿童期较高的空气细颗粒物(PM2.5)暴露水平可能与部分脑区较低的灰质体积和较差的信息处理速度以及推理和问题解决能力存在关联。本项目尝试从环境-遗传协同角度探索精神分裂症等精神障碍的脑结构和功能异常机制，为疾病的发病机理研究提供线索。研究结果提示，环境风险因素对特定脑结构和功能环路的影响与精神分裂症、抑郁症等精神疾病遗传易感性存在交互。对于精神疾病发病过程中，具体环境因素的影响及其分子机制仍有待在今后研究中进一步探讨。