遗传与环境因素影响精神分裂症患病风险的脑机制研究

Neuropsychiatric diseases like schizophrenia are common, complex genetic disorders that affect cognition and emotion, burdening individuals and society. Our long-term goal is to define specific molecular mechanisms of canonical neural information processing circuits implicated in increased neuropsychiatric risk from urban childhoods. We leverage China’s uniquely large urban-rural demographic changes from recent economic development to powerfully examine the neural effects of different degrees of rural and urban childhoods within its population of relatively limited ancestral diversity. We have recently defined higher cognitive prefrontal circuit deficits associated with genetic risk for psychosis (Kaplan et al, Brain, 2016 In Press; Jiang et al PlosOne 2015); we found these effects may also be accentuated in association with urban childhoods. In this new study period, we aim to study twins and first-episode schizophrenia patients, testing new hypotheses about how prevalent urban social inequality stressors and executive information processes, together interact with the childhood environment, to influence genetic brain mechanisms of psychosis. In Aim 1, we will define, using functional MRI in healthy monozygotic and dizygotic twins with differing urban and rural childhoods, target prefrontal networks associated with genetic and environmental effects, and influenced by experimentally induced social inequality stress during executive cognition. We will further define their overlap with divergent childhood environmental effects in first-episode schizophrenia patients. In Aim 2, we will examine if the childhood environment might differentially influence effects of specific genetic variation, from prior genome-wide association studies or in a genome-wide search, on targeted brain networks defined in Aim 1. We will acquire new imaging data, and with earlier data, form discovery and replication samples. These associations will be further interrogated in prefrontal, caudate and hippocampal postmortem brain expression profiles across the human lifespan. We will thus study uniquely large-scale urbanization changes with new emotional cognitive imaging paradigms. We will engage special healthy, twin and patient samples to iteratively define potentially novel neuropsychiatric disease mechanisms by which specific genes influence urban and rural environmental exposures to affect brain development, function and disease risk.

既往文献及本课题组前期工作提示，人脑认知与情感功能与特定大脑神经环路相关，并受到遗传和环境因素交互作用的影响，但具体机制不明。本项目将围绕“遗传-环境交互作用通过影响应激相关脑环路增加精神分裂症(SCH)患病风险”这一研究假说开展以下研究：1.利用前期建立的情景记忆神经心理学应激模型，继续扩大已有健康成人和首发SCH患者样本，重复验证应激相关脑功能环路与不同儿童期城乡环境成长经历关联等前期工作发现；2.通过比较新收集的健康志愿者及首发SCH患者关键影像学指标的差异(负性场景脑功能激活及连接、静息态脑网络、结构改变)，发现儿童期城乡成长环境因素对健康志愿者及SCH患者大脑应激环路的影响模式；3.经过关键影像学指标与遗传数据及具体环境因素的相关分析，确定儿童期城乡环境暴露因素以及风险基因变异位点。本项目预期结果将初步明确SCH遗传和环境因素的交互作用以及对大脑应激环路结构与功能产生的特定影响。

认知与情感功能与特定大脑神经环路相关，并受到遗传和环境因素交互作用的影响，本课题组近期工作提示，儿童期城市化与社会应激相关大脑内侧前额叶功能及抑郁症多基因风险存在关联。本项目围绕“遗传-环境交互作用通过影响应激等相关脑环路增加精神疾病患病风险”这一研究假说开展研究工作，主要发现包括：1）基于前期发现的应激下工作记忆相关的内侧前额叶和纹状体活动抑制，继续扩大已有健康成人和精神分裂症等精神障碍患者样本，发现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；2）精神分裂症和强迫障碍患者尽管在社会竞争应激下工作记忆相关的纹状体功能活动方面存在相似的特征，但是两者纹状体的静息态功能连接存在差异，可能反映了疾病的特征性改变；3）更高的城市化水平与个体更快的信息处理速度关联，DNA甲基化水平和颞上回静息态局部脑功能活动参与上述关联的表观遗传和神经机制；4）个体遗传变异预测的蛋白表达水平与情景记忆任务中负性图片回忆的海马活动关联，并且在城市和农村被试中呈现不同的相关关系。本项目发现提示环境风险与精神疾病遗传易感性共同作用于大脑神经环路，影响个体行为和认知功能水平。对于遗传-环境交互作用增加精神疾病患病风险的分子和神经机制提供了初步的研究证据。

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