利用影像遗传策略探讨抑郁症自杀行为的脑网络机制

Major depression disorder（MDD）has become a global public health problem. Recent studies have suggested that suicidal behavior has become the most dangerous symptom of MDD patients and significantly affect the occurrence, development and outcome of depression. Therefore, build on our previous accumulations, we will recruit the first-episode MDD patients without suicidal ideation (SI), MDD with SI, MDD with suicidal behavior and well-matched healthy controls to investigate the potential mechanism underlying suicide behavior associated with suicide-related genes and imaging characteristics in MDD patients, by integrating multidimensional neuropsychological assessment. Firstly, using high-throughput whole exon sequencing technology, we will detect the difference of neural indicators in peripheral blood , including dopaminergic, 5-hydroxytryptamine and inflammation related indicators, and determine the potential candidate biomarkers at the different level of suicide behavior in MDD patients; Secondly, we will screen the key susceptible genes associated with suicidal ideation and suicidal behavior of MDD patients in dopamine system, serotonin system and neural inflammation system, to explore the clustering effects of these important candidate genes on clinical and pathological phenotypes of MDD. Further, we will investigate the effects of these genes on the gray matter volumes of vulnerable brain regions, the patterns and information integration of structural and functional networks related to MDD. The current study might preliminary screen for bio-imaging markers that can be used for differentiating suicidal behaviors or ideation in depression and reveal the genetic regulatory mechanism of brain structure and function networks targeting on the MDD suicidal population. Taken together, we will integrate above findings to establish an early identification system for high-risk suicidal population in MDD patients, and provide empirical evidence for clinical prevention and early intervention of MDD suicidal behavior.

抑郁症（MDD）已经成为全球的公共卫生健康问题。研究表明，自杀行为已经成为抑郁症患者最危险的症状，并显著影响抑郁症发生、发展和转归。本研究团队将基于前期积累，整合多维度神经心理学评估，同期选择首发抑郁症无自杀意念组、抑郁症伴自杀意念组、抑郁症伴自杀行为组及其匹配健康对照组，利用高通量全外显子测序技术筛选多巴胺、5-羟色胺和神经炎症等通路与MDD自杀关联的关键易感基因，构建抑郁症自杀相关基因群，分析重要候选基因的集聚效应对抑郁症患者自杀意念/行为、脑结构和功能网络的模式特征的影响；结合影像遗传学策略，分析不同通路自杀相关易感基因及其集聚效应对MDD自杀人群脑结构及功能网络的调控机制，寻找可用于抑郁症不同自杀行为或意念的生物-影像学标记物；最后，利用组学整合分析方法，揭示MDD不同程度自杀行为、与自杀相关基因群、以及影像学特征的内在关联机制，为临床早期预防和干预抑郁症患者自杀行为提供依据。

抑郁症（MDD）已经成为全球的公共卫生健康问题。研究表明，自杀行为已经成为抑郁症患者最危险的症状，并显著影响抑郁症发生、发展和转归。本课题利用多模态fMRI技术，研究抑郁症患者自杀相关神经环路的结构基础和功能连接模式特征：证实伴有自杀意念抑郁症患者存在独特的脑血流和脑网络异常，并强调楔前叶、前额叶-边缘系统以及感觉运动皮层在自杀过程中的潜在作用；结合散张量成像，证实抑郁症患者自杀意念与核心结构网络改变相关，为了解 MDD 患者自杀相关行为的潜在发病机制提供了新线索。童年虐待(CM)被认为是MDD的重要危险因素。大尺度脑网络分析显示，网络改变，特别是扣带盖网络内连接值可以中介调节CM和抑郁评分间的关系；岛叶功能网络也被证实可以中介调节CM经历与MDD症状之间的关系：早期暴露于CM可能会通过影响大脑的自我调节和认知加工回路，增加抑郁症的易感性；此外，我们还证实了杏仁核网络的异常及其与抑郁与焦虑严重程度的相关性，证实了抑郁与焦虑的共病基础。利用遗传影像学策略，从系统水平揭示遗传因素影响抑郁症的可能机制：发现环状RNA DYM水平在抑郁患者和抑郁样小鼠模型中显著降低，进一步研究表明其可抑制microRNA-9 (miR-9)活性，从而导致小胶质细胞活化减少；还发现 CM、miR-9 和抑郁严重程度对 MDD 患者双侧杏仁核功能连接的重叠影响主要位于前额-纹状体通路和边缘系统，证实miR-9 可在 CM 产生前额叶边缘区域脑改变过程中发挥关键作用，并随后导致抑郁。结合图论分析技术，证实抑郁症患者呈现出较低的标准聚类系数及小世界性，默认网络节点效率增高，而海马及基底节网络的节点效率降低。提示抑郁症患者存在脑功能网络的拓扑性质改变。最后，结合神经心理学评估，初步揭示自杀相关神经环路在抑郁症发病机制中的重要地位，解析抑郁症自杀相关环路的整合机制及其与临床认知表型的关系，为明确抑郁症自杀相关行为的神经病理机制，并为后续随访研究寻找疾病特异性的神经环路特征及早期诊断的影像表征模型奠定基础。