早年创伤抑郁奖赏系统受损及其胶质细胞外泌体Par4调控机制

Depression is a disease with high heterogeneity. Depression that emerges as a result of early life trauma (ELT) is often characterized by anhedonia, an important clinical feature of depression. Anhedonia has been linked to the dysfunction of the dopaminergic reward system, especially abnormal of dopamine receptor D2 (DRD2). Being abundant in glia-depreved exosome, prostate apoptosis response protein 4 (Par4) is a regulator of DRD2 activity, and its expression in the striatum is downregulated during depression. However, it is unknown whether the Par4 in glial exosome is involved in the development of depression with ELT by regulating DRD2 activity and downstream signaling pathways in the dopaminergic reward system. In this proposal, we will: (1) investigate the behavioral features and clinical phenotypes of depressed patients with ELT; (2) identify the structural and functional impairments in the dopaminergic reward system in depressed patients with ELT, and acquire some brain characteristics to distinguish patients with or without ELT; (3) determine whether Par4 carried by glial exosome regulates neural DRD2 and its downstream signaling pathway, and elucidate the molecular mechanism of impaired dopaminergic reward system in the development of depression with ELT. This study will provide evidences for determining subtypes of depression and contribute to developing accurate treatment for depression from findings in patients, animals, cells, to molecules.

抑郁症是高异质性疾病，早年创伤抑郁可能是一种特殊的抑郁亚型，以快感缺失为主要临床特征。快感缺失与多巴胺奖赏系统尤其是多巴胺D2受体（DRD2）功能有关。前列腺凋亡反应蛋白（Par4）是DRD2功能的关键调节因子，参与抑郁发生的神经胶质细胞可分泌富含Par4的外泌体，但是否参与早年创伤抑郁个体奖赏系统受损和DRD2功能的调控及其分子机制有待研究。本研究拟从人群、动物、细胞、分子水平深入研究：（1）观察与评估早年创伤抑郁个体的表现特征，以确定其临床表型；（2）检测早年创伤抑郁个体奖赏系统脑区的结构与功能改变及其与抑郁行为的关系，获得可有效区分有无早年创伤抑郁的特征性脑区和脑连接；（3）检测神经胶质细胞源性外泌体Par4对DRD2信号通路的调控作用，明确早年创伤抑郁个体奖赏系统受损的分子机制。本研究结果能为抑郁症的异质性、分类诊断和精准治疗提供方向和实验依据，为新型抗抑郁药物的研发提供思路。

早年创伤是抑郁发生的危险因素，但早年创伤致抑郁发生发展的机制尚不十分清楚。本项目分为人群研究和动物实验两部分，从人群、动物、细胞、分子各水平展开研究，探讨早年创伤抑郁奖赏系统受损及其胶质细胞外泌体Par4调控机制。研究结果发现：（1）早年创伤损害快感体验，经历过早年创伤的个体其快感缺失水平升高，这一现象不仅出现在经历过早年创伤的抑郁症患者中，在经历过早年创伤的健康人群中也同样存在着不同程度的快感缺失；（2）早年创伤影响奖赏环路核心区域腹侧纹状体与眶额叶皮层的功能连接，该结果提示，奖赏环路功能异常可能是与早年创伤有关的快感缺失的重要神经基础；（3）早年创伤影响社会脑功能和结构，社会脑功能和结构异常是与早年创伤有关的社会快感缺失的重要神经基础；（4）早年不良应激特异性地增加了成年大鼠快感缺失抑郁样行为的发生，其机制可能是早年应激引起伏隔核内DRD2基因表达和分布发生改变，增强其下游β-arrestin2-cofilin/F-actin信号通路活性，当成年再次经历慢性不可预知性应激时，导致DRD2/β-arrestin2-cofilin/F-actin信号通路过度激活，从而引起神经突触可塑性改变，进而损伤伏隔核的结构和功能，最终导致快感缺失的发生。这些研究结果揭示，有早年创伤经历的抑郁个体表现出以高水平快感缺失为特征的临床表型，并表现出特异的奖赏环路受损及其分子调控机制，提示有早年创伤经历的抑郁可能是一种从病因，到发病机制，到临床表现均不同于无早年创伤抑郁的一种特定的抑郁亚型，本研究结果为抑郁症的异质性、分类诊断和精准治疗提供实验依据，同时也为早年创伤抑郁的预防提供了方向。