细胞外信号调节蛋白激酶（ERK）对于抑郁症“无助感”相关脑功能网络的作用及调控机制

Helplessness may be the potential mechanism of patients with major depressive disorder (MDD). The alteration of neurogenesis in the dentate gyrus of hippocampus was found to be the basis of abnormal neuron circuit in learned helplessness (LH) mice. Our previous fMRI study reported that the hippocampus might be one of the key brain areas in the abnormal functional connectivity network related with helplessness of MDD patients. Results from animal studies indicated ERK may regulate the neurogenesis in the dentate gyrus of hippocampus. Thus, the relationship between ERK, hippocampus, and helplessness need to be further explored. In this project, three parts of studies will be combined to test the proposed hypotheses. First, resting state fMRI-BOLD data will be acquired from patients with MDD. Hippocampus dentate gyrus will be seeded to build a functional connectivity network by analyzing its connectivity with the sub-regions of hippocampus and other mood-cognition brain areas. The relationship between the functional connectivity network with the helplessness of patients with MDD will be further explored. Then the role of the dentate gyrus in the brain network related with helplessness will be tested by the effective connectivity analysis and the little world model analysis. Second, LH mouse model will be used to explore the biological mechanism of the dentate gyrus related with helplessness. Colchicines will be used to damage the dentate gyrus of hippocampus in LH mouse to examine the potential imbalanced alterations between neurogenesis and neuron apoptosis in different brain regions among the neuron circuit of the dentate gyrus. Third, the ERK signaling pathway will be blocked by U0126, and ERK levels in different regions among the neuron circuit of the dentate gyrus will be examined to explore their associations with neurogenesis and neuron apoptosis. A variety of methodologies including brain functional network analysis of pateints with MDD , cell and molecule examinations using LH mouse model will be integrated in this project to explore the regulating mechanism of ERK on the brain network related with helplessness of the hippocampus dentate gyrus in MDD.

无助感是研究抑郁症机制的重要切入点，研究表明海马齿状回神经细胞变化是习得性无助（LH）大鼠神经环路异常的物质基础。本项目组前期的功能磁共振（fMRI）研究提示海马是抑郁症患者无助感相关脑功能网络的关键脑区；动物研究提示ERK可能调控海马齿状回神经细胞新生与凋亡，而ERK、海马与无助感网络的相关机制有待研究。本项目首先拟用抑郁症患者静息态脑fMRI数据，探索海马齿状回与情绪认知脑区的功能连接网络及其与无助感的关系，以效应连接和小世界模型分析确定齿状回对该网络的作用。进而借助LH大鼠，研究齿状回被秋水仙碱损毁后，海马各亚区及远隔脑区神经新生与凋亡失衡情况；进一步用抑制剂U0126阻断齿状回ERK信号通路，研究各脑区ERK水平改变，及其对神经细胞新生与凋亡的调控。项目结合临床影像与动物实验，探讨ERK对海马齿状回及远隔脑区的作用，预期结果有助于阐明ERK调控抑郁症无助感脑功能网络的分子细胞机制。

异常脑功能网络模块诱导了抑郁症患者的无助感，海马作为关键脑区，对神经网络的作用机制未明。此外，其异常脑功能的内在生物学机制仍待研究。REK、NLRP3及下游IL-6等因子可能参与了其神经免疫炎症的调控。本研究采用临床研究与动物研究相结合的方法进行相互探究。首先，临床方面，采用脑结构态、功能态及DTI脑影像数据探究抑郁症患者脑网络拓扑学的特征，以及该异常影像特征与“无助感”症状之间的联系。其次，鉴于神经炎症反应可能参与抑郁症患者脑功能活动的调控，进一步探究其犬尿氨酸通路中关键分子的表达情况。最后，作为抑郁症核心特征之一的快感缺失，我们亦探究了抑郁发作患者愉快感缺失的脑电生理机制。动物研究方面，构建抑郁模型鼠，探究神经免疫炎症，例如ERK、NLRP3和IL-6等分子，可能对海马等脑区的影响机制。我们发现，抑郁症患者“无助感”的脑皮质内在固有连接在局部水平上存在着受损，且抑郁症患者海马与额枕叶的纤维连接存在着异常。同时，抑郁症患者血样中的犬尿喹啉酸及喹啉酸等的表达水平异常，提示神经免疫炎症可能参与了抑郁症患者脑功能失衡的调控。此外，我们发现抑郁发作患者存在期待性快感体验及消费性快感体验的下降，且抑郁症患者对奖赏敏感度下降、反馈负波的波幅下调。动物研究方面，我们发现，NLRP3炎症小体及下游促炎因子（包括IL-6和TNF-α）等相关分子在海马及前额叶脑区的表达异常，且在外周组织中（例如脾脏）的表达亦出现显著增高，而氟西汀药物干预后则出现缓解。该部分结果提示，神经免疫炎症等分子可能通过相关的分子机制，通过影响大脑的结构/功能，进而产生了抑郁样外表型。本项目以抑郁症患者的“无助感”研究作为切入点，结合抑郁动物模型，逐层研究ERK、NLRP3、IL-6等分子对海马相关脑功能网络的作用和调控机制，探索了神经免疫炎症在抑郁症“无助感”相关脑环路中的重要作用。该研究发现，为抑郁症的精准靶向治疗提供了潜在的生物学基础。