替代激活的小胶质细胞对抑郁症模型动物神经发生的影响

Major depressive disorder (MDD) is a common and sometimes fatal disorder that has increasingly become a public health concern. Accumulating evidence suggests that chronic low grade inflammation plays an important role in the pathology of depression, which is involved in hippocampal neurogenesis impairment. Based on our previous researches, we hypothesize that stress-induced depression is associated with neurogenesis impairment due to classical or alternative activation of microglia. The present project aims to: (1) establish the depression model by chronic mild stress protocol, detect the number, morphology and phenotype of microglia in different brain regions, and determine the role of classical and alternative activated microglia in neurogenesis and its relationship with depression; (2) construct the expression vector of AAV-IL-4 to induce microglial alternative activation by injecting into lateral ventricles, and assay the influence of alternative activated microglia on neurogenesis and the effects on depressive-like behavors in mice; (3) culture primary microglia to explore STAT6 and PPARγ signal pathway in IL-4-induced alternative activation microglia; coculture microglia and neural precursor cells to examine the effect of IL-4 on proneurogenesis in alternative activation microglia. Using molecular biology, cell biology and behavior methods in vivo and in vitro, we aim to reveal the mechanism of microglia in depression and provide a new target for antidepressant treatment.

抑郁是一种常见的精神障碍。近年研究表明中枢的持续炎症及由此引起的神经发生减少是抑郁的病理基础之一。基于本课题组的前期研究结果，我们提出的科学假设是：小胶质细胞的经典或替代激活途径及其对神经发生的影响与应激所致抑郁的发生发展及转归相关。拟开展如下研究：（1）采用慢性温和应激的抑郁小鼠模型，检测多个脑区小胶质细胞的数量、形态与表型，以探讨小胶质细胞激活途径对神经发生的影响及其在抑郁病理过程中的意义；（2）通过构建AAV-IL-4表达载体，在体诱导小胶质细胞的替代激活表型，并研究其对神经发生的影响及其抗动物抑郁样行为；（3）体外实验分析IL-4诱导小胶质细胞替代激活STAT6、PPARγ信号通路，并以原代小胶质细胞与神经前体细胞混合培养以探究替代激活小胶质细胞的促神经发生作用及其可能的机制。本项目通过体内外实验揭示小胶质细胞参与抑郁症病理过程的细胞与分子机制，为探索新的抗抑郁措施奠定基础。

课题组聚焦于“应激、小胶质细胞、行为”的主题词，从分子、细胞和行为层次分析小胶质细胞激活途径在应激所致抑郁发生的病理意义，解析小胶质细胞调控神经发生的途径和机制，探索基于小胶质细胞表型的抗抑郁策略和措施。本项目的开展，形成了较为系统的研究，获得了一些有意义的发现，回答了抑郁发生与小胶质细胞的激活途径相关，对小胶质细胞的非免疫功能做了有益的探讨，初步鉴定一种促神经发生的小胶质细胞Arg1+表型，丰富了抑郁症的病理和治疗的“神经免疫”内涵。