小胶质细胞经典与替代激活途径在抑郁发生中的作用研究

Major depressive disorder (MDD), generally associated with severe functional impairment and high health care costs, has increasingly become a public health concern. One of the most common causes of MDD is long-term life stress though its precise mechanism remains elusive. Based on our previous research of inflammation in MDD, we hypothesize that stress-induced depression is associated with dysregulation of pro-/anti-inflammatory cytokines expression due to classical or alternative activation of microglia. The present project aims to: 1) establish the depression animal model by chronic mild stress (CMS) protocol, and detect the mRNA and protein expressions of cytokines in various brain areas of depressive animal to analyze the changing relations between pro- and anti-inflammatory cytokines; 2) determine the phenotype of microglia by flow cytometry and immunohistochemistry to reveal the classical or alternative activation of microglia in CMS-treated rats; and 3) probe the association of the microglial phenotypes and pathogenesis of depression by blocking the activation of microglia. By studying the relationship of classical or alternative activation of microglia with the expression of the pro- and anti-inflammatory cytokines in central nervous system, we hope to explore the pathogenesis of stress-induced depression, thus to supply information for possible new treatment of depression.

抑郁症是一种常见的精神障碍。长期应激是导致抑郁发生的重要因素，但其机制不清。基于炎症与抑郁的研究进展和本课题组前期研究结果，本项目的科学假设是：应激所致抑郁与小胶质细胞激活途径的改变，并由此引起的促炎症与抗炎症细胞因子失衡相关。拟开展如下研究：（1）以慢性温和应激建立抑郁动物模型，分别从核酸和蛋白水平检测应激所致促炎症与抗炎症细胞因子在多个脑区的平衡变化；（2）采用流式细胞术、免疫组化等手段探究抑郁模型动物的小胶质细胞表型改变；（3）改变小胶质细胞的激活途径，结合行为学方法，探讨小胶质细胞激活与抑郁发生的联系。通过研究应激所致中枢炎症因子失衡及其细胞基础，以揭示小胶质细胞激活途径与抑郁发生的联系，探索抑郁的病理机制，并为抑郁的治疗提供新思路。

本项目基于“中枢炎症细胞因子失衡与行为认知相关”的科学假设，采用分子生物学与行为学等方法对慢性应激动物模型神经免疫机制进行了系统研究。主要研究成果如下：（1）慢性应激所致促炎症因子增高而抗炎症因子降低在抑郁病理过程中发挥重要作用；（2）小胶质细胞表型（M1或M2）是应激所致炎症细胞因子失衡的细胞基础，米诺环素通过抑制抑制小胶质细胞促炎症表型（M1）而发挥神经保护作用；（3）小胶质细胞表型的切换与PPARγ途径相关，PPARγ激动剂吡格列酮能够小胶质细胞激活状态并具抗抑郁样作用；（4）抗炎症细胞因子IL-10通过调节色氨酸-犬尿氨酸途径，抑制IDO在星形胶质细胞中的表达和活性。本项目的实施，通过探讨应激与行为关联的神经免疫途径及其生物学意义，为抑郁的治疗提供新的思路。