摘要
抑郁症是一种以持续情绪低落和认知功能障碍为主要临床特征的精神疾病,患病率高,也是自杀的最主要原因,已成为全球重大的公共卫生问题和突出的社会问题。在病因学上,抑郁症是环境与基因交互作的复杂疾病,其发病机制尚不清楚,至今仍然缺乏安全、有效的治疗措施。适宜的动物模型对于揭示抑郁症的病理机制以及药物开发都是至关重要的,慢性温和应激(Chronic Mild Stress,CMS)是一种被普遍认可的抑郁模型,它在行为表现(Face validity)、病因病理(Construct validity)以及对治疗应答的有效性(Predictive validity)等方面与人类疾病有较高的相似性。以临床观察为基础,学术界近年提出了抑郁的"炎症因子学说",持续低级别的神经炎症反应在抑郁发生中是一个中心环节。本实验室以"中枢炎症细胞因子失衡与行为认知相关"的线索,以小胶质细胞为主角,采用分子生物学与行为学等方法探索啮齿动物抑郁症模型的神经免疫机制。研究发现:(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调节小胶质细胞的激活状态并发挥抗抑郁样作用;(4)抗炎症细胞因子IL-4诱导小胶质细胞M2表型,能够促进神经发生,具有抗抑郁样作用。从应激、小胶质细胞表型、神经发生和抑郁样行为等多层次揭示应激所致抑郁的生物学机制,探索基于小胶质细胞途径的抗抑郁途径,可为抑郁的治疗提供新的治疗策略。
Major depressive disorder is a common illness worldwide, characterized by long-lasting low mood and cognitive impairment, with high morbidity and high suicide rates, which brings about a heavy socio-economic burden worldwide and is a serious public health problem. Due to the complicated interaction of genetic susceptibility and environmental stress, the pathogenesis of depression remains unclear. The classical antidepressants based on monoamine hypothesis of depression have been challenged for clinical limitations and adverse effects. Rodent models of depression make substantial contributions to our understanding of t the pathophysiology and treatment of depression. The models are generally evaluated for their ability to reproduce in animals aspects of the illness in humans(face validity), and etiological(construct) and pharmacological(predictive) validities. The chronic mild stress(CMS) paradigm was adopted with a series of different stress conditions exposed to rats or mice over a period of several(6–8) weeks. The model provides natural induction of chronic depressive-like state that develops gradually over time in response to stress, therefore probably the most valid animal model of depression. 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 CMS-induced imbalance between pro- and anti-inflammatory cytokines in the brain associated with cognitive deficits and behavioral abnormalities, possibly because the phenotypic dysregulation of microglial activation. The research data indicated(1) the imbalance between pro- and anti-inflammatory played a crucial role in CMS-induced depression, with upward trend of the pro-inflammatory cytokines and downward trend of anti-inflammatory cytokines in brain;(2) the dysregulated microglial activation(M1 vs M2) led to the imbalance of pro- and anti-inflammatory cytokines, and minocycline could inhibit M1-biased microglial response and had beneficial effects in CMS model;(3) the microglial activation phenotypes were partially dependent on peroxisome proliferator-activated receptor gamma(PPARγ) pathway, and PPARγ agonist pioglitazone had antidepressant-like effects through promoting M2 polarization in CMS mouse model;(4)anti-inflammatory cytokine interleukin-4(IL-4) was able to induce expression of genes typifying the M2 phenotype, ameliorate depression-like behavior, and promote neurogenesis in vivo and in vitro. 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.
引文
