NLRP1炎症小体-自噬信号在慢性不可预见性轻度应激致小鼠抑郁样行为中的作用

Major depressive disorder（MDD）, a common psychiatric disorder characterized by altered mood and cognitive dysfunction, is projected to become the primary cause of global disease burden because of high mortality and morbidity. However, the underlying mechanisms of MDD are unclear. Increasing evidence demonstrated that inflammatory disturbance is involved in the pathogenesis of MDD：The level of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α is increased significantly in depression both in patients and in animal models. IL-1β is regarded as “main factor” and mediated the release of other pro-inflammatory cytokines, and its maturation depends on the activity of inflammasome. Recent studies show NLRP3 inflammasome involved in MDD. However, the role NLRP1 inflammasome in MDD maintains unclear. Cognitive impairment is a core symptom of MDD. The studies show that neuronal excessive autophagy implicated in cognitive impairment in MDD, while autophagy could be regulated by inflammasome. However， the effect of inflammasome-autophagy signal on cognitive impairment of MDD is unclear. Here, we will establish a mouse model of depression by chronic unpredictable mild stress （CUMS）and investigated the role of NLRP1 inflammasome in depressive-like behaviors of mice through various experimental methods. Moreover, we will also examine the effect of NLRP1 inflammasome on autophagy and the role of NLRP1 inflammasome-autophagy signal in cognitive impairment of depressive-like mice. We hope that NLRP1 inflammasome could become a novel therapeutic target of MDD.

抑郁症是一种常见的以情绪低落、认知损伤等为表现的精神疾病。高发病率、高致死率使其将居于全球负担性疾病的首位，但发病机制还不清楚。大量研究表明炎症与抑郁症关系密切：在抑郁症患者和动物模型均发现IL-1β，IL-6、TNF-α等致炎因子水平明显升高，而被认为是“主因子”介导其他因子释放的IL-1β的成熟依赖炎症小体激活；最近研究表明NLRP3炎症小体与抑郁症发病相关，但NLRP1炎症小体与抑郁症的关系还不清楚。认知损伤是抑郁症核心症状，研究表明抑郁症患者认知损伤与神经元过度自噬有关，而自噬又可被炎症小体调节，但炎症小体-自噬信号在抑郁症认知损伤中的作用还不清楚；本项目运用多种实验方法，通过慢性不可预见性轻度应激建立小鼠抑郁症模型，观察NLRP1炎症小体在小鼠抑郁样行为中的作用，明确NLRP1炎症小体对神经元自噬的影响及其在抑郁小鼠认知损伤中的作用，以期为其成为临床抑郁症治疗新靶点提供理论依据。

抑郁症是一种常见的以情绪低落、认知损伤等为表现的精神疾病。高发病率、高致死率使其将居于全球负担性疾病的首位，但发病机制还不清楚。大量研究表明炎症与抑郁症关系密切，而作为炎症反应的重要调节机制，炎症小体介导炎症反应参与了多种神经系统疾病。最近研究表明NLRP3炎症小体与抑郁症发病相关，但NLRP1炎症小体与抑郁症的关系还不清楚。本项目通过慢性不了预见性轻度应激（chronic unpredictable mild stress，CUMS）、慢性束缚应激（chronic restrain stress，CRS）、慢性社会挫败应激（chronic social defeat stress，CSDS）和重复社会挫败应激（repeat social defeat stress，RSDS）四种慢性应激方式建立小鼠抑郁模型，发现慢性应激导致海马NLRP1炎症小体及其介导的炎症信号被激活，同时CXCL1/CXCR2信号也被激活，BDNF表达下调，Nlrp1a敲低抑制了炎症和CXCL1/CXCR2/BDNF信号激活，改善了小鼠抑郁样行为。而且，NLRP1炎症小体/CXCL1/BDNF信号还参与了年龄相关的抑郁样行为的发生。自噬与抑郁症发生密切相关，我们还发现关键自噬相关蛋白在慢性应激诱导的抑郁样小鼠海马表达明显降低，Nlrp1a敲低明显抑制了这一效应，而给予自噬激动剂Rapamycin处理则能显著改善慢性应激诱导的抑郁样行为。此外我们还发现应激诱导的糖皮质激素水平升高可能通过大电导钙激活钾通道（Large-conductance Ca2+and voltage-activated K+ channel，BK）激活NLRP1炎症小体，参与了抑郁样行为和认知功能损伤。这些表明，NLRP1炎症小体介导的炎症反应参与了慢性应激诱导小鼠抑郁样行行为，其机制可能与激活CXCL1/CXCR2信号，下调BDNF表达水平及神经元自噬功能有关，我们的研究为NLRP1炎症小体成为潜在临床抑郁症治疗新靶点提供了理论依据。