The Role Of NLRP1 Inflammasome In Mice Depressive-like Behaviors Induced By Chronic Stress

Depression is now a major contributor to the global burden of disease.At present,the pathogenesis of depression is not clear,and the immune inflammatory hypothesis is getting more and more attention.The levels of IL-1?,IL-6,TNF-? and other inflammatory factors in serum and brain were significantly higher in depressed patients,and the levels of these factors are related to the severity of depression.NLRP1 inflammasome is a muti-protein complex that consist of NLRP1,ASC and pro-caspase-1,active capsase-1 resulting in the maturation of proinflammatory cytokines IL-1? and IL-18.It plays important roles in many psychological disorders.But the relationship between NLRP1 inflammasome and depression still not clear.This study aims to study the relationship between NLRP1 inflammasome and chronic stress-induced depression-like behaviors in mice,and provide new ideas for treatment of depression.Objectives: Observe the role of NLRP1 inflammasome in mice depression behavior induced by chronic unpredictable mild stress(CUMS)and chronic restrain stress(CRS),and the improved depression behavior after NLRP1 was inhibited in mice.Methods: The effects of CRS and CUMS treatment with different time courses on body weight and depressive-like behaviors in mice were observed by OFT,TST,FST and SPT.The expression of NLRP1 inflammasome complex NLRP1,ASC,Caspase-1 and pro-inflammation cytokines IL-18,IL-1?,IL-6 and TNF-? in hippocampus tissues of mice were detected by western blot.The levels of pro-inflammation cytokines IL-18,IL-1?,IL-6 and TNF-? were detected by enzyme-linked immunosorbent assay(ELISA)in mice hippocampus tissues with different time course of CUMS treatment.The mice were received a stereoscopic injection of the shRNA in hippocampus,then CUMS and CRS treatment was played,the improved depression behavior after NLRP1 was inhibited were detected by OFT,TST,FST and SPT.Results: 1.When the mice were subjected to CUMS with different time courses,compared with the control group,the weight of mice in CUMS 4W and 6W groups were significantly decreased.CUMS treatment for 4W and 6W significantly decreased the sucrose preference in mice,and the immobility time in FST and TST were significantly increased.The distance,average speed,the number of lines crossing and the number of standing times were significantly decreased in the mice of 4W and 6W groups.The expression of NLRP1 inflammasome complex NLRP1,ASC,Caspase-1 and pro-inflammation cytokines IL-18,IL-1?,IL-6 and TNF-? in hippocampus tissues with CUMS treatment for 4W and 6W mice were significantly increased compared with control group.2.After NLRP1 was inhibited in the hippocampus and the mice were subjected to CUMS for 6 weeks.Compared to control group,the sucrose preference was significantly decreased,the immobility time in FST and TST were significantly increased.The distance,average speed,the number of lines crossing and the number of standing times were significantly decreased in CUMS group.When compared to AAV-NC group,the sucrose preference was significantly increased,the immobility time in FST and TST were decreased significantly.The distance,average speed,the number of lines crossing and the number of standing times were significantly increased in AAV-Nlrp1 a group.3.When the mice were subjected to CRS for 10 days,SPT,FST,TST and OFT were detected and we found that mice exposed to CRS displayed depressive-like symptoms,including decreased sucrose preference,the immobility time in FST and TST were increased.In OFT,the distance,average speed,the number of lines crossing and the number of standing times were obviously decreased compared with control group.The expression of NLRP1 inflammasome complex NLRP1,ASC,Caspase-1 and pro-inflammation cytokines IL-18,IL-1?,IL-6 and TNF-? in hippocampus tissues of mice were significantly increased compared with control group.4.After NLRP1 was inhibited in the hippocampus and the mice were subjected to CRS for 10 days.Compared to control group,the sucrose preference was significantly decreased,the immobility time in FST and TST were significantly increased.The distance,average speed,the number of lines crossing and the number of standing times were obviously decreased in CRS group.When compared to AAV-NC group,the sucrose preference was obviously increased,the immobility time in FST and TST were decreased significantly.The distance,average speed,the number of lines crossing and the number of standing times were significantly increased in AAV-Nlrp1 a group.Conclusion: NLRP1 inflammasome is involved in chronic unpredictable mild stress and chronic restraint stress induced mice depressive-like behaviors.Inhibition of NLRP1 in the hippocampus can improve the depressive-like behaviors in mice.