NLRP3 in the dorsal raphe nucleus manipulates the depressive-like behaviors

Major depressive disorder is one of the most common psychiatric disorders, and the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in depression. Dorsal raphe nucleus (DRN), as the main origin of producing serotonin in the brain, is an important functional brain region in depressive disorders. However, the relationship between NLRP3 in the DRN and depression has not been clarified in previous studies. So, we focus on demonstrating the role of NLRP3 expressed in DRN in depression. In this study, the male C57BL/6 J mice were exposed to chronic unpredictable mild stimulation and the expression and cellular localization of NLRP3 in DRN were analyzed. Subsequently, the mice were treated with the NLRP3 inhibitor MCC950 to inhibit NLRP3 inflammasome, and the expression of NLRP3 was knocked down in certain cells within the DRN of NLRP3^fl/fl mice to investigate the role of NLRP3 in regulating depressive phenotype. Compared with the control group, the expression of NLRP3 in DRN of CUMS group was significantly increased, especially in the microglia and neuron. Furthermore, treatment with the NLRP3 inhibitor induced a significant antidepressant effect, and the depressive phenotype of NLRP3^fl/fl mice was rescued after knocking down NLRP3 in the microglia or neuron. In addition, the expression levels of related molecules in the NLRP3 inflammasome pathway were significantly higher in the CUMS group compared to the control group. These results illustrated that NLRP3 played an important role in regulating depressive phenotype in DRN, and suggested a new therapy target for depression.