Transcutaneous vagus nerve stimulation modulates depression‐like phenotype induced by high‐fat diet via P2X7R/NLRP3/IL‐1β in the prefrontal cortex.

Background: Depression is a common psychiatric disorder in diabetic patients. Depressive mood associated with obesity/metabolic disorders is related to the inflammatory response caused by long‐term consumption of high‐fat diets, but its molecular mechanism is unclear. In this study, we investigated whether the antidepressant effect of transcutaneous auricular vagus nerve stimulation (taVNS) in high‐fat diet rats works through the P2X7R/NLRP3/IL‐1β pathway. Methods: We first used 16S rRNA gene sequencing analysis and LC–MS metabolomics assays in Zucker diabetic fatty (ZDF) rats with long‐term high‐fat diet (Purina #5008) induced significant depression‐like behaviors. Next, the forced swimming test (FST) and open field test (OFT) were measured to evaluate the antidepressive effect of taVNS. Immunofluorescence and western blotting (WB) were used to measure the microglia state and the expression of P2X7R, NLRP3, and IL‐1β in PFC. Results: Purina#5008 diet induced significant depression‐like behaviors in ZDF rats and was closely related to purine and inflammatory metabolites. Consecutive taVNS increased plasma insulin concentration, reduced glycated hemoglobin and glucagon content in ZDF rats, significantly improved the depressive‐like phenotype in ZDF rats through reducing the microglia activity, and increased the expression of P2X7R, NLRP3, and IL‐1β in the prefrontal cortex (PFC). Conclusion: The P2X7R/NLRP3/IL‐1β signaling pathway may play an important role in the antidepressant‐like behavior of taVNS, which provides a promising mechanism for taVNS clinical treatment of diabetes combined with depression. [ABSTRACT FROM AUTHOR]