5-HT1A + Treg cells and their associated signaling pathways may be the key mediators determining susceptibility in mouse models of depression

Rationale Chronic social defeat stress (CSDS) can naturally distinguish between susceptible and resistant individuals, and in-depth exploration of its specific mechanisms holds significant potential value for the prevention and treatment of depression. Objective To investigate the key molecular biological mechanisms and signaling pathways that determine susceptibility versus resilience in the CSDS mouse model. Method Adolescent C57BL/6J mice were exposed to CD-1 mouse cages for 10 consecutive days to establish the CSDS model. After distinguishing between susceptible and resilient mice, behavioral indicators were validated in each group. Differentially expressed proteins and pathways were screened using Olink Proteomics technology and the Kyoto Encyclopedia of Genes and Genomes (KEGG). The expression of key cytokine mRNAs, including Il17a, Ifng, and Il4, in the in vitro co-culture system of regulatory T cells (Treg) and microglia was detected using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Result (1) Significant differences in behavioral indicators were observed between the susceptible group and the control group. (2) Olink and KEGG enrichment analyses identified 4 common differentially expressed proteins (EBI3_IL27, LRIG1, NAGK, SPN) and 2 shared pathways (hsa04060 and hsa04657). (3) Co-culture experiments demonstrated that WAY100635 could block 5-HT-induced downregulation of Il17a and Ifng mRNA expression, as well as upregulation of Il4 mRNA. Conclusion In the CSDS model, 5-HT1A ⁺ Treg cells and their associated cytokine pathways may be the key mediators determining susceptibility to stress.