Demyelination of the amygdala mediates psychological stress-induced emotional disorders partially contributed by activation of P2X7R/NLRP3 cascade

Psychological stress can lead to emotional disorders, such as anxiety and depression; however, the underlying mechanisms are complicated and remain unclear. In this study, we established a mouse psychological stress model using an improved communication box, in which the psychologically stressed mice received visual, auditory, and olfactory emotional stimuli from the mice receiving electric foot shock, thus avoiding physical stress interference. After the 14-day psychological stress paradigm, our mice exhibited a significant increase in depressive and anxious behaviors. We then performed proteomic liquid chromatography-tandem mass spectrometry for proteomic data analysis of the amygdala, and the results demonstrated that differentially expressed proteins were more enriched in myelin-related biological processes, cellular components, and molecular functions, indicating a correlation between psychological stress-induced emotional disorders and amygdala myelin damage. Molecular and morphological evidence further confirmed that psychological stress damages myelin ultrastructure, downregulated myelin basic protein and proteolipid protein expression, and reduced oligodendrocyte proliferation in the amygdala. Moreover, clemastine, an antimuscarinic and antihistaminic compound that has been shown to enhance oligodendrocyte differentiation and myelination, rescued depressive behaviors accompanied by increased oligodendrogenesis. In the amygdala, psychological stress was also noted to activate microglia and increase the levels of NOD-like receptor protein 3 (NLRP3) and the proinflammatory cytokines interleukin 1β and tumor necrosis factor α, as indicated by ELISA and Western blot analyses. Moreover, in stressed mice, the administration of Brilliant Blue G, a purinergic ligand-gated ion channel 7 receptor (P2X7R) antagonist, completely reversed the increases in NLRP3 and cleaved caspase-1 levels and partially prevented amygdala myelin damage. In conclusion, amygdala demyelination may mediate psychological stress-induced emotional disorders, and P2X7R/NLRP3 cascade activation partially contributes to amygdala myelin damage after psychological stress.