Intermittent transcutaneous auricular vagus nerve stimulation reverses acute stress-induced memory deficits via O-GlcNAc modulation

In recent years, transcutaneous auricular vagus nerve stimulation (taVNS), as a non-invasive therapy, has been increasingly employed to ameliorate cognitive deficits. O-linked β-N-acetylglucosamine (O-GlcNAc) modification plays a crucial role in neuronal function and is closely related to stress responses and memory regulation. However, the impact of taVNS on O-GlcNAc modification and memory function under acute stress conditions remains unclear. This study aims to explore the effects of taVNS on memory impairment in acutely stressed mice and elucidate the potential mechanisms involving O-GlcNAc in this process. The results indicate that intermittent taVNS, compared to continuous taVNS, significantly improved memory function in acutely stressed mice, with the 5 Hz stimulation showing the most significant effect and effectively reducing O-GlcNAc levels in the hippocampus. Furthermore, bioinformatic analysis revealed that blocking O-GlcNAc led to abnormal activation of the STAT3 pathway. Subsequent biochemical analysis confirmed that intermittent taVNS modulated the expression of IL-6 and phosphorylated STAT3, suggesting that it protects memory function by mediating neuroinflammatory responses through the regulation of O-GlcNAc modification. Notably, the memory-protective effect of taVNS was significantly diminished after blocking hippocampal O-GlcNAc flux, supporting the hypothesis that taVNS safeguards memory function via O-GlcNAc modification. This study underscores the efficacy of intermittent 5 Hz taVNS in reversing acute stress-induced memory deficits. It highlights the pivotal role of O-GlcNAc modification in the hippocampus during this process, offering new insights for developing therapeutic strategies targeting stress-related cognitive disorders.