Anti-neuroinflammation effects of transcutaneous auricular vagus nerve stimulation against depression-like behaviors via hypothalamic alpha 7nAchR/JAK2/STAT3/NF-kappa B pathway in rats exposed to chronic unpredictable mild stress

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) is a vital neuromodulation for the treatment of depression, but its antidepressant molecular mechanism is unclear. The alpha 7 nicotinic acetylcholine receptor (alpha 7nAchR) is a key mediator of the vagus nerve that mediates its anti-inflammatory efficacy. Here, we investigated whether the antidepressant effect of taVNS in chronic unpredicted mild stress (CUMS)-exposed rats works through the alpha 7nAchR/JAK2/STAT3/NF-kappa B pathway. Methods: The depression model was established by CUMS for continuous 6 weeks in rats. From the 4th week of the experiment, CUMS-exposed rats were subjected to taVNS for 3 weeks. To clarify the role of alpha 7nAchR in the antidepressant effect of taVNS, we used alpha 7nAchR(-/-) gene knockout rats. The sucrose preference test (SPT), open field test (OFT), and forced swimming test (FST) were used to evaluate depression-like behaviors of rats. Immunofluorescent staining was used to observe the morphology of microglia in the hypothalamus. Western blot was used to examine the protein expression of alpha 7nAchR, p-JAK2, p-STAT3, IL-1 beta, NF-kappa B p65, and p-NF-kappa B p65 in the hypothalamus. Results: Depression-like behaviors in CUMS-exposed rats were manifested by decreased SPT ratio, increased FST immobility time, decreased total distance, vertical movement score, and activity time of OFT. Hypothalamic neuroinflammation in CUMS-exposed rats was manifested by an amoebic-like activated state of microglia, downregulated expression of alpha 7nAchR, p-JAK2, p-STAT3, and upregulated expression of NF-kappa B p65, p-NF-kappa B p65, and IL-1 beta. TaVNS could significantly reverse the above-mentioned phenomena, but had a poor improvement effect for CUMS-exposed alpha 7nAchR(-/-) rats. Conclusion: The hypothalamic alpha 7nAchR/JAK2/STAT3/NF-kappa B signaling pathway may play an important role in the antidepressant-like behavior of taVNS.