Anti‐neuroinflammation effects of transcutaneous auricular vagus nerve stimulation against depression‐like behaviors via hypothalamic α7nAchR/JAK2/STAT3/NF‐κB pathway in rats exposed to chronic unpredictable mild stress

Abstract

Background Transcutaneous auricular vagus nerve stimulation (taVNS) is a vital neuromodulation for the treatment of depression, but its antidepressant molecular mechanism is unclear. The α7 nicotinic acetylcholine receptor (α7nAchR) 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 α7nAchR/JAK2/STAT3/NF‐κB 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 α7nAchR in the antidepressant effect of taVNS, we used α7nAchR−/− 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 α7nAchR, p‐JAK2, p‐STAT3, IL‐1β, NF‐κB p65, and p‐NF‐κB 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 α7nAchR, p‐JAK2, p‐STAT3, and upregulated expression of NF‐κB p65, p‐NF‐κB p65, and IL‐1β. TaVNS could significantly reverse the above‐mentioned phenomena, but had a poor improvement effect for CUMS‐exposed α7nAchR−/− rats. Conclusion The hypothalamic α7nAchR/JAK2/STAT3/NF‐κB signaling pathway may play an important role in the antidepressant‐like behavior of taVNS.

Quercetin alleviates chronic unpredictable mild stress‐induced depression‐like behavior by inhibiting NMDAR1 with α2δ‐1 in rats

“…The intake of sugar water was measured 2 h after administration of solutions. To avoid positional adaptation of rats, the positions of sucrose solution and pure water bottle were changed after 1 h 33 . The sucrose preference index was calculated using the formula shown below:$$$$ \mathrm{Sucrose}\ \mathrm{preference}\left(\%\right)=\frac{\mathrm{V}\left(\mathrm{sucrose}\ \mathrm{consumption}\right)}{\mathrm{V}\left(\mathrm{sucrose}\ \mathrm{consumption}+\mathrm{water}\ \mathrm{consumption}\right)}\times 100\% $$$$…”

“…The intake of sugar water was measured 2 h after administration of solutions. To avoid positional adaptation of rats, the positions of sucrose solution and pure water bottle were changed after 1 h. 33 The sucrose preference index was calculated using the formula shown below: …”

Transcutaneous auricular vagus nerve stimulation ameliorates adolescent depressive‐ and anxiety‐like behaviors via hippocampus glycolysis and inflammation response

“…The CUMS procedure was conducted according to the previously described protocol with a minor adjustment. 32 Rats from the Mod and taVNS groups were subjected to a range of stressors, encompassing various stimuli as follows: wet bedding for 24 h (200 mL of water per cage), day and night reversal for 24 h, cold swimming for 5 min (at 4°C), food deprivation for 24 h, water deprivation for 24 h, restrained for 24 h, tail nip for 1 min (1 cm from the end of the tail), and inversion of the light/dark cycle for 24 h. The rats were subjected to one of these stimulations randomly each day, with no consecutive application of the same stressor on 2 consecutive days in order to prevent the rats from predicting its occurrence. The control group remained undisturbed, except for necessary procedures such as routine cage cleaning.…”

Wenyang-Tianjing-Jieyu Decoction Improves Depression Rats of Kidney Yang Deficiency Pattern by Regulating T Cell Homeostasis and Inflammation Level

“…Activated JAK families can mediate STAT3 phosphorylation, causing Th17/Treg cell imbalance and eventually causing inflammation and depression. 48,49 TLR4/TRAF6/NF-κB signaling pathway is one of the important pathways for regulating specific immune inflammation, 50 inhibiting this pathway activation reduces inflammatory cytokine levels, weakens microglial overactivation, reduces neuroinflammation, and improves Th1/Th2 cell immune imbalance, alleviating chronic stress-induced depression-like behavior. [51][52][53] Therefore, lowering proinflammatory factor levels, increasing anti-inflammatory factor levels, and maintaining Th17/Treg and Th1/Th2 cell homeostasis are feasible mechanisms for alleviating depression.…”