Mechanisms underlying antidepressant effect of transcutaneous auricular vagus nerve stimulation on CUMS model rats based on hippocampal α7nAchR/NF-κB signal pathway

Abstract

Background Stress-induced neuroinflammation was considered to play a critical role in the pathogenesis of depression. Transcutaneous auricular vagus nerve stimulation (taVNS) is a relatively non-invasive alternative treatment for patients suffering from major depressive disorder. The anti-inflammatory signal of vagus nerve is mediated by α7 nicotinic acetylcholine receptor (α7nAchR), and the hippocampus, the region with the most distribution of α7nAchR, regulates emotions. Here, we investigated the role of α7nAchR mediating hippocampal neuroinflammation in taVNS antidepressant effect though homozygous α7nAChR (−/−) gene knockout and α7nAchR antagonist (methyllycaconitine, MLA). Methods There were control, model, taVNS, α7nAChR(−/−) + taVNS, hippocampus (Hi) MLA + taVNS and Hi saline + taVNS groups. We used the chronic unpredicted mild stress (CUMS) method to establish depressive model rats for 42 days, excepting control group. After the successful modeling, except the control and model, the rats in the other groups were given taVNS, which was applied through an electroacupuncture apparatus at the auricular concha (2/15 Hz, 2 mA, 30 min/days) for 21 days. Behavioral tests were conducted at baseline, after modeling and after taVNS intervention, including sucrose preference test (SPT), open field test (OFT) and forced swimming test (FST). These tests are widely used to evaluate depression-like behavior in rats. The samples were taken after experiment, the expressions of α7nAchR, NF-κB p65, IL-1β and the morphology of microglia were detected. Results Depression-like behavior and hippocampal neuroinflammation in CUMS model rats were manifested by down-regulated expression of α7nAchR, up-regulated expression of NF-κB p65 and IL-1β, and the morphology of microglia was in amoebic-like activated state. TaVNS could significantly reverse the above-mentioned phenomena, but had rare improvement effect for α7nAChR(−/−) rats and Hi MLA rats. Conclusion The antidepressant effect of taVNS is related to hippocampal α7nAchR/NF-κB signal pathway.

Neuroinflammation mechanisms of neuromodulation therapies for anxiety and depression

“…α- and β-adrenergic receptor activators indirectly activate NF-kB [ 143 ], and α-adrenergic receptor blockers reduce stress-induced IL-6 elevation in peripheral blood in humans [ 144 ]. Parasympathetic excitation and acetylcholine release activate the A7 subunit of the nicotinic acetylcholine receptor (NAChR), which regulates the transcription and translation of cytokines and exerts anti-inflammatory effects [ 145 – 147 ]. Studies have shown a 42–53.1% two-year remission rate for refractory depression with VNS (≥50% reduction in HDRS scores from baseline) [ 148 , 149 ].…”

Novel Murine models of Mania and Depression

“…4). The amphetamine (AMP) model [25, 26] was established by intraperitoneal injection of 2.5 mg/kg amphetamine for 10 days. For the corticosterone (COR) model 20 mg/kg corticosterone was intraperitoneally injected for 28 days [15, 27].…”

Effects of auricular acupuncture stimulation on healthy adults’ upper limb motor-evoked potentials: A randomized, crossover, double-blind study

“…In that investigation, stimulation from the ear vagus branch traveled via the vagus nerve to the medulla oblongata, establishing an ear–brainstem connection. Several other studies using electric stimulation or TMS to stimulate the vagus have suggested that vagus fibers are distributed in the ear ( Fang et al, 2016 ; Zhang Y. et al, 2019 ; Luo et al, 2020 ; Wang et al, 2021 ; Zhang et al, 2021 ). Auricular acupuncture may influence the central nervous system through sensory circuitry, enhancing the excitability of the motor cortex through the sensory cortex.…”