Transcutaneous auricular vagus nerve stimulation : unveiling its underlying neural mechanisms and potential for alleviating depression

Abstract

Depression is a highly prevalent neuropsychiatric illness and one of the leading causes of health-related disease burden. The COVID-19 pandemic has exacerbated the detrimental conditions for depression, with an enormous upsurge in cases. The unsatisfactory response of depression episodes to currently available treatments poses a major clinical and socioeconomic problem. The complex pathophysiology of depression may involve multiple central and peripheral nervous systems, resulting in challenges to treating it effectively. Therefore, alternative therapeutic strategies are needed to target multiple depression-related mechanisms for improving treatment efficiency. Transcutaneous auricular vagus nerve stimulation (taVNS) is a novel and promising non-invasive technique for treating depression. Here, we investigated the antidepressant-like activities of chronic taVNS and its potential mechanisms related to the regulation of the hypothalamic-pituitary-adrenal axis, hippocampal neurotransmission, metabolisms, and neuroplasticity, and modulation of the gut-brain axis in a chronic restraint stress (CRS) mouse model of depression. Moreover, we examined whether the chronic taVNS-induced antidepressant-like activity was dependent on monoaminergic neurotransmission. In our study, 10-week-old male C57BL/6J mice were subjected to 6 h daily restraint stress for 3 weeks. Mice with taVNS (n=8-10/group) received 30 min of taVNS at stimulation parameters (frequency: 20 Hz; pulse width: 300 μs; amplitudes: 250, 500, or 1000 μA) for 3 weeks, while the taVNS-sham received no electrical stimulation. CRS-mice (n=10) were intraperitoneally injected with vortioxetine for 3 weeks daily to compare its antidepressant-like effects with taVNS. All groups were compared with non-CRS-sham as a control group to validate the CRS model and to examine the treatment effects in rescuing the depressive-like symptoms induced by CRS. Behavioural tests were conducted after 3 weeks of taVNS and we found that 250 μA taVNS induced a remarkable antidepressant-like effect in the CRS mouse model. Strikingly, we demonstrated that taVNS reduced the plasma levels of corticosterone and adrenocorticotropic hormones, as well as hippocampal Crh expression, while increasing hippocampal Nr3c2 expression. These findings were further supported by normalisation of hippocampal levels of various monoamine neurotransmitters (e.g., dopamine, serotonin, and norepinephrine) and receptors, as well as metabolites related to essential amino acid and energy metabolism functions. Interestingly, hippocampal concentration of lactic acid was elevated by chronic taVNS. These modulations by chronic taVNS potentially contributed to its adult hippocampal neurogenesis-enhancing effect. Furthermore, Lactobacillus—a genus that might mediate vagus nerve-dependent GABA neurotransmission—was found enriched by chronic taVNS. Finally, the chronic taVNS-induced antidepressant-like activity was dependent on dopaminergic, serotonergic, and noradrenergic systems. These findings revealed that taVNS alleviates depression by regulating the hypothalamic-pituitary-adrenal axis, hippocampal neurotransmission, energy metabolism and neurogenesis, as well as the gut-brain axis. Overall, our study provides a comprehensive mechanistic insight into the antidepressant-like effects induced by taVNS, shedding light on potential therapeutic strategies for managing depression, and contributing to our understanding of the neuromodulating effects of taVNS, particularly in the hippocampus and gut.