The vagus nerve, also known as the tenth cranial nerve, is one of the 12 cranial nerves that emerge directly from the brain. It plays a crucial role in the parasympathetic nervous system, which regulates numerous unconscious bodily functions such as heart rate, digestion, and respiratory rate. Further, the vagus nerve has been implicated in the body’s response to stress. The activation of the vagus nerve can induce relaxation and calmness [12]. Consequently, despite the use of VNS for depression treatment, its precise mechanisms remain incompletely understood.

Information from several peripheral organs is relayed to the brain, particularly to the nucleus of the solitary tract (NTS) in the brainstem. The NTS is interconnected with various brain regions responsible for synthesizing specific neurotransmitters, including the locus coeruleus, which produces norepinephrine, the dorsal raphe nucleus, which synthesizes serotonin, and the VTA, which produces DA [13]. This suggests that VNS can be used to treat various neuropsychiatric disorders, including depression, by modulating these neurotransmitter systems throughout the brain.

Although previous studies have reported that invasively implanted VNS induces an antidepressant effect [14, 15] and activates VTADA [16], whether and how non-invasive taVNS elicits an antidepressant effect currently remains unclear. Invasive VNS is effective for treating various neuropsychiatric disorders and has sustained therapeutic effects. However, it carries the risks of surgery, including infection, pain, and high cost [17]. Conversely, taVNS offers a non-invasive approach without the need for surgical procedures, along with high levels of safety, ease of use, and relatively low cost [18].

Overall, our findings suggest that taVNS in anesthetized mice triggers antidepressant effects by enhancing VTADA activity. Further investigation is required to identify the specific brain regions where the heightened VTADA activity induced by taVNS results in increased DA release and whether this contributes to the antidepressant effect. Furthermore, preclinical validation in animal models of depression is essential to confirm whether taVNS is effective for clinical application based on the mechanisms we have elucidated.