Transcutaneous auricular vagus nerve stimulation might reduce fear memory in fear-conditioned mice through an anti-neuroinflammatory mechanism

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To the Editor: Posttraumatic stress disorder (PTSD), a severe psychiatric disorder post-trauma, is closely linked to fear memory.[1] Current treatments like selective serotonin reuptake inhibitors have limited effectiveness and side effects, necessitating new non-invasive approaches. PTSD often co-occurs with depression, and both are connected to inflammatory system disruptions, with increased proinflammatory cytokines in patients.[2,3] Transcutaneous auricular vagus nerve stimulation (taVNS) shows promise for treating depression by reducing neuroinflammation.[4] taVNS combines traditional Chinese medicine auricular acupuncture and neuroanatomy, targeting the auricular branch of the vagus nerve to influence brain regions like the thalamus and hippocampus. This study hypothesizes that taVNS may reduce fear memory among fear-conditioned mice through the modulation of inflammatory responses. We utilized a fear-conditioning mouse model to evaluate the impact on freezing behavior and quantify inflammatory markers, including corticosterone, interleukin-10 (IL-10) and interleukin-1β (IL-1β), within both serum and brain regions. In this study, the effects of taVNS in fear-conditioning PTSD mouse model were tested. Twelve-week-old C57BL/6J mice were provided by Beijing SPF Biotechnology Co., Ltd., Beijing, China. All animal experiments were approved by the Ethics Committee for Animal Experiments of Beijing Tongren Hospital, Capital Medical University (No. TRLAWEC2024-25). For detailed experimental methods, refer to the Supplementary File, https://links.lww.com/CM9/C239. The impact of taVNS on fear memory in fear-conditioned mice was examined, with mice divided randomly into control and taVNS groups [Figure 1A]. Initial freezing times were equivalent across groups in Context A (the 1st conditioned stimulus [CS]; Figure 1B), and no statistically significant differences in freezing time were observed during the final CS in Context A (the 10th CS; Figure 1C), suggesting similar fear memory levels. However, taVNS significantly reduced freezing time in Context A after two treatments [Figure 1D]. Auditory-cued fear memory was also diminished in taVNS mice compared to controls on the 5th and 7th days in Context B [Figure 1E, F]. Depression-like behaviors were assessed using the open field test (OFT) after taVNS treatment on the 3rd day. Locomotor activity was accounted for, showing no difference in total distance traveled [Figure 1G]. Yet, taVNS increased both the total distance [Figure 1H] and time traveled [Figure 1I] in the central zone, indicating reduced depression-like behaviors.Figure 1: The effect of taVNS on fear memory and improve neuroinflammation in fear-conditioned mice. (A) The experimental flowchart. (B) The baseline percentage (the 1st CS) of freezing time was similar between the two groups of mice in Context A (n = 18). (C) The fear conditioning for the 10th CS was comparable between the two groups in Context A (n = 18). (D) After two taVNS treatments, the percentage of freezing time induced by the contextual stimulus in Context A was significantly decreased (n = 18). (E, F) In Context B, the percentage of freezing time in the taVNS group was significantly shorter than that in the control group on the 5th and 7th days (n = 18). (G) There was no significant difference in the total distance traveled in the OFT (n = 18). (H, I) taVNS significantly increased the total distance traveled and the total time spent traveling in the central zone (n = 18). (J, K) taVNS significantly increased the serum concentration of corticosterone and the anti-inflammatory factor IL-10 in fear-conditioned mice (n = 12). (L) taVNS decreased the level of the proinflammatory factor IL-1β in the serum of fear-conditioned mice (n = 8). (M, N) taVNS increased the level of the anti-inflammatory factor IL-10 and decreased the level of the proinflammatory factor IL-1β in the hypothalamus (n = 8). (O, P) taVNS increased the level of the anti-inflammatory factor IL-10 and decreased the level of the proinflammatory factor IL-1β in the hippocampus (n = 8). The data are shown as the mean ± SEM; unpaired Student’s t-test, * P <0.05, † P <0.01, ‡ P <0.001 vs. the control group. CS: Conditioned stimulus; IL-1β: Interleukin-1β; IL-10: Interleukin-10; ns: Not significant; OFT: Open field test; SEM: Standard error of the mean; taVNS: Transcutaneous auricular vagus nerve stimulation; US: Unconditioned stimulus.Enzyme-linked immunosorbent assays (ELISAs) measured serum levels of corticosterone, IL-1β, and IL-10 to evaluate the systemic inflammatory response. taVNS increased corticosterone and IL-10 while decreasing IL-1β compared to the control group [Figure 1J–L]. Given the hypothalamus’s role in PTSD and the hypothalamic–pituitary–adrenal (HPA) axis, central inflammation was assessed. taVNS increased IL-10 and decreased IL-1β in the hypothalamus [Figure 1M, N], suggesting a modulation of inflammation. Neuroinflammation in the hippocampus, relevant to PTSD, was also tested. taVNS treatment enhanced IL-10 and reduced IL-1β levels, indicating anti-inflammatory effects [Figure 1O,P]. This pioneering study explores the impact of taVNS on fear memory in fear-conditioned mice, hypothesizing a potential anti-neuroinflammatory mechanism. Our results show that taVNS significantly reduced both contextual and auditory-cued fear memory. This was reflected in an increased total distance traveled and time spent in the central zone during the OFT, indicating a reduction in fear memory without affecting motor activity. Serum analysis revealed increased corticosterone and IL-10, and decreased IL-1β following taVNS, suggesting an anti-inflammatory response. Consistent with this, the hypothalamus and hippocampus exhibited increased IL-10 and reduced IL-1β levels, pointing to a neuroinflammatory modulation. The study utilizes the fear-conditioned mouse model, crucial for PTSD research, employing contextual fear memory tests post taVNS treatments. The OFT ruled out the influence of taVNS on locomotor activity, confirming its specific effect on fear memory. While previous clinical studies have indicated the potential of taVNS in treating PTSD,[5] this study is conducted to explore its mechanisms, suggesting that taVNS might offer antidepressant effects by reducing neuroinflammation in the hippocampus and hypothalamus. The vagus nerve’s stimulation by taVNS is believed to regulate immune activity, thereby influencing inflammation and supporting its antidepressant properties. Our findings encourage further investigation. Though promising, the need for larger clinical trials and deeper research is essential to establish taVNS as a potential PTSD treatment by modulating neuroinflammatory responses. Given PTSD’s complexity, a multifaceted approach including psychotherapy and pharmacotherapy may benefit from the addition of non-invasive methods like taVNS. In conclusion, our data showed that taVNS might reduce fear memory in fear-conditioned mice, at least in part through an anti-neuroinflammatory mechanism. Furthermore, taVNS is worth studying for its potential as a treatment for PTSD and other mental disorders characterized by fear memory. Funding This work was supported by grants from the priming scientific research foundation for the junior researcher in Beijing Tongren Hospital, Capital Medical University (No. 2023-YJJ-ZZL-018), the National Natural Science Foundation of China (No. 82270411), the Beijing Hospitals Authority’s Ascent Plan (No. DFL20220203), and the Capital’s Funds for Health Improvement and Research (No. CFH2024-2-2058). Conflicts of interest None.

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