Original Articles

Transcutaneous auricular vagus nerve stimulation improves emotional and cognitive functions in post-traumatic stress disorder rats through anti-inflammation, neuroprotection, and modulation of the hippocampal nuclear factor erythroid 2-related factor 2-heme oxygenase-1-glutathione peroxidase 4 pathway

  • ZHENG Yanfeng ,
  • ZHANG Xinjiang ,
  • ZHANG Xiaomeng ,
  • LI Xiangji ,
  • XIN Chen ,
  • KONG Jingwei ,
  • WANG Xin ,
  • SUN Lan ,
  • RONG Peijing
Expand
  • 1 Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China
    2 Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China
    3 Department of Gastroenterology, State Key Laboratory of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
    4 Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
SUN Lan, Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China. sunlan462@163.com;
RONG Peijing, Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China. drrongpj@163.com; Telephone: +86-18022386176

Received date: 2025-10-16

  Accepted date: 2026-02-05

  Online published: 2026-04-04

Supported by

Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences Neurobiophysical Investigation on the Amelioration of Post-traumatic Stress Disorder through Transcutaneous Auricular Electromagnetic Stimulation in the THz Frequency Range(CI2023C017YL);National Natural Science Foundation of China Explore the Mechanism by which Transcutaneous Auricular Vagus Nerve Stimulation Improves Depressive Behaviors Based on the Sirtuin 1/Nuclear Factor Erythroid 2-related Factor 2/Glutathione Peroxidase 4 Signaling Pathway(82304914)

Abstract

OBJECTIVE: To investigate the role and potential molecular mechanisms of transcutaneous auricular vagus nerve stimulation (taVNS) in post-traumatic stress disorder (PTSD).

METHODS: A single prolonged stress (SPS) model of PTSD was used to conduct behavioral tests and evaluate the effects of taVNS on the emotion-cognitive function in PTSD animals. Focusing on the prefrontal cortex-hippocampus brain region, we systematically evaluated the growth status of neurons and astrocytes, as well as the level of microglial-mediated neuroinflammation. Key indicators of the nuclear factor erythroid 2-related (NRF2)-heme oxygenase-1 (HO-1)-glutathione peroxidase 4 (GPX4) signaling pathway were detected and analyzed. Additionally, immune and oxidative stress levels in peripheral plasma were also assessed.

RESULTS: Two weeks of taVNS significantly improved the abnormal emotion-cognitive function in PTSD animals and partially inhibited peripheral oxidative stress injury and immune-inflammatory responses. Compared with the prefrontal cortex, taVNS markedly alleviated hippocampal neuron loss, microglial activation, and astrocyte dysfunction in PTSD rats, suggesting that the NRF2-HO-1-GPX4 signaling pathway may play a critical role in this process.

CONCLUSION: taVNS extensively modulates the functions of neurons and glial cells by regulating both central and peripheral oxidative stress and immune-inflammatory responses, thereby ameliorating the abnormal emotional and cognitive functions observed in PTSD animals.

Cite this article

ZHENG Yanfeng , ZHANG Xinjiang , ZHANG Xiaomeng , LI Xiangji , XIN Chen , KONG Jingwei , WANG Xin , SUN Lan , RONG Peijing . Transcutaneous auricular vagus nerve stimulation improves emotional and cognitive functions in post-traumatic stress disorder rats through anti-inflammation, neuroprotection, and modulation of the hippocampal nuclear factor erythroid 2-related factor 2-heme oxygenase-1-glutathione peroxidase 4 pathway[J]. Journal of Traditional Chinese Medicine, 2026 , 46(2) : 326 -338 . DOI: 10.19852/j.cnki.jtcm.2026.02.006

References

1. Maercker A, Cloitre M, Bachem R, et al. Complex post-traumatic stress disorder. Lancet 2022; 400: 60-72.
2. Morina N, Ford JD, Risch AK, Morina B, Stangier U. Somatic distress among Kosovar civilian war survivors: relationship to trauma exposure and the mediating role of experiential avoidance. Soc Psychiatry Psychiatr Epidemiol 2010; 45: 1167-77.
3. Morina N, Ford JD. Complex sequelae of psychological trauma among Kosovar civilian war victims. Int J Soc Psychiatry 2008; 54: 425-36.
4. Cao C, Wang L, Fang R, et al. Anxiety, depression, and PTSD symptoms among high school students in china in response to the COVID-19 pandemic and lockdown. J Affect Disord 2022; 296: 126-9.
5. McLaughlin KA, Koenen KC, Friedman MJ, et al. Subthreshold posttraumatic stress disorder in the world health organization world mental health surveys. Biol Psychiatry 2015; 77: 375-84.
6. Steenkamp MM, Litz BT, Hoge CW, Marmar CR. Psychotherapy for military-related PTSD: a review of randomized clinical trials. JAMA 2015; 314: 489-500.
7. Shalev A, Liberzon I, Marmar C. Post-traumatic stress disorder. N Engl J Med 2017; 376: 2459-69.
8. Innamorato NG, Rojo AI, García-Yagüe AJ, Yamamoto M, de Ceballos ML, Cuadrado A. The transcription factor Nrf2 is a therapeutic target against brain inflammation. J Immunol 2008; 181: 680-9.
9. Grasser LR, Javanbakht A. Treatments of posttraumatic stress disorder in civilian populations. Curr Psychiatry Rep 2019; 21: 11.
10. Santhanam P, Teslovich T, Wilson SH, Yeh PH, Oakes TR, Weaver LK. Decreases in white matter integrity of ventro-limbic pathway linked to post-traumatic stress disorder in mild traumatic brain injury. J Neurotrauma 2019; 36: 1093-8.
11. Kasai K, Yamasue H, Gilbertson MW, Shenton ME, Rauch SL, Pitman RK. Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder. Biol Psychiatry 2008; 63: 550-6.
12. Bremner JD. Traumatic stress: effects on the brain. Dialogues Clin Neurosci 2006; 8: 445-61.
13. Ressler KJ, Berretta S, Bolshakov VY, et al. Post-traumatic stress disorder: clinical and translational neuroscience from cells to circuits. Nat Rev Neurol 2022; 18: 273-88.
14. Pitman RK, Rasmusson AM, Koenen KC, et al. Biological studies of post-traumatic stress disorder. Nat Rev Neurosci 2012; 13: 769-87.
15. Shin LM, McNally RJ, Kosslyn SM, et al. Regional cerebral blood flow during script-driven imagery in childhood sexual abuse-related PTSD: a PET investigation. Am J Psychiatry 1999; 156: 575-84.
16. Gold AL, Shin LM, Orr SP, et al. Decreased regional cerebral blood flow in medial prefrontal cortex during trauma-unrelated stressful imagery in Vietnam veterans with post-traumatic stress disorder. Psychol Med 2011; 41: 2563-72.
17. Rojo AI, McBean G, Cindric M, et al. Redox control of microglial function: molecular mechanisms and functional significance. Antioxid Redox Signal 2014; 21: 1766-801.
18. Wishart DS, Tzur D, Knox C, et al. HMDB: the Human Metabolome Database. Nucleic Acids Res 2007; 35: D521-6.
19. Miller MW, Sadeh N. Traumatic stress, oxidative stress and post-traumatic stress disorder: neurodegeneration and the accelerated-aging hypothesis. Mol Psychiatry 2014; 19: 1156-62.
20. Katrinli S, Maihofer AX, Wani AH, et al. Epigenome-wide Meta-analysis of PTSD symptom severity in three military cohorts implicates DNA methylation changes in genes involved in immune system and oxidative stress. Mol Psychiatry 2022; 27: 1720-8.
21. Peruzzolo TL, Pinto JV, Roza TH, et al. Inflammatory and oxidative stress markers in post-traumatic stress disorder: a systematic review and Meta-analysis. Mol Psychiatry 2022; 27: 3150-63.
22. Tang C, Gao J, Li S, et al. Chlorogenic acid improves SPS-induced PTSD-like behaviors in rats by regulating the crosstalk between Nrf2 and NF-κB signaling pathway. Free Radic Biol Med 2025; 231: 136-52.
23. J?tc? G, Stoicescu R, Májai E. Cannabidiol Treatment in a predator-based animal model of PTSD: assessing oxidative stress and memory performance. Int J Mol Sci 2025; 26: 4491.
24. Liu J, Litt L, Segal MR, Kelly MJ, Pelton JG, Kim M. Metabolomics of oxidative stress in recent studies of endogenous and exogenously administered intermediate metabolites. Int J Mol Sci 2011; 12: 6469-501.
25. Taira J, Ogi T. Induction of antioxidant protein HO-1 through Nrf2-ARE signaling due to pteryxin in peucedanum japonicum thunb in RAW264.7 macrophage cells. Antioxidants (Basel) 2019; 8: 621.
26. Richter-Levin G, Stork O, Schmidt MV. Animal models of PTSD: a challenge to be met. Mol Psychiatry 2019; 24: 1135-56.
27. Koo JW, Duman RS. IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci U S A 2008; 105: 751-6.
28. Maier SF, Watkins LR. Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol Rev 1998; 105: 83-107.
29. Faborode OS, Dalle E, Mabandla MV. Exposure to footshock stress downregulates antioxidant genes and increases neuronal apoptosis in an Aβ(1-42) rat model of Alzheimer’s disease. Neurochem Int 2021; 150: 105170.
30. Muhie S, Gautam A, Yang R, et al. Molecular signatures of post-traumatic stress disorder in war-zone-exposed veteran and active-duty soldiers. Cell Rep Med 2023; 4: 101045.
31. Austelle CW, O’Leary GH, Thompson S, et al. A comprehensive review of vagus nerve stimulation for depression. Neuromodulation 2022; 25: 309-15.
32. Badran BW, Dowdle LT, Mithoefer OJ, et al. Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation (taVNS) via electrical stimulation of the tragus: a concurrent taVNS/fMRI study and review. Brain Stimul 2018; 11: 492-500.
33. Chen Y, Zhang Y, Wang J, et al. 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. CNS Neurosci Ther 2023; 29: 2634-44.
34. Wang L, Zhang J, Guo C, et al. The efficacy and safety of transcutaneous auricular vagus nerve stimulation in patients with mild cognitive impairment: a double blinded randomized clinical trial. Brain Stimul 2022; 15: 1405-14.
35. Zhang S, Zhao Y, Qin Z, et al. Transcutaneous auricular vagus nerve stimulation for chronic insomnia disorder: a randomized clinical trial. JAMA Netw Open 2024; 7: e2451217.
36. Wang JY, Zhang Y, Chen Y, et al. Mechanisms underlying antidepressant effect of transcutaneous auricular vagus nerve stimulation on CUMS model rats based on hippocampal α7nAchR/NF-κB signal pathway. J Neuroinflammation 2021; 18: 291.
37. Siracusa R, Paola RD, Cuzzocrea S, Impellizzeri D. Fibromyalgia: pathogenesis, mechanisms, diagnosis and treatment options update. Int J Mol Sci 2021; 22: 3891.
38. Daskalakis NP, Iatrou A, Chatzinakos C, et al. Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood. Science 2024; 384: eadh3707.
39. Cai M, Tong L, Dong B, Hou W, Shi L, Dong H. Kelch-like ECH-associated protein 1-dependent nuclear factor-E2-related factor 2 activation in relation to antioxidation induced by sevoflurane preconditioning. Anesthesiology 2017; 126: 507-21.
40. Yang W, Wang Y, Zhang C, et al. Maresin1 protect against ferroptosis-induced liver injury through ROS inhibition and Nrf2/HO-1/GPX4 activation. Front Pharmacol 2022; 13: 865689.
41. Xie P, Chen L, Wang J, Wang X, Yang S, Zhu G. Polysaccharides from polygonatum cyrtonema Hua prevent post-traumatic stress disorder behaviors in mice: mechanisms from the perspective of synaptic injury, oxidative stress, and neuroinflammation. J Ethnopharmacol 2024; 319: 117165.
42. Zhang JB, Lu GD, Sun DN, et al. Pellitorine protects chronic restraint stress-induced cognitive deficits via inhibiting neural inflammation and ferroptosis. Int Immunopharmacol 2025; 162: 115166.
43. Wang Z, Lai C, Shen B, et al. Effects of evodiamine on behavior and hippocampal neurons through inhibition of angiotensin-converting enzyme and modulation of the renin angiotensin pathway in a mouse model of post-traumatic stress disorder. Nutrients 2024; 16: 1957.
44. Dang R, Wang M, Li X, et al. Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx 4 pathway. J Neuroinflammation 2022; 19: 41.
45. Paciello F, Pisani A, Rolesi R, et al. Oxidative stress and inflammation cause auditory system damage via glial cell activation and dysregulated expression of gap junction proteins in an experimental model of styrene-induced oto/neurotoxicity. J Neuroinflammation 2024; 21: 4.
46. Romero-Miguel D, Casquero-Veiga M, MacDowell KS, et al. A Characterization of the effects of minocycline treatment during adolescence on structural, metabolic, and oxidative stress parameters in a maternal immune stimulation model of neurodevelopmental brain disorders. Int J Neuropsychopharmacol 2021; 24: 734-48.
47. Lu S, Ge Q, Yang M, et al. Decoupling the mutual promotion of inflammation and oxidative stress mitigates cognitive decline and depression-like behavior in rmTBI mice by promoting myelin renewal and neuronal survival. Biomed Pharmacother 2024; 173: 116419.
48. Jiang M, Zhang C, Chen J, et al. Unveiling aging and Alzheimer’s disease-associated dynamics of LINE1 DNA content and protein expression in mouse brains. Aging Cell 2025; 24: e70296.
49. Morera PMA, Beserra-Filho JIA, Soares-Silva B, et al. Mixed granulocytic airway inflammation impairs aversive learning and alters neuroimmune biomarkers in mice. Sci Rep 2025; 15: 39804.
50. Dionisie V, Ciobanu AM, Toma VA, et al. Escitalopram targets oxidative stress, Caspase-3, BDNF and MeCP2 in the hippocampus and frontal cortex of a rat model of depression induced by chronic unpredictable mild stress. Int J Mol Sci 2021; 22: 7483.
51. Li Y, Li L, Wang Y, et al. Cholinergic signaling to CA1 astrocytes controls fear extinction. Sci Adv 2025; 11: eads7191.
52. Jamnicki-Abegg M, Weihrauch D, Pagel PS, et al. Isoflurane inhibits cardiac myocyte apoptosis during oxidative and inflammatory stress by activating Akt and enhancing Bcl-2 expression. Anesthesiology 2005; 103: 1006-14.
53. Qi YF, Liu Y, Liu YY, Li YY, et al. Therapeutic potential of Traditional Chinese Medicine Yisui Shengxue pills to inhibit hypoxia-inducible factor-1alpha and general control nonderepressible 2 to regulate the post-chemotherapy immune response: integrating network pharmacology and experimental validation. J Tradit Chin Med 2025; 45: 1087-97.
54. Wang RQ, Hao LY, Lu Y, et al. Mechanism analysis of Tongqiao Yizhi decoction in treating vascular dementia rats by brain tissue untargeted metabonomics and fecal 16S rRNA gene sequencing. J Tradit Chin Med 2025; 45: 759-69.
Outlines

/