Scalp electroacupuncture targeting trigeminal nerve activation alleviates post-traumatic stress disorder–induced depression and neuroinflammation in mice

Bombi Lee , Yoongeun Kim , Hyungjun Kim , Dae-Hyun Hahm

Animal Models and Experimental Medicine ›› 2026, Vol. 9 ›› Issue (5) : 991 -1001.

PDF (2932KB)
Animal Models and Experimental Medicine ›› 2026, Vol. 9 ›› Issue (5) :991 -1001. DOI: 10.1002/ame2.70164
ORIGINAL ARTICLE
Scalp electroacupuncture targeting trigeminal nerve activation alleviates post-traumatic stress disorder–induced depression and neuroinflammation in mice
Author information +
History +
PDF (2932KB)

Abstract

Background: Scalp electroacupuncture (SA) has been clinically used as a novel treatment for ischemic stroke and depression. This study aimed to investigate whether stimulation of SA of the Baihui (GV20) and Yintang (EX-HN3) acupoints, which regulate the trigeminal nerve (TN), can alleviate depression and anxiety caused by post-traumatic stress disorder (PTSD) and to identify its therapeutic mechanism.

Methods: After stimulation of SA, vasodilation and leakage within the TN area and c-Fos expression in the TN pathway of the brain were analyzed. Also, the anti-inflammatory, antidepressant, and anxiolytic effects of SA were investigated in a mouse model of PTSD induced by single prolonged stress.

Results: SA activated the TN pathway, inducing vasodilation along the TN pathway, and increased c-Fos expression in the brain, including the spinal trigeminal nucleus, locus coeruleus (LC), amygdala, and entorhinal cortex. SA significantly alleviated depression- and anxiety-related behaviors, decreased pro-inflammatory cytokines, and increased the expression of neurotrophic factors in the hippocampus. Also, SA decreased the expression of P2X7 receptors in the microglia and norepinephrine transporter in the LC and hippocampus.

Conclusions: These results demonstrated that SA exhibited anti-inflammatory, antidepressant, and anxiolytic effects through the P2X7 receptor pathway and the LC-norepinephrine system.

Keywords

anti-inflammation / depression / post-traumatic stress disorder / scalp electroacupuncture / trigeminal nerve

Cite this article

Download citation ▾
Bombi Lee, Yoongeun Kim, Hyungjun Kim, Dae-Hyun Hahm. Scalp electroacupuncture targeting trigeminal nerve activation alleviates post-traumatic stress disorder–induced depression and neuroinflammation in mice. Animal Models and Experimental Medicine, 2026, 9 (5) : 991-1001 DOI:10.1002/ame2.70164

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

Thakur A, Coudhary D, Kumar B, Chaudhary A. A review on post-traumatic stress disorder (PTSD): symptoms, therapies and recent case studies. Curr Mol Pharmacol. 2022; 15: 502-516.

[2]

Flory JD, Yehuda R. Comorbidity between post-traumatic stress disorder and major depressive disorder: alternative explanations and treatment considerations. Dialogues Clin Neurosci. 2015; 17: 141-150.

[3]

Muhie S, Gautam A, Chakraborty M, et al. Molecular indicators of stress-induced neuroinflammation in a mouse model simulating features of post-traumatic stress disorder. Transl Psychiatry. 2017; 5:e1135.

[4]

Kim TD, Lee S, Yoon S. Inflammation in post-traumatic stress disorder (PTSD): a review of potential correlates of PTSD with a neurological perspective. Antioxidants. 2020; 9: 107-129.

[5]

Zhao YF, Tang Y, Illes P. Astrocytic and oligodendrocytic P2X7 receptors determine neuronal functions in the CNS. Front Mol Neurosci. 2021; 14:6415701.

[6]

Ribeiro DE, Roncalho AL, Glaser T, Ulrich H, Wegener G, Joca S. P2X7 receptor signaling in stress and depression. Int J Mol Sci. 2019; 20:2778.

[7]

Torres-Rodríguez O, Rivera-Escobales Y, Castillo-Ocampo Y, Velazquez B, Colón M, Porter JT. Purinergic P2X7 receptor-mediated inflammation precedes PTSD-related behaviors in rats. Brain Behav Immun. 2023; 10: 107-118.

[8]

Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2020; 53: 865-871.

[9]

Mansari ME, Crnic A, Oosterhof C, Blier P. Long-term administration of the antidepressant vilazodone modulates rat brain monoaminergic systems. Neuropharmacology. 2015; 99: 696-704.

[10]

Trevizol AP, Sato IA, Cook IA, Shiozawa P, Lowenthal R, Cordeiro Q. Trigeminal nerve stimulation (TNS) for posttraumatic stress disorder and major depressive disorder: an open-label proof-of-concept trial. Epilepsy Behav. 2016; 60: 240-241.

[11]

Koizumi M, Asano S, Furukawa A, et al. P2X3 receptor upregulation in trigeminal ganglion neurons through TNFα production in macrophages contributes to trigeminal neuropathic pain in rats. J Headache Pain. 2021; 22:31.

[12]

Wang C, Wang J, Wu X, et al. Comprehensive review on sexual dimorphism to improve scalp acupuncture in nervous system disease. CNS Neurosci Ther. 2024; 30:e14447.

[13]

Jin GY, Jin LL, Jin BX, Zheng J, He BJ, Li SJ. Neural control of cerebral blood flow: scientific basis of scalp acupuncture in treating brain diseases. Front Neurosci. 2023; 15:1210537.

[14]

Jiang H, Chen L, Li Y, et al. Effects of acupuncture on regulating the hippocampal inflammatory response in rats exposed to post-traumatic stress disorder. Neurosci Lett. 2023; 796:137056.

[15]

Tu M, Xiong S, Lv S, et al. Acupuncture for major depressive disorder: a data mining-based literature study. Neuropsychiatr Dis Treat. 2023; 19: 1069-1084.

[16]

Li Q, Yue N, Liu SB, et al. Effects of chronic electroacupuncture on depression- and anxiety-like behaviors in rats with chronic neuropathic pain. Evid Based Complement Alternat Med. 2024; 2014:158987.

[17]

DeGiorgio CM, Fanselow EE, Schrader LM, Cook IA. Trigeminal nerve stimulation: seminal animal and human studies for epilepsy and depression. Neurosurg Clin N Am. 2011; 22: 449-456.

[18]

Li W, Zhu Y, Saud SM, et al. Electroacupuncture relieves depression-like symptoms in rats exposed to chronic unpredictable mild stress by activating ERK signaling pathway. Neurosci Lett. 2017; 642: 43-50.

[19]

Wang S, Liu K, Wang Y, et al. A proposed neurologic pathway for scalp acupuncture: trigeminal nerve-meninges-cerebrospinal fluid-contacting neurons-brain. Med Acupunct. 2017; 29: 322-326.

[20]

Lee B, Yang CH, Hahm DH, et al. Inhibitory effects of ginseng total saponins on behavioral sensitization and dopamine release induced by cocaine. Biol Pharm Bull. 2008; 31: 436-441.

[21]

Sur B, Lee B. Ginsenoside Rg3 modulates spatial memory and fear memory extinction by the HPA axis and BDNF-TrkB pathway in a rat post-traumatic stress disorder. J Nat Med. 2022; 76: 821-831.

[22]

Oh JY, Kim YK, Kim SN, et al. Acupuncture modulates stress response by the mTOR signaling pathway in a rat post-traumatic stress disorder model. Sci Rep. 2018; 8: 11864-11880.

[23]

Lin D, Gao J, Lu M, et al. Scalp acupuncture regulates functional connectivity of cerebral hemispheres in patients with hemiplegia after stroke. Front Neurol. 2023; 25:1083066.

[24]

Li S, Dai A, Zhou Y, et al. Efficacy of combination scalp acupuncture for post-stroke cognitive impairment: a systematic review and meta-analysis. Front Neurosci. 2024; 29:1468331.

[25]

Takagi K, Tanahashi N, Amagasu N, Mizuno K, Kawanokuchi J, Ishida T. Effect of manual acupuncture stimulation at “Bai-Hui” (GV 20) or “Yintáng” (Ex-HN3) on depressed rats. J Acupunct Meridian Stud. 2017; 10: 26-32.

[26]

Mercante B, Enrico P, Floris G, et al. Trigeminal nerve stimulation induces Fos immunoreactivity in selected brain regions, increases hippocampal cell proliferation and reduces seizure severity in rats. Neuroscience. 2017; 361: 69-80.

[27]

Wang S, Wang J, Liu K, et al. Signaling interaction between facial and meningeal inputs of the trigeminal system mediates peripheral neurostimulation analgesia in a rat model of migraine. Neuroscience. 2020; 1: 184-199.

[28]

Sanders RD. The trigeminal (V) and facial (VII) cranial nerves: head and face sensation and movement. Psychiatry (Edgmont). 2010; 7: 13-16.

[29]

Hassamal S. Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories. Front Psychiatry. 2023; 14:1130989.

[30]

Zhang LW, Cui CA, Liu C, et al. Auraptene-ameliorating depressive-like behaviors induced by lipopolysaccharide combined with chronic unpredictable mild stress in mice mitigate hippocampal neuroinflammation mediated by microglia. Int Immunopharmacol. 2024; 136:12330.

[31]

Chiluwal A, Narayan RK, Chaung W, et al. Neuroprotective effects of trigeminal nerve stimulation in severe traumatic brain injury. Sci Rep. 2017; 7:6792.

[32]

Ito G, Suekawa Y, Watanabe M, et al. P2X7 receptor in the trigeminal sensory nuclear complex contributes to tactile allodynia/hyperalgesia following trigeminal nerve injury. Eur J Pain. 2013; 17: 185-199.

[33]

Bhattacharya A. Recent advances in CNS P2X7 physiology and pharmacology: focus on neuropsychiatric disorders. Front Pharmacol. 2018; 9: 30-36.

[34]

Yue N, Huang H, Zhu X, et al. Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors. J Neuroinflammation. 2017; 14: 102-114.

[35]

Fan Y, Chen P, Li Y, et al. Corticosterone administration up-regulated expression of norepinephrine transporter and dopamine β-hydroxylase in rat locus coeruleus and its terminal regions. J Neurochem. 2014; 128: 445-458.

[36]

Owens MJ, Krulewicz S, Simon JS, et al. Estimates of serotonin and norepinephrine transporter inhibition in depressed patients treated with paroxetine or venlafaxine. Neuropsychopharmacology. 2008; 33: 3201-3212.

[37]

Nwokafor C, Serova LI, Tanelian A, Nahvi RJ, Sabban EL. Variable response of norepinephrine transporter to traumatic stress and relationship to hyperarousal. Front Behav Neurosci. 2021; 15:725091.

[38]

Hou Y, Li M, Jin Y, et al. Protective effects of tetramethylpyrazine on dysfunction of the locus coeruleus in rats exposed to single prolonged stress by anti-ER stress mechanism. Psychopharmacology. 2021; 238: 2923-2936.

[39]

Nakai S, Matsunaga W, Ishida Y, Isobe K, Shirokawa T. Effects of BDNF infusion on the axon terminals of locus coeruleus neurons of aging rats. Neurosci Res. 2006; 54: 213-219.

[40]

Mello-Carpes PB, Vargas LDSD, Gayer MC, Roehrs R, Izquierdo I. Hippocampal noradrenergic activation is necessary for object recognition memory consolidation and can promote BDNF increase and memory persistence. Neurobiol Learn Mem. 2016; 127: 84-92.

[41]

Lu B, Nagappan G, Lu Y. BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol. 2014; 220: 223-250.

[42]

Xu J, Wu S, Huo L, et al. Trigeminal nerve stimulation restores hippocampal dopamine deficiency to promote cognitive recovery in traumatic brain injury. Prog Neurobiol. 2023; 227:102477.

Rights & permissions

2026 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.

PDF (2932KB)

0

Accesses

0

Citation

Detail

Sections
Recommended

/

〈 〉