Effects of repetitive transcranial magnetic stimulation on neuronal excitability and ion channels in hindlimb unloading mice_Journal of Biomedical Engineering

Authors：

HOU Wentao ^1,2 , FU Rui ^1,2 , ZHU Mingqiang ^1,2 , ZHU Haijun ^1,3 ,  DING Chong ^1,2

1. Hebei Key Laboratory of Bioelectromagnetics and Neural Engineering, School of Health Sciences & Biomedical Engineering, Hebei University of Technology, Tianjin 300130, P. R. China;
2. Tianjin Key Laboratory of Bioelectricity and Intelligent Health, School of Health Sciences & Biomedical Engineering, Hebei University of Technology, Tianjin 300130, P. R. China;
3. Key Laboratory of Digital Medical Engineering of Hebei Province, College of Electronic and Information Engineering, Hebei University, Baoding, Hebei 071002, P. R. China;

Corresponding author：

DING Chong, Email: dingchong@hebut.edu.cn

Keywords：

Repetitive transcranial magnetic stimulation; Hindlimb unloading mouse; Nerve excitability; Voltage-gated sodium channels; Voltage-gated potassium channels

DOI：

10.7507/1001-5515.202205008

Video：

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Weightlessness in the space environment affects astronauts’ learning memory and cognitive function. Repetitive transcranial magnetic stimulation has been shown to be effective in improving cognitive dysfunction. In this study, we investigated the effects of repetitive transcranial magnetic stimulation on neural excitability and ion channels in simulated weightlessness mice from a neurophysiological perspective. Young C57 mice were divided into control, hindlimb unloading and magnetic stimulation groups. The mice in the hindlimb unloading and magnetic stimulation groups were treated with hindlimb unloading for 14 days to establish a simulated weightlessness model, while the mice in the magnetic stimulation group were subjected to 14 days of repetitive transcranial magnetic stimulation. Using isolated brain slice patch clamp experiments, the relevant indexes of action potential and the kinetic property changes of voltage-gated sodium and potassium channels were detected to analyze the excitability of neurons and their ion channel mechanisms. The results showed that the behavioral cognitive ability and neuronal excitability of the mice decreased significantly with hindlimb unloading. Repetitive transcranial magnetic stimulation could significantly improve the cognitive impairment and neuroelectrophysiological indexes of the hindlimb unloading mice. Repetitive transcranial magnetic stimulation may change the activation, inactivation and reactivation process of sodium and potassium ion channels by promoting sodium ion outflow and inhibiting potassium ion, and affect the dynamic characteristics of ion channels, so as to enhance the excitability of single neurons and improve the cognitive damage and spatial memory ability of hindlimb unloading mice.

Citation： HOU Wentao, FU Rui, ZHU Mingqiang, ZHU Haijun, DING Chong. Effects of repetitive transcranial magnetic stimulation on neuronal excitability and ion channels in hindlimb unloading mice. Journal of Biomedical Engineering, 2023, 40(1): 8-19. doi: 10.7507/1001-5515.202205008 Copy

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2.	王峻, 白延强, 秦海波, 等. 空间站任务航天员心理问题及心理支持. 中国载人航天, 2012, 18(2): 68-74.
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4.	Newberg A B. Changes in the central nervous system and their clinical correlates during long-term spaceflight. Aviat Space Environ Med, 1994, 65(6): 562-572.
5.	林煜, 刘宗琳, 骞爱荣, 等. 一种模拟失重性骨丢失小鼠尾悬吊模型的建立. 航天医学与医学工程, 2012, 25(4): 239-242.
6.	Wang Q, Zhang Y L, Li Y H, et al. The memory enhancement effect of Kai Xin San on cognitive deficit induced by simulated weightlessness in rats. J Ethnopharmacol, 2016, 187: 9-16.
7.	Wu X R, Li D, Liu J L, et al. Dammarane sapogenins ameliorates neurocognitive functional impairment induced by simulated long-duration spaceflight. Front Pharmacol, 2017, 8: 315.
8.	Frigeri A, Iacobas D A, Iacobas S, et al. Effect of microgravity on gene expression in mouse brain. Exp Brain Res, 2008, 191(3): 289-300.
9.	Shang X L, Bo X, Li Q, et al. Neural oscillations as a bridge between glutamatergic system and emotional behaviors in simulated microgravity-induced mice. Behav Brain Res, 2017, 317: 286-291.
10.	Rosa M A, Lisanby S H. Somatic treatments for mood disorders. Neuropsychopharmacol, 2012, 37(1): 102.
11.	Nguyen J P, Suarez A, Kemoun G, et al. Repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer’s disease. Neurophysiol Clin, 2017, 47(1): 47-53.
12.	董国亚, 汤志华, 韩婷彦, 等. 各向异性真实头模型下深部脑刺激电场分布. 电工技术学报, 2015(S2): 37-41.
13.	李江涛, 曹辉, 郑敏军, 等. 多通道经颅磁刺激线圈阵列的驱动与控制. 电工技术学报, 2017, 32(22): 158-165.
14.	Ahmed M A, Darwish E S, Khedr E M, et al. Effects of low versus high frequencies of repetitive transcranial magnetic stimulation on cognitive function and cortical excitability in Alzheimer’s dementia. J Neurol, 2012, 259(1): 83-92.
15.	Ziemann U, Müllerdahlhaus F. Metaplasticity in human cortex. Neuroentist, 2014, 21(2): 185.
16.	Zhu H J, Xu G Z, Fu L D, et al. The effects of repetitive transcranial magnetic stimulation on the cognition and neuronal excitability of mice. Electromagn Biol Med, 2019, 39(1): 1-11.
17.	Ma J, Wang J H, Lv C N, et al. The role of hippocampal structural synaptic plasticity in repetitive transcranial magnetic stimulation to improve cognitive function in male SAMP8 mice. Cell Physiol Biochem, 2017, 41(1): 137.
18.	Xiang S T, Zhou Y, Fu J X, et al. rTMS pre-treatment effectively protects against cognitive and synaptic plasticity impairments induced by simulated microgravity in mice. Behav Brain Res, 2018, 359: 639-647.
19.	Zhang X Q, Li L, Huo J T, et al. Effects of repetitive transcranial magnetic stimulation on cognitive function and cholinergic activity in the rat hippocampus after vascular dementia. Neural Regen Res, 2018, 13(8): 1384-1389.
20.	Campanac E, Debanne D. Plasticity of neuronal excitability: Hebbian rules beyond the synapse. Arch Ital Biol, 2007, 145(3-4): 277.
21.	Zhao Z G, Gu H G. Transitions between classes of neuronal excitability and bifurcations induced by autapse. Sci Rep, 2017, 7(1): 6760.
22.	Zhai B H, Fu J X, Xiang S T, et al. Repetitive transcranial magnetic stimulation ameliorates recognition memory impairment induced by hindlimb unloading in mice associated with BDNF/TrkB signaling. Neurosci Res, 2020, 153: 40-47.
23.	杨佳佳. 三聚氰胺对大鼠海马CA1区神经元兴奋性的影响及其机制的研究. 天津: 南开大学, 2011.
24.	Ekberg J, Craik D J, Adams D J. Conotoxin modulation of voltage-gated sodium channels. Int J Biochem Cell Biol, 2008, 40(11): 2363-2368.
25.	Luna V M, Anacker C, Burghardt N S, et al. Adult-born hippocampal neurons bidirectionally modulate entorhinal inputs into the dentate gyrus. Science, 2019, 364(6440): 578-583.
26.	汪铭. 慢性铝暴露对大白鼠海马DG区突触可塑性的影响及药物防治的在位研究. 合肥: 中国科学技术大学, 2002.
27.	Tan T, Xie J C, Tong Z Q, et al. Repetitive transcranial magnetic stimulation increases excitability of hippocampal CA1 pyramidal neurons. Brain Res, 2013, 1520(3): 23-35.
28.	朱海军, 丁冲, 徐桂芝. 膜片钳技术及其在神经科学研究中的应用. 生命科学研究杂志, 2017, 21(3): 251-256.
29.	Nelson M T, Quayle J M. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol, 1995, 268(4): C799-C822.
30.	Liu Y H, Wang L N, Bian Y H, et al. Effect of repetitive transcranial magnetic stimulation with different frequency on cognitive function and behavioral and psychological symptoms in patients with senile dementia. Int J Psychiat, 2017, 2: 75-78.
31.	Wang H L, Xian X H, Wang Y Y, et al. Chronic high-frequency repetitive transcranial magnetic stimulation improves age-related cognitive impairment in parallel with alterations in neuronal excitability and the voltage-dependent Ca²⁺ current in female mice. Neurobiol Learn Mem, 2015, 118: 1-7.
32.	Dong Z F, Han H L, Wang Y T. Long-term potentiation decay and memory loss are mediated by AMPAR endocytosis. J Clin Invest, 2015, 125(1): 234-247.
33.	Coetzee W A, Amarillo Y, Chiu J, et al. Molecular diversity of K⁺ channels. Ann N Y Acad Sci, 1999, 868(1): 233-285.

1. Manzey D, Lorenz B, Schiewe A, et al. Behavioral aspects of human adaptation to space analyses of cognitive and psychomotor performance in space during an 8-day space mission. Clin Ooral Invest, 1993, 71(9): 725-731.
2. 王峻, 白延强, 秦海波, 等. 空间站任务航天员心理问题及心理支持. 中国载人航天, 2012, 18(2): 68-74.
3. Alexander A A, Ole D, Jeffrey A, et al. Mice display learning and behavioral deficits after a 30-day spaceflight on Bion-M1 satellite. Behav Brain Res, 2021, 419(12): 113682.
4. Newberg A B. Changes in the central nervous system and their clinical correlates during long-term spaceflight. Aviat Space Environ Med, 1994, 65(6): 562-572.
5. 林煜, 刘宗琳, 骞爱荣, 等. 一种模拟失重性骨丢失小鼠尾悬吊模型的建立. 航天医学与医学工程, 2012, 25(4): 239-242.
6. Wang Q, Zhang Y L, Li Y H, et al. The memory enhancement effect of Kai Xin San on cognitive deficit induced by simulated weightlessness in rats. J Ethnopharmacol, 2016, 187: 9-16.
7. Wu X R, Li D, Liu J L, et al. Dammarane sapogenins ameliorates neurocognitive functional impairment induced by simulated long-duration spaceflight. Front Pharmacol, 2017, 8: 315.
8. Frigeri A, Iacobas D A, Iacobas S, et al. Effect of microgravity on gene expression in mouse brain. Exp Brain Res, 2008, 191(3): 289-300.
9. Shang X L, Bo X, Li Q, et al. Neural oscillations as a bridge between glutamatergic system and emotional behaviors in simulated microgravity-induced mice. Behav Brain Res, 2017, 317: 286-291.
10. Rosa M A, Lisanby S H. Somatic treatments for mood disorders. Neuropsychopharmacol, 2012, 37(1): 102.
11. Nguyen J P, Suarez A, Kemoun G, et al. Repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer’s disease. Neurophysiol Clin, 2017, 47(1): 47-53.
12. 董国亚, 汤志华, 韩婷彦, 等. 各向异性真实头模型下深部脑刺激电场分布. 电工技术学报, 2015(S2): 37-41.
13. 李江涛, 曹辉, 郑敏军, 等. 多通道经颅磁刺激线圈阵列的驱动与控制. 电工技术学报, 2017, 32(22): 158-165.
14. Ahmed M A, Darwish E S, Khedr E M, et al. Effects of low versus high frequencies of repetitive transcranial magnetic stimulation on cognitive function and cortical excitability in Alzheimer’s dementia. J Neurol, 2012, 259(1): 83-92.
15. Ziemann U, Müllerdahlhaus F. Metaplasticity in human cortex. Neuroentist, 2014, 21(2): 185.
16. Zhu H J, Xu G Z, Fu L D, et al. The effects of repetitive transcranial magnetic stimulation on the cognition and neuronal excitability of mice. Electromagn Biol Med, 2019, 39(1): 1-11.
17. Ma J, Wang J H, Lv C N, et al. The role of hippocampal structural synaptic plasticity in repetitive transcranial magnetic stimulation to improve cognitive function in male SAMP8 mice. Cell Physiol Biochem, 2017, 41(1): 137.
18. Xiang S T, Zhou Y, Fu J X, et al. rTMS pre-treatment effectively protects against cognitive and synaptic plasticity impairments induced by simulated microgravity in mice. Behav Brain Res, 2018, 359: 639-647.
19. Zhang X Q, Li L, Huo J T, et al. Effects of repetitive transcranial magnetic stimulation on cognitive function and cholinergic activity in the rat hippocampus after vascular dementia. Neural Regen Res, 2018, 13(8): 1384-1389.
20. Campanac E, Debanne D. Plasticity of neuronal excitability: Hebbian rules beyond the synapse. Arch Ital Biol, 2007, 145(3-4): 277.
21. Zhao Z G, Gu H G. Transitions between classes of neuronal excitability and bifurcations induced by autapse. Sci Rep, 2017, 7(1): 6760.
22. Zhai B H, Fu J X, Xiang S T, et al. Repetitive transcranial magnetic stimulation ameliorates recognition memory impairment induced by hindlimb unloading in mice associated with BDNF/TrkB signaling. Neurosci Res, 2020, 153: 40-47.
23. 杨佳佳. 三聚氰胺对大鼠海马CA1区神经元兴奋性的影响及其机制的研究. 天津: 南开大学, 2011.
24. Ekberg J, Craik D J, Adams D J. Conotoxin modulation of voltage-gated sodium channels. Int J Biochem Cell Biol, 2008, 40(11): 2363-2368.
25. Luna V M, Anacker C, Burghardt N S, et al. Adult-born hippocampal neurons bidirectionally modulate entorhinal inputs into the dentate gyrus. Science, 2019, 364(6440): 578-583.
26. 汪铭. 慢性铝暴露对大白鼠海马DG区突触可塑性的影响及药物防治的在位研究. 合肥: 中国科学技术大学, 2002.
27. Tan T, Xie J C, Tong Z Q, et al. Repetitive transcranial magnetic stimulation increases excitability of hippocampal CA1 pyramidal neurons. Brain Res, 2013, 1520(3): 23-35.
28. 朱海军, 丁冲, 徐桂芝. 膜片钳技术及其在神经科学研究中的应用. 生命科学研究杂志, 2017, 21(3): 251-256.
29. Nelson M T, Quayle J M. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol, 1995, 268(4): C799-C822.
30. Liu Y H, Wang L N, Bian Y H, et al. Effect of repetitive transcranial magnetic stimulation with different frequency on cognitive function and behavioral and psychological symptoms in patients with senile dementia. Int J Psychiat, 2017, 2: 75-78.
31. Wang H L, Xian X H, Wang Y Y, et al. Chronic high-frequency repetitive transcranial magnetic stimulation improves age-related cognitive impairment in parallel with alterations in neuronal excitability and the voltage-dependent Ca²⁺ current in female mice. Neurobiol Learn Mem, 2015, 118: 1-7.
32. Dong Z F, Han H L, Wang Y T. Long-term potentiation decay and memory loss are mediated by AMPAR endocytosis. J Clin Invest, 2015, 125(1): 234-247.
33. Coetzee W A, Amarillo Y, Chiu J, et al. Molecular diversity of K⁺ channels. Ann N Y Acad Sci, 1999, 868(1): 233-285.

Journal of Biomedical Engineering

Effects of repetitive transcranial magnetic stimulation on neuronal excitability and ion channels in hindlimb unloading mice

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