Repetitive transcranial magnetic stimulation significantly improves cognitive impairment and neuronal excitability during aging in mice
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摘要: 重复经颅磁刺激是一种无创的脑刺激技术，作为一种治疗性神经康复手段备受关注。已有研究表明，高频重复经颅磁刺激可以提高动物在行为测试中的认知能力和神经元兴奋性。本文旨在研究小鼠自然老化过程中，高频重复经颅磁刺激对其认知能力和神经兴奋性的影响。实验采用青年小鼠、成年小鼠、老年小鼠各 12 只，且每个年龄段小鼠被随机分成刺激组和对照组。刺激组小鼠接受连续 15 天的高频重复经颅磁刺激，对照组接受连续 15 天的伪刺激。刺激结束之后，进行新物体识别与跳台测试，用以检查小鼠的学习记忆能力。行为学测试结束之后，进行全细胞脑片膜片钳实验，用以记录并分析海马齿状回颗粒神经元的静息膜电位、动作电位及其相关电特性指标。数据分析表明，小鼠认知能力与神经兴奋性随着老化而显著衰退，高频重复经颅磁刺激能显著改善认知损伤并缓解神经电特性指标的衰退。通过改变海马齿状回颗粒神经元电生理特性以及提高神经元兴奋性，可能是重复经颅磁刺激缓解认知损伤、提高认知能力的机制之一。Abstract: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that has been paid attention to with increasing interests as a therapeutic neural rehabilitative tool. Studies confirmed that high-frequency rTMS could improve the cognitive performance in behavioral test as well as the excitability of the neuron in animals. This study aimes to investigate the effects of rTMS on the cognition and neuronal excitability of Kunming mice during the natural aging. Twelve young mice, 12 adult mice, and 12 aged mice were used, and each age group were randomly divided into rTMS group and control group. rTMS-treated groups were subjected to high-frequency rTMS treatment for 15 days, and control groups were treated with sham stimulation for 15 days. Then, novel object recognition and step-down tests were performed to examine cognition of learning and memory. Whole-cell patch clamp technique was used to record and analyze resting membrane potential, action potential (AP), and related electrical properties of AP of hippocampal dentate gyrus (DG) granule neurons. Data analysis showed that cognition of mice and neuronal excitability of DG granule neurons were degenerated significantly as the age increased. Cognitive damage and degeneration of some electrical properties were alleviated under the condition of high-frequency rTMS. It may be one of the mechanisms of rTMS to alleviate cognitive damage and improve cognitive ability by changing the electrophysiological properties of DG granule neurons and increasing neuronal excitability.
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Key words:
- resting membrane potential /
- action potential /
- novel object recognition /
- step-down test
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图 5 新物体识别认知指数
a. 测试Ⅰ期认知指数；b.测试Ⅱ期认知指数。**P < 0.01，***P < 0.001
Figure 5. Cognitive index of novel object recognition test
a. cognitive index of test Ⅰ phase; b. cognitive index of test Ⅱ phase. **P < 0.01, ***P < 0.001
图 6 跳台实验数据分析
a. 潜伏期；b. 犯错误次数；c. 跳台停留时间百分比；d. 被动逃避潜伏期。**P < 0.01，***P < 0.001
Figure 6. Data analysis of step-down test
a. step-down latency; b. number of mistakes; c. percentage of residence time on the platform; d. passive escape latency. **P < 0.01, ***P < 0.001
图 7 膜电位及动作电位相关电特性数据分析
a. 静息膜电位；b. 动作电位发放个数；c. 后超极化电位；d. 动作电位峰值；e. 动作电位达峰时间；f. 动作电位上升支平均斜率；g. 动作电位下降支平均斜率。*P < 0.05，**P < 0.01，***P < 0.001
Figure 7. Data analysis of membrane potential and related electrical characteristics of action potential (AP)
a. resting membrane potential; b. the number of APs released; c. after-hyperpolarizing potential; d. AP peak amplitude; e. time to AP peak amplitude; f. average rise slope of AP; g. average down slope of AP. *P < 0.05, **P < 0.01, ***P < 0.001
表 1 切片液、人工脑脊液与电极内液离子成分
Table 1. The ionic composition of cutting solution, artificial cerebrospinal fluid and internal solutions
名称 成分/(mmol·L−1) pH 渗透压/mOsm 切片液 KCl 2.5, CaCl2 1, MgCl2 6, NaH2PO4·2H2O 1.625, NaHCO3 26, glucose 11, sucrose 220 7.4 — 人工脑脊液 NaCl 124, KCl 3, CaCl2 2, MgCl2 2, NaH2PO4·2H2O 1.625, NaHCO3 26, glucose 11, HEPES 5 7.4 310～320 电极内液 K-gluconate 125, NaCl 15, MgCl2 2, CaCl2 1, EGTA 11, HEPES 10, Na-ATP 3, Na-GTP 0.3 7.2～7.3 285～290 
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[1] Walsh V, Cowey A. Transcranial magnetic stimulation and cognitive neuroscience. Nat Rev Neurosci, 2000, 1(1): 73-79. doi: 10.1038/35036239 [2] Simonetta-Moreau M. Non-invasive brain stimulation (NIBS) and motor recovery after stroke. Ann Phys Rehabil Med, 2014, 57(8): 530-542. doi: 10.1016/j.rehab.2014.08.003 [3] Klomjai W, Katz R, Lackmy-Vallée A. Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS) Ann Phys Rehabil Med, 2015, 58(4): 208-213. [4] Rossi S, Hallett M, Rossini P M, et al. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol, 2009, 120(12): 2008-2039. doi: 10.1016/j.clinph.2009.08.016 [5] 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. doi: 10.1007/s00415-011-6128-4 [6] Arendash G W, Mori T, Dorsey M, et al. Electromagnetic treatment to old Alzheimer's mice reverses β-amyloid deposition, modifies cerebral blood flow, and provides selected cognitive benefit. PLoS One, 2012, 7(4): e35751. doi: 10.1371/journal.pone.0035751 [7] Garcia-Toro M, Salva J, Daumal J, et al. High (20-Hz) and low (1-Hz) frequency transcranial magnetic stimulation as adjuvant treatment in medication-resistant depression. Psychiatry Res, 2006, 146(1): 53-57. doi: 10.1016/j.pscychresns.2004.08.005 [8] George M S, Nahas Z, Molloy M, et al. A controlled trial of daily left prefrontal cortex TMS for treating depression. Biol Psychiatry, 2000, 48(10): 962-970. doi: 10.1016/S0006-3223(00)01048-9 [9] Lee S H, Kim W, Chung Y C, et al. A double blind study showing that two weeks of daily repetitive TMS over the left or right temporoparietal cortex reduces symptoms in patients with schizophrenia who are having treatment-refractory auditory hallucinations. Neurosci Lett, 2005, 376(3): 177-181. doi: 10.1016/j.neulet.2004.11.048 [10] Wölwer W, Lowe A, Brinkmeyer J, et al. Repetitive transcranial magnetic stimulation (rTMS) improves facial affect recognition in schizophrenia. Brain Stimul, 2014, 7(4): 559-563. doi: 10.1016/j.brs.2014.04.011 [11] Mally J, Stone T W. Therapeutic and “dose‐dependent” effect of repetitive microelectroshock induced by transcranial magnetic stimulation in Parkinson's disease. J Neurosci Res, 1999, 57(6): 935-940. doi: 10.1002/(SICI)1097-4547(19990915)57:6<935::AID-JNR19>3.0.CO;2-8 [12] Cantarero G, Lloyd A, Celnik P. Reversal of long-term potentiation-like plasticity processes after motor learning disrupts skill retention. J Neurosci, 2013, 33(31): 12862-12869. doi: 10.1523/JNEUROSCI.1399-13.2013 [13] Cantarero G, Tang B, O'malley R, et al. Motor learning interference is proportional to occlusion of LTP-like plasticity. J Neurosci, 2013, 33(11): 4634-4641. doi: 10.1523/JNEUROSCI.4706-12.2013 [14] Ogiue-Ikeda M, Kawato S, Ueno S. The effect of repetitive transcranial magnetic stimulation on long-term potentiation in rat hippocampus depends on stimulus intensity. Brain Res, 2003, 993(1/2): 222-226. [15] Lenz M, Platschek S, Priesemann V, et al. Repetitive magnetic stimulation induces plasticity of excitatory postsynapses on proximal dendrites of cultured mouse CA1 pyramidal neurons. Brain Struct Funct, 2015, 220(6): 3323-3337. doi: 10.1007/s00429-014-0859-9 [16] Yang Huiyun, Liu Yang, Xie Jiacun, et al. Effects of repetitive transcranial magnetic stimulation on synaptic plasticity and apoptosis in vascular dementia rats. Behav Brain Res, 2015, 281: 149-155. doi: 10.1016/j.bbr.2014.12.037 [17] Wang Hualong, Xian Xiaohui, Wang Yanyong, 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. doi: 10.1016/j.nlm.2014.11.002 [18] Shang Yingchun, Wang Xin, Shang Xueliang, et al. Repetitive transcranial magnetic stimulation effectively facilitates spatial cognition and synaptic plasticity associated with increasing the levels of BDNF and synaptic proteins in Wistar rats. Neurobiol Learn Mem, 2016, 134(Pt B): 369-378. [19] Sun Peng, Wang Furong, Wang Li, et al. Increase in cortical pyramidal cell excitability accompanies depression-like behavior in mice: a transcranial magnetic stimulation study. J Neurosci, 2011, 31(45): 16464-16472. doi: 10.1523/JNEUROSCI.1542-11.2011 [20] Hölscher C. Synaptic plasticity and learning and memory: LTP and beyond. J Neurosci Res, 1999, 58(1): 62-75. doi: 10.1002/(SICI)1097-4547(19991001)58:1<62::AID-JNR7>3.0.CO;2-G [21] Xavier G F, Costa V C. Dentate gyrus and spatial behaviour. Prog Neuro-Psychoph, 2009, 33(5): 762-773. doi: 10.1016/j.pnpbp.2009.03.036 [22] Tarragon E, Lopez D, Estrada C, et al. Memantine prevents reference and working memory impairment caused by sleep deprivation in both young and aged Octodon degus. Neuropharmacology, 2014, 85: 206-214. doi: 10.1016/j.neuropharm.2014.05.023 [23] Bevins R A, Besheer J. Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study 'recognition memory'. Nat Protoc, 2006, 1(3): 1306-1311. doi: 10.1038/nprot.2006.205 [24] Gomes-Osman J, Indahlastari A, Fried P J, et al. Non-invasive brain stimulation: probing intracortical circuits and improving cognition in the aging brain. Front Aging Neurosci, 2018, 10: 177. doi: 10.3389/fnagi.2018.00177 [25] Estrada C, Fernández-Gómez F J, López D, et al. Transcranial magnetic stimulation and aging: Effects on spatial learning and memory after sleep deprivation in Octodon degus. Neurobiol Learn Mem, 2015, 125: 274-281. doi: 10.1016/j.nlm.2015.09.011 [26] Barker G R, Warburton E C. When is the hippocampus involved in recognition memory. J Neurosci, 2011, 31(29): 10721-10731. doi: 10.1523/JNEUROSCI.6413-10.2011 [27] Zhang Xiaochen, Yang Chunxiao, Gao Jing, et al. Voluntary running-enhanced synaptic plasticity, learning and memory are mediated by Notch1 signal pathway in C57BL mice. Brain Struct Funct, 2018, 223(2): 749-767. doi: 10.1007/s00429-017-1521-0 [28] Kameyama T, Nabeshima T, Kozawa T. Step-down-type passive avoidance- and escape-learning method. J Pharmacol Methods, 1986, 16(1): 39-52. doi: 10.1016/0160-5402(86)90027-6 [29] Nasehi M, Piri M, Nouri M, et al. Involvement of dopamine D1/D2 receptors on harmane-induced amnesia in the step-down passive avoidance test. Eur J Pharmacol, 2010, 634(1/3): 77-83. [30] Wang Hualong, Geng Yuan, Han Bing, et al. Repetitive transcranial magnetic stimulation applications normalized prefrontal dysfunctions and cognitive-related metabolic profiling in aged mice. PLoS One, 2013, 8(11): e81482. doi: 10.1371/journal.pone.0081482 [31] Tang A D, Hong I, Boddington L J, et al. Low-intensity repetitive magnetic stimulation lowers action potential threshold and increases spike firing in layer 5 pyramidal neurons in vitro. Neuroscience, 2016, 335: 64-71. doi: 10.1016/j.neuroscience.2016.08.030 -
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