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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