Ma Qinying, Geng Yuan, Wang Hua-Long, Han Bing, Wang Yan-Yong, Li Xiao-Li, Wang Lin, Wang Ming-Wei
Department of Neurology, the First Hospital of Hebei Medical University, Shijiazhuang, China.
Brain Aging and Cognitive Neuroscience Key Laboratory of Hebei, Shijiazhuang, China.
Front Aging Neurosci. 2019 Sep 18;11:235. doi: 10.3389/fnagi.2019.00235. eCollection 2019.
Normal aging is accompanied by hippocampus-dependent cognitive impairment, which is a risk factor of Alzheimer's disease. This study aims to investigate the effect of high frequency-repetitive transcranial magnetic stimulation (HF-rTMS) on hippocampus-dependent learning and memory in aged mice and explore its underlying mechanisms. Forty-five male Kunming mice (15 months old) were randomly divided into three groups: aged sham, 5 Hz rTMS, and 25 Hz rTMS. Two sessions of 5 Hz or 25 Hz rTMS comprising 1,000 pulses in 10 trains were delivered once a day for 14 consecutive days. The aged sham group was treated by the reverse side of the coil. In the adult sham group, 15 male Kunming mice (3 months old) were treated the same way as the aged sham group. A Morris water maze (MWM) was conducted following the stimulation, and synaptic ultrastructure was observed through a transmission electron microscope. HF-rTMS improved spatial learning and memory impairment in the aged mice, and 5 Hz was more significant than 25 Hz. Synaptic plasticity-associated gene profiles were modified by HF-rTMS, especially neurotrophin signaling pathways and cyclic adenosine monophosphate response element binding protein (CREB) cofactors. Compared to the aged sham group, synaptic plasticity-associated proteins, i.e., synaptophysin (SYN) and postsynaptic density (PSD)-95 were increased; brain-derived neurotrophic factor (BDNF) and phosphorylated CREB (pCREB) significantly increased after the 5 Hz HF-rTMS treatment. Collectively, our results suggest that HF-rTMS ameliorated cognitive deficits in naturally aged mice. The 5 Hz rTMS treatment significantly enhanced synaptic structural plasticity and activated the BDNF/CREB pathway in the hippocampus.
正常衰老伴随着海马体依赖性认知障碍，这是阿尔茨海默病的一个风险因素。本研究旨在探讨高频重复经颅磁刺激（HF-rTMS）对老年小鼠海马体依赖性学习和记忆的影响，并探索其潜在机制。45只雄性昆明小鼠（15月龄）随机分为三组：老年假刺激组、5Hz rTMS组和25Hz rTMS组。每天进行一次包含10串、每串1000个脉冲的5Hz或25Hz rTMS刺激，连续进行14天。老年假刺激组接受线圈反面的治疗。在成年假刺激组中，15只雄性昆明小鼠（3月龄）接受与老年假刺激组相同的治疗。刺激后进行莫里斯水迷宫（MWM）实验，并通过透射电子显微镜观察突触超微结构。HF-rTMS改善了老年小鼠的空间学习和记忆障碍，5Hz比25Hz更显著。HF-rTMS改变了与突触可塑性相关的基因谱，尤其是神经营养因子信号通路和环磷酸腺苷反应元件结合蛋白（CREB）辅因子。与老年假刺激组相比，与突触可塑性相关的蛋白，即突触素（SYN）和突触后致密蛋白（PSD）-95增加；5Hz HF-rTMS治疗后，脑源性神经营养因子（BDNF）和磷酸化CREB（pCREB）显著增加。总的来说，我们的结果表明HF-rTMS改善了自然衰老小鼠的认知缺陷。5Hz rTMS治疗显著增强了突触结构可塑性，并激活了海马体中的BDNF/CREB通路。
