中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2020, Vol. 15 ›› Issue (12): 2327-2334.doi: 10.4103/1673-5374.285005

• 原著:退行性病与再生 • 上一篇    下一篇

丰富环境刺激老年小鼠可改善认知功能

  

  • 出版日期:2020-12-15 发布日期:2020-08-05
  • 基金资助:
    国家自然科学基金(81672242，81972141）；中国博士后科学基金(No.2017M621675）; 中国江苏省自然科学基金面上项目（BK20171280）; 江苏省六级高层次卫生人才科研计划项目（LGY2017028，LGY2018027）；江苏省重点青年医学人才项目（QNRC2016339）；扬州的“科教强威”“十三五”计划（ZDRC65）；上海市生物医学科学技术重点项目（17411953900）。

Enriched environment enhances histone acetylation of NMDA receptor in the hippocampus and improves cognitive dysfunction in aged mice

Xin Wang 1, 2 , Zhao-Xiang Meng 2 , Ying-Zhu Chen 2 , Yu-Ping Li 2 , Hong-Yu Zhou 2 , Man Yang 3 , Ting-Ting Zhao 3 , Yu-Lai Gong 4 , Yi Wu 1, Tao Liu 5   

  1. 1 Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China
    2 Department of Rehabilitation, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, China
    3 Department of Rehabilitation, First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning Province, China
    4 Department of Rehabilitation Medicine, Sichuan Provincial Rehabilitation Hospital Affiliated to Chengdu University of TCM, Chengdu, Sichuan Province, China
    5 South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China
  • Online:2020-12-15 Published:2020-08-05
  • Contact: Yi Wu, MD, PhD, wuyi@fudan.edu.cn; Tao Liu, PhD, lt045021@gzucm.edu.cn.
  • Supported by:
    The study was supported by the National Natural Science Foundation of China, Nos. 81672242, 81972141 (both to YW); the China Postdoctoral Science Fund, No. 2017M621675 (to XW); the Natural Science Foundation of Jiangsu Province of China, No. BK20171280 (to XW); the Six One Project of Scientific Research Project for High-Level Health Talents of Jiangsu Province of China, Nos. LGY2017028, LGY2018027 (to XW); the Key Young Medical Talents Project of Jiangsu Province, No. QNRC2016339 (to XW); the Yangzhou’s 13 th Five-Year Plan for “Ke Jiao Qiang Wei” of China, No. ZDRC65 (to XW); the Key Project of Shanghai Science and Technology on Biomedicine of China, No. 17411953900 (to YW).

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摘要：

近期研究显示，与年龄相关记忆障碍机制可能与谷氨酸受体功能和染色质修饰有关。为观察了丰富环境对年龄相关记忆障碍小鼠认知功能的影响，实验将3月龄C57BL/6雄性青年小鼠饲养于标准环境中，将24月龄C57BL/6雄性年龄相关记忆障碍小鼠分别饲养于标准环境和包含运动、感觉等多种刺激的丰富环境中。(1)采用水迷宫实验测试小鼠的认知功能发现，与标准环境中的青年小鼠相比，标准环境中的年龄相关记忆障碍小鼠的水迷宫成绩显著性下降。(2)采用实时定量聚合酶链反应和免疫印迹法检测小鼠右侧海马组织NMDA受体一种亚型GluN2B mRNA和蛋白表达，采用染色质免疫沉淀法测定海马GluN2B基因启动子上乙酰化组蛋白的表达发现，与标准环境中青年小鼠相比，标准环境中与年龄相关记忆障碍小鼠海马组织乙酰化总组蛋白和CREB结合蛋白表达明显下降，GluN2B蛋白及相关mRNA表达明显下降，GluN2B基因启动子组蛋白乙酰化程度下降；而经丰富环境干预后，与年龄相关记忆障碍小鼠的水迷宫成绩和上述分子生物学指标均显著性改善；(3)上述数据证实，丰富环境可改善年龄相关记忆障碍小鼠的认知功能障碍，其机制可能与增加年龄相关记忆障碍小鼠海马CREB结合蛋白的表达和增加总组蛋白乙酰化程度有关。

orcid:
0000-0003-4854-9898 (Yi Wu)
0000-0002-2756-1161 (Tao Liu)

Abstract: The mechanisms of age-associated memory impairment may be associated with glutamate receptor function and chromatin modification. To observe the effect of an enriched environment on the cognitive function of mice with age-associated memory impairment, 3-month- old C57BL/6 male mice (“young” mice) were raised in a standard environment, while 24-month-old C57BL/6 male mice with memory impairment (“age-associated memory impairment” mice) were raised in either a standard environment or an enriched environment. The enriched environment included a variety of stimuli involving movement and sensation. A water maze test was then used to measure cog- nitive function in the mice. Furthermore, quantitative real-time polymerase chain reaction and western blot assays were used to detect right hippocampal GluN2B mRNA as well as protein expression of GluN2B and CREB binding protein in all mice. In addition, chromatin immunoprecipitation was used to measure the extent of histone acetylation of the hippocampal GluN2B gene promoters. Compared with the young mice, the water maze performance of age-associated memory impairment mice in the standard environment was significantly decreased. In addition, there were significantly lower levels of total histone acetylation and expression of CREB binding protein in the hippocampus of age-associated memory impairment mice in the standard environment compared with the young mice. There were also significantly lower levels of histone acetylation, protein expression, and mRNA expression of GluN2B in the hippocampus of these mice. In contrast, in the age-associated memory impairment mice with the enriched environment intervention, the water maze performance and molecular biological indexes were significantly improved. These data confirm that an enriched environment can improve cognitive dys- function in age-associated memory impairment mice, and suggest that the mechanisms may be related to the increased expression of CREB binding protein and the increased degree of total histone acetylation in the hippocampus of age-associated memory impairment mice, which may cause the increase of histone acetylation of GluN2B gene promoter and the enhancement of GluN2B mRNA transcription and protein expression in hippocampus. The animal experiment was approved by the Animal Ethics Committee of Yangzhou University, China (approval No. 20170312001) in March 2017.

Key words: brain, central nervous system, factor, in vitro, model, mice, recovery, regenerations protein