《中国康复理论与实践》

《中国康复理论与实践》

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卒中后认知障碍小鼠胆碱能神经环路组蛋白乙酰化内稳态失衡的机制研究①

王鑫，孙彩花，徐旸，朱小云，陈霞，施伟，杨敏   

  1. 扬州大学医学院附属江苏省扬州五台山医院神经康复科，江苏扬州市225001。
  • 出版日期:2016-06-25 发布日期:2016-07-04

Change of Histone Acetylation Homeostasis of Central Cholinergic Circuits in Mice with Post-stroke Cognitive Impairment

WANG Xin, SUN Cai-hua, XU Yang, ZHU Xiao-yun, CHEN Xia, SHI Wei, YANG Min   

  1. Department of Neurological Rehabilitation, Affiliated Wutaishan Hospital, Medical College of Yangzhou University, Yangzhou, Jiangsu 225001, China
  • Published:2016-06-25 Online:2016-07-04

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摘要： 目的观察卒中后认知障碍小鼠胆碱能神经环路组蛋白乙酰化内稳态变化。方法选用清洁级ICR雄性小鼠分为假手术组(n=60)和卒中后认知障碍组(PSCI 组，n=60)。采用线栓法制备大脑中动脉栓塞(MCAO)模型。水迷宫测试检测小鼠认知功能；分子生物学等方法检测小鼠梗死对侧胆碱能神经环路功能和组蛋白乙酰化内稳态变化情况。结果与假手术组相比，PSCI 组水迷宫成绩下降(t>29.412, P<0.05)；中枢胆碱能神经环路中，乙酰胆碱(ACh)的含量降低(t>26.227, P<0.05)，胆碱乙酰基转移酶(ChAT)mRNA和蛋白的表达降低(t>28.593, P<0.05)，乙酰化组蛋白H3(Ac-H3)水平降低(t>24.126, P<0.05)，磷酸化cAMP反应元件结合蛋白(p-CREB)和CREB结合蛋白(CBP)表达降低(t>25.634, P<0.05)，ChAT基因M型启动子组蛋白乙酰化水平下降(t>24.704, P<0.05)。结论短暂性MCAO模型可以引起小鼠认知功能障碍。PSCI 小鼠中枢胆碱能神经环路的胆碱能系统功能受损，乙酰化内稳态失衡，ChAT基因启动子组蛋白乙酰化程度下降；这些很可能与脑卒中导致环路中相应脑区中p-CREB和CBP表达降低有关。

关键词: 卒中后认知障碍, 胆碱能环路, 乙酰胆碱, 组蛋白乙酰化, cAMP反应元件结合蛋白, 小鼠

Abstract: Objective To observe the change of histone acetylation homeostasis of the central cholinergic circuits in mice with post-stroke cognitive impairment (PSCI). Methods The male ICR mice were divided into sham group (n=60) and PSCI group (n=60). The middle cerebral artery occlusion (MCAO) model was established. The Morris water maze test was used to test the cognitive function, and the changes of function and the histone acetylation homeostasis of the central cholinergic circuits of unaffected side were detected by molecular biology methods. Results Compared with the sham group, the scores of Morris water maze test decreased in PSCI group (t>29.412, P< 0.05); while the acetylcholine (Ach) level decreased (t>26.227, P<0.05), as well as the expression of choline acetyltransferase (ChAT) mRNA and protein (t>28.593, P<0.05), acetylated histone H3 (Ac-H3) (t>24.126, P<0.05), phosphorylated cAMP response element-binding protein (p-CREB) and CREB binding protein (CBP) (t>25.634, P<0.05), and the acetylated histone level of M promoter of ChAT (t>24.704, P<0.05). Conclusion Transient MCAO could cause PSCI. The function of the central cholinergic circuits was impaired, especially the histone acetylation homeostasis of the central cholinergic circuits, such as the acetylated histone level of ChAT promoter decreased. All of that might be related with the decline of p-CREB and CBP level in the corresponding brain regions induced by stroke.

Key words: post-stroke cognitive impairment, cholinergic circuits, acetylcholine, histone acetylation, cAMP response element-binding