内侧隔核注射淀粉样β蛋白损害大鼠的长时程增强和认知行为
武美娜¹, 孔林林^1,2, 张军¹, 胡梦明¹, 王昭君¹, 蔡红艳³, 祁金顺^1,*
1山西医科大学生理学系，细胞生理学省部共建教育部重点实验室，太原 030001；²浙江大学医学院附属第二医院神经内科，杭州 310009；³山西医科大学微生物与免疫教研室，太原 030001
摘要
胆碱能神经元的逐渐丢失和进行性认知功能障碍是阿尔茨海默病(Alzheimer’s disease, AD)的主要特征。脑内胆碱能神经元集中分布的区域之一是基底前脑的内侧隔核(medial septum, MS)，其发出投射纤维至海马。尽管AD患者和动物模型脑内淀粉样β蛋白(amyloid β protein, Aβ)的神经毒性包括特异性损伤胆碱能神经系统的作用已被广泛报道，但仍不清楚聚集在MS的Aβ是否会影响海马突触可塑性，进而影响学习记忆行为。本研究采用Morris水迷宫、Y型迷宫和在体海马长时程增强(long-term potentiation, LTP)记录，观察了MS注射Aβ对大鼠海马LTP及认知行为的影响，同时还以能特异性损伤γ氨基丁酸(γ-aminobutyric acid, GABA)能神经元的海人藻酸(kainic acid, KA)作为对照，进行了效应比较。结果显示：(1) MS注射Aβ25–35，而非KA，明显损伤了大鼠在经典Morris水迷宫和对位水迷宫中的空间学习记忆能力；(2) MS注射Aβ25–35和KA均损害了大鼠在Y迷宫中的新异环境探索能力；(3) MS注射Aβ25–35，而非KA，明显抑制了大鼠海马CA1区在体LTP；(4) Aβ25–35和KA均未影响大鼠在行为学测试中的运动能力和电生理记录中的海马CA1区双脉冲易化(paired-pulse facilitation, PPF)。以上结果表明，MS注射Aβ能够损伤大鼠空间学习记忆能力、学习记忆灵活性和探索行为，并压抑海马LTP。结合以往研究，本研究提示：MS的胆碱能神经元及其海马投射可能是AD病程中受Aβ神经毒性作用损害的主要细胞和组织，选择性损伤MS中的胆碱能神经元会导致AD病程中的海马突触可塑性损伤和认知功能伤害。
关键词： 内侧隔核; 淀粉样β蛋白; 海人藻酸; Morris水迷宫; Y迷宫; 长时程增强
分类号：R338.6

Amyloid β protein injection into medial septum impairs hippocampal long-term potentiation and cognitive behaviors in rats
WU Mei-Na¹, KONG Lin-Lin^1,2, ZHANG Jun¹, HU Meng-Ming¹, WANG Zhao-Jun¹, CAI Hong-Yan³, QI Jin-Shun^1,*
1Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China；²Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China；³Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan 030001, China
Abstract
The specific loss of cholinergic neurons and the progressive deficits of cognitive function are the most primary characteristics of Alzheimer’s disease (AD). Although the neurotoxicity of amyloid β protein (Aβ) in AD has been investigated extensively, it is still unclear whether the Aβ aggregated in the medial septum (MS), a major cholinergic nucleus projecting to the hippocampus, could affect hippocampal synaptic plasticity and further impair the memory behaviors. The present study investigated the effects of Aβ injection into the MS on hippocampal long-term potentiation (LTP) and cognitive behaviors of rats by using Morris water maze (MWM), Y maze and in vivo hippocampal LTP recording. The effects of kainic acid (KA), an agent with specific neurotoxicity to GABAergic neurons, were also observed. The results showed that: (1) Intra-MS injection of Aβ25–35, not KA, impaired spatial learning and memory of rats in classical and reversal MWM tests; (2) Both Aβ25–35 and KA impaired novelty-seeking behavior of rats in Y maze; (3) Intra-MS injection of Aβ25–35, not KA, suppressed in vivo hippocampal LTP in the CA1 region of rats; (4) Both Aβ25–35 and KA did not affect the motor ability in behavioral tests and the hippocampal paired-pulse facilitation (PPF) in electrophysiological recording. These results indicate that intra-MS injection of Aβ could impair spatial memory, cognitive flexibility and exploratory motivation, as well as hippocampal LTP in rats, suggesting that the cholinergic neurons in the MS and the septo-hippocampal projection could be important targets of neurotoxic Aβ, and the specific damage of cholinergic neurons in the MS is likely responsible for the impairments of hippocampal synaptic plasticity and cognitive function in AD.
Key words: medial septum; amyloid β protein; kainic acid; Morris water maze; Y maze; long-term potentiation

收稿日期：2018-02-04　　录用日期：2018-05-02
通讯作者：祁金顺　　E-mail: jinshunqi2009@163.com
DOI: 10.13294/j.aps.2018.0039
引用本文：
武美娜, 孔林林, 张军, 胡梦明, 王昭君, 蔡红艳, 祁金顺. 内侧隔核注射淀粉样β蛋白损害大鼠的长时程增强和认知行为[J]. 生理学报 2018; 70 (3): 217-227.
WU Mei-Na, KONG Lin-Lin, ZHANG Jun, HU Meng-Ming, WANG Zhao-Jun, CAI Hong-Yan, QI Jin-Shun. Amyloid β protein injection into medial septum impairs hippocampal long-term potentiation and cognitive behaviors in rats. Acta Physiol Sin 2018; 70 (3): 217-227



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