GABA系统调节对阿尔兹海默病及正常衰老的影响

发布时间：2018-04-26 05:27

本文选题：阿尔茨海默病 + 衰老　；参考：《昆明理工大学》2017年硕士论文

【摘要】：阿尔茨海默病(Alzheimer's Disease,AD)也被称为老年性痴呆症,是一种慢性进行性神经退行性疾病,发病隐袭,常见于老年期,其致病机制不清楚,尚无有效治疗药物。衰老是一个全脑的过程,分为生理性脑衰老和病理性脑衰老,而病理性脑的变化与AD等神经退行性疾病相关。AD和衰老过程都伴随有记忆减退、神经递质水平与神经活动异常,提示二者有着相似的神经病理学基础。伽玛氨基丁酸(γ-Aminobutyricacid,GABA)是中枢神经系统中最重要的抑制性神经递质,在衰老和AD等神经退行性病变过程中发挥重要作用。GABA系统通过对兴奋性神经元的抑制作用而调控整个神经网络系统。脑电图(Electroencephalogram,EEG)是即时监测大脑活动状态的一种较为敏感的方法,在多种神经、精神性疾病的诊断和治疗中具有重要临床应用价值。本研究主要探讨激动或拮抗GABA能系统对AD模型小鼠和衰老小鼠空间识别记忆及EEG的影响。研究使用了 GABAa受体激动剂蝇蕈醇(Muscimol)与拮抗剂荷包牡丹碱(Bicuculline);EEG记录位点为海马、前额叶与皮层。首先,我们采用药物的低、中、高三种剂量在青年小鼠上进行剂量筛选实验,采用矿场实验分析小鼠活动力,探索型Y迷宫范式评价小鼠空间识别记忆,以及三个脑区自发状态EEG记录研究大脑活动变化。之后,将药物的一个有效剂量应用于AD模型小鼠和衰老小鼠上进行实验,研究两组小鼠之间活动力、空间识别记忆、自发EEG之间的异同,并且,我们也研究了该剂量下两组小鼠在探索型Y迷宫任务态下三个脑区局部EEG之间的异同。实验结果如下:首先,在青年动物剂量筛选实验中,低剂量的Muscimol(0.1 mg/kg)轻微增加了青年小鼠活动力,明显促进其在Y迷宫实验中的空间识别记忆力,并且在药物给予之后的两小时之内,显著影响三个脑区的自发EEG活动;而相同剂量的Bicuculline对小鼠活动力与空间识别记忆力均无显著影响,但在药物给予之后的两小时之内,显著影响前额叶的自发EEG活动。之后,我们将该低剂量两种药物用于AD模型小鼠及衰老小鼠(≈12月龄)进行研究,结果发现该剂量Muscimol和Bicuculline对两组小鼠活动力均无显著影响;但Muscimol明显影响了小鼠海马和皮层的自发EEG活动,而Bicuculline对三个脑区的自发EEG活动均有显著影响,两组小鼠的自发EEG活动的显著性差异主要体现在海马和前额叶。尤其重要的是,AD小鼠的空间识别记忆能力与衰老小鼠相比明显降低,而0.1 mg/kg的Muscimol和Bicuculline均可显著提高AD小鼠的空间识别记忆能力,但在衰老小鼠上Muscimol无明显作用,而Bicuculline具有损害作用。同时,Y迷宫任务态EEG活动分析显示,两种药物主要影响两组小鼠的前额叶活动。最后,合并AD小鼠和衰老小鼠不同给药组数据,结果发现,在衰老小鼠上,Y迷宫任务态中三个脑区的五个基本频段(2-100 Hz)EEG活动与其空间识别记忆能力显著相关,而在AD小鼠中,仅海马和前额叶的低频Delta波段(2-4 Hz)EEG活动与其空间识别记忆能力显著相关。主要结论:低剂量GABA能系统的正向或负向药理调节均可以促进AD小鼠的空间识别记忆能力,可能与海马、前额叶的低频脑电活动降低有关,而这两种调节在衰老小鼠上却有不同的作用,与多个脑区广泛频率的脑电活动协同变化相关。本研究对于揭示AD及衰老的发生、发展以及有效诊断和治疗具有重要临床意义。GABA系统有望成为AD、衰老等神经退行性疾病相关记忆修复的有效靶点。
[Abstract]:Alzheimer's Disease (AD) is also known as Alzheimer's disease. It is a chronic progressive neurodegenerative disease. It is a chronic progressive neurodegenerative disease. It is common in the old age. Its pathogenesis is not clear and there is no effective treatment. Senescence is a whole brain process, which is divided into physiological brain senescence and pathological brain senescence, and pathological brain changes. The.AD and aging processes associated with AD and other neurodegenerative diseases are associated with memory impairment, neurotransmitter level and abnormal neuroactivity, suggesting that the two have a similar neuropathological basis. Gamma aminobutyric acid (gamma -Aminobutyricacid, GABA) is the most important inhibitory neurotransmitter in the central nervous system, and it retreats in senescence and AD. The.GABA system plays an important role in regulating the whole neural network system through the inhibition of excitatory neurons. Electroencephalogram (EEG) is a more sensitive method for real-time monitoring of brain activity. It has important clinical values in the diagnosis and treatment of many kinds of neurologic and psychic diseases. The purpose of this study was to investigate the effects of GABA energy system on spatial recognition memory and EEG in AD model mice and aging mice. The study used the GABAa receptor agonist, muscinol (Muscimol) and antagonist (Bicuculline), and the EEG recording site was the hippocampus, prefrontal lobe and cortex. First, we used drugs low, In the young mice, the dose screening experiment was conducted on the young mice. The activity of mice was analyzed by the field experiment. The Y maze model was used to evaluate the memory of the mice, and the EEG records of three brain regions were used to study the changes of brain activity. After that, an effective dose of the drug was applied to the AD model mice and the aging mice. Experiments were conducted to study the activity of the two groups of mice, the spatial recognition memory, and the similarities and differences between the spontaneous EEG, and we also studied the similarities and differences between the two groups of mice in the three brain regions of the exploratory Y labyrinth task state. The results were as follows: first, low dose of Muscimol (0.1 mg/) was used in the screening experiment of animal dose in young animals. Kg) slightly increased the activity of young mice, significantly promoted the spatial recognition memory in the Y labyrinth experiment, and significantly affected the spontaneous EEG activity in the three brain regions within two hours after the drug administration, while the same dose of Bicuculline had no significant influence on the activity and spatial recognition memory of the mice, but the drug was given by the drug. After two hours, the spontaneous EEG activity in the prefrontal lobe was significantly affected. After that, we used the low dose of two drugs to study the AD model mice and the aging mice (12 month old). The results showed that the dose of Muscimol and Bicuculline had no significant effect on the activity of the two groups of mice; but Muscimol significantly affected the hippocampus and the cortex of the mice. Spontaneous EEG activity, while Bicuculline has significant influence on spontaneous EEG activity in the three brain regions. The significant difference in spontaneous EEG activity in the two groups is mainly in the hippocampus and prefrontal lobe. Especially, the spatial recognition and memory ability of AD mice is significantly lower than that of aging mice, while the 0.1 mg/kg Muscimol and Bicuculline can be shown to be significant. The ability of spatial recognition and memory of AD mice was improved, but Muscimol had no obvious effect on aging mice, and Bicuculline had damage. At the same time, the analysis of EEG activity in the task state of Y maze showed that the two drugs mainly affected the prefrontal activity of two groups of mice. Finally, the data of different drug groups were combined with AD mice and aging mice, and the results were found, On aging mice, five basic frequencies (2-100 Hz) EEG activity in the three brain regions in the Y maze task state were significantly related to their spatial recognition and memory ability. In AD mice, the low frequency Delta band (2-4 Hz) EEG activity in the hippocampus and prefrontal lobe was significantly correlated with the spatial recognition memory ability. The main conclusion: the low dose GABA energy system was positive or negative. Pharmacological regulation can promote the spatial recognition and memory ability of AD mice, which may be related to the low frequency electroencephalogram activity in the hippocampus and prefrontal lobe, but these two kinds of regulation have different effects on the aging mice, which are related to the extensive frequency of brain electrical activity in multiple brain regions. This study reveals the development and development of AD and senescence. Effective diagnosis and treatment is of great clinical significance..GABA system is expected to become an effective target for memory repair related to AD, aging and other neurodegenerative diseases.

【学位授予单位】：昆明理工大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.16

【参考文献】