本文選題：阿爾茨海默病 + 衰老　； 參考：《昆明理工大學(xué)》2017年碩士論文

【摘要】：阿爾茨海默病(Alzheimer's Disease,AD)也被稱(chēng)為老年性癡呆癥,是一種慢性進(jìn)行性神經(jīng)退行性疾病,發(fā)病隱襲,常見(jiàn)于老年期,其致病機(jī)制不清楚,尚無(wú)有效治療藥物。衰老是一個(gè)全腦的過(guò)程,分為生理性腦衰老和病理性腦衰老,而病理性腦的變化與AD等神經(jīng)退行性疾病相關(guān)。AD和衰老過(guò)程都伴隨有記憶減退、神經(jīng)遞質(zhì)水平與神經(jīng)活動(dòng)異常,提示二者有著相似的神經(jīng)病理學(xué)基礎(chǔ)。伽瑪氨基丁酸(γ-Aminobutyricacid,GABA)是中樞神經(jīng)系統(tǒng)中最重要的抑制性神經(jīng)遞質(zhì),在衰老和AD等神經(jīng)退行性病變過(guò)程中發(fā)揮重要作用。GABA系統(tǒng)通過(guò)對(duì)興奮性神經(jīng)元的抑制作用而調(diào)控整個(gè)神經(jīng)網(wǎng)絡(luò)系統(tǒng)。腦電圖(Electroencephalogram,EEG)是即時(shí)監(jiān)測(cè)大腦活動(dòng)狀態(tài)的一種較為敏感的方法,在多種神經(jīng)、精神性疾病的診斷和治療中具有重要臨床應(yīng)用價(jià)值。本研究主要探討激動(dòng)或拮抗GABA能系統(tǒng)對(duì)AD模型小鼠和衰老小鼠空間識(shí)別記憶及EEG的影響。研究使用了 GABAa受體激動(dòng)劑蠅蕈醇(Muscimol)與拮抗劑荷包牡丹堿(Bicuculline);EEG記錄位點(diǎn)為海馬、前額葉與皮層。首先,我們采用藥物的低、中、高三種劑量在青年小鼠上進(jìn)行劑量篩選實(shí)驗(yàn),采用礦場(chǎng)實(shí)驗(yàn)分析小鼠活動(dòng)力,探索型Y迷宮范式評(píng)價(jià)小鼠空間識(shí)別記憶,以及三個(gè)腦區(qū)自發(fā)狀態(tài)EEG記錄研究大腦活動(dòng)變化。之后,將藥物的一個(gè)有效劑量應(yīng)用于AD模型小鼠和衰老小鼠上進(jìn)行實(shí)驗(yàn),研究?jī)山M小鼠之間活動(dòng)力、空間識(shí)別記憶、自發(fā)EEG之間的異同,并且,我們也研究了該劑量下兩組小鼠在探索型Y迷宮任務(wù)態(tài)下三個(gè)腦區(qū)局部EEG之間的異同。實(shí)驗(yàn)結(jié)果如下:首先,在青年動(dòng)物劑量篩選實(shí)驗(yàn)中,低劑量的Muscimol(0.1 mg/kg)輕微增加了青年小鼠活動(dòng)力,明顯促進(jìn)其在Y迷宮實(shí)驗(yàn)中的空間識(shí)別記憶力,并且在藥物給予之后的兩小時(shí)之內(nèi),顯著影響三個(gè)腦區(qū)的自發(fā)EEG活動(dòng);而相同劑量的Bicuculline對(duì)小鼠活動(dòng)力與空間識(shí)別記憶力均無(wú)顯著影響,但在藥物給予之后的兩小時(shí)之內(nèi),顯著影響前額葉的自發(fā)EEG活動(dòng)。之后,我們將該低劑量?jī)煞N藥物用于AD模型小鼠及衰老小鼠(≈12月齡)進(jìn)行研究,結(jié)果發(fā)現(xiàn)該劑量Muscimol和Bicuculline對(duì)兩組小鼠活動(dòng)力均無(wú)顯著影響;但Muscimol明顯影響了小鼠海馬和皮層的自發(fā)EEG活動(dòng),而B(niǎo)icuculline對(duì)三個(gè)腦區(qū)的自發(fā)EEG活動(dòng)均有顯著影響,兩組小鼠的自發(fā)EEG活動(dòng)的顯著性差異主要體現(xiàn)在海馬和前額葉。尤其重要的是,AD小鼠的空間識(shí)別記憶能力與衰老小鼠相比明顯降低,而0.1 mg/kg的Muscimol和Bicuculline均可顯著提高AD小鼠的空間識(shí)別記憶能力,但在衰老小鼠上Muscimol無(wú)明顯作用,而B(niǎo)icuculline具有損害作用。同時(shí),Y迷宮任務(wù)態(tài)EEG活動(dòng)分析顯示,兩種藥物主要影響兩組小鼠的前額葉活動(dòng)。最后,合并AD小鼠和衰老小鼠不同給藥組數(shù)據(jù),結(jié)果發(fā)現(xiàn),在衰老小鼠上,Y迷宮任務(wù)態(tài)中三個(gè)腦區(qū)的五個(gè)基本頻段(2-100 Hz)EEG活動(dòng)與其空間識(shí)別記憶能力顯著相關(guān),而在AD小鼠中,僅海馬和前額葉的低頻Delta波段(2-4 Hz)EEG活動(dòng)與其空間識(shí)別記憶能力顯著相關(guān)。主要結(jié)論:低劑量GABA能系統(tǒng)的正向或負(fù)向藥理調(diào)節(jié)均可以促進(jìn)AD小鼠的空間識(shí)別記憶能力,可能與海馬、前額葉的低頻腦電活動(dòng)降低有關(guān),而這兩種調(diào)節(jié)在衰老小鼠上卻有不同的作用,與多個(gè)腦區(qū)廣泛頻率的腦電活動(dòng)協(xié)同變化相關(guān)。本研究對(duì)于揭示AD及衰老的發(fā)生、發(fā)展以及有效診斷和治療具有重要臨床意義。GABA系統(tǒng)有望成為AD、衰老等神經(jīng)退行性疾病相關(guān)記憶修復(fù)的有效靶點(diǎn)。
[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.

【學(xué)位授予單位】：昆明理工大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R749.16

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本文編號(hào)：1804694