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系統識別號 U0026-0812200911262633
論文名稱(中文) 週邊給予脂多醣對小鼠學習與記憶之研究
論文名稱(英文) The effects of peripheral lipopolysaccharide administration on the learning and memory of mouse
校院名稱 成功大學
系所名稱(中) 細胞生物及解剖學研究所
系所名稱(英) Institute of Cell Biology and Anatomy
學年度 93
學期 2
出版年 94
研究生(中文) 蔡幸容
研究生(英文) Tsai hsing-jung
學號 T9690103
學位類別 碩士
語文別 中文
論文頁數 88頁
口試委員 指導教授-郭余民
召集委員-陳洵瑛
口試委員-游一龍
中文關鍵字 脂多醣 
英文關鍵字 lipopolysaccharide 
學科別分類
中文摘要   脂多醣(lipopolysaccaride)是葛蘭氏陰性菌外膜的成分之一,目前已被廣泛應用在刺激免疫細胞產生細胞激素(cytokines)和誘發發炎反應的實驗上。先前的研究指出,以腹腔內注射的方式給予脂多醣所造成之週邊發炎反應,會導致中樞神經系統神經膠細胞(microglia)之活化。根據研究顯示,在腦中海馬迴和顳葉兩個區域內神經膠細胞活化,會造成學習和記憶的損傷。本論文的目的是研究慢性週邊發炎反應對小鼠學習記憶的影響。此外,有研究指出運動可以促進神經新生並且改善學習和記憶的能力。因此,本研究的另一目的是探討運動訓練對經脂多醣處理的小鼠學習與記憶之影響。本研究選用跑步機訓練做為運動模式,因為此方式可以調控運動的強度和持續的時間。實驗小鼠以腹腔內注射的方式給予每週一劑每公斤體重一毫克之濃度的脂多醣,連續處理四週。對照組則給予相同體積的生理食鹽水。脂多醣組和對照組再各分為有運動組(運動加脂多醣處理組以及運動加生理食鹽水處理組),與不運動組(脂多醣和生理食鹽水)。小鼠經兩週之運動訓練結束後,開始給予每週一劑每公斤一毫克之脂多醣,以腹腔內注射的方式連續處理四週。全程之運動訓練完畢的兩天後,一半數量的動物以莫利斯水津迷宮(Morris water maze)的方法來評估學習和記憶之能力。另一半數量的動物群,斷頭犧牲後,灌流取腦,進行形態學上的分析。實驗結果顯示,經脂多醣處理的小鼠,免疫組織染色顯示,脂多醣組和運動加脂多醣處理組在海馬迴(hippocampus)、內嗅皮質區(entorhinal cortex)、杏仁核(amygdala)有神經膠細胞活化的情形。而沒有任何組之星型膠細胞(astrocytes)有活化的現象。此外,脂多醣會誘發血腦障壁(blood-brain barrier)破損,此現象可藉由伊凡藍(Evans blue)染劑來偵測。五週之運動訓練可改善血腦障壁破損。脂多醣處理組在莫利斯水津迷宮的表現比生理食鹽水處理組差。小鼠經脂多醣處理後,需花更多的時間找到平台。在游泳速度方面,脂多醣組和生理食鹽水組則無顯著差異。運動並無法改善脂多醣所造成學習與記憶的損傷。總括來說,本論文證明了慢性週邊的發炎反應會誘發中樞神經系統之微小膠細胞的活化、血腦障壁破損以及學習與記憶能力的缺失。雖然五週的運動訓練,可以減少脂多醣所誘發之微小膠細胞活化與血腦障壁破損的程度,但是無法很顯著改善脂多醣所導致的學習與記憶能力的缺失。

英文摘要  Lipopolysaccharide (LPS), a constituent of the outer membrane of Gram-negative bacteria, is widely used to stimulate experimentally the production of cytokines and inflammatory responses. The intraperitoneal (i.p.) administration of LPS causes a peripheral inflammatory cascade that is transduced to the brain and causes microglia activation. Previous studies have suggested that activation of microglia within specific brain regions might impair the learning and memory performance. The first objective of this study is to investigate the effects of chronic systemic inflammation on the performance of learning and memory. It has been suggested that exercise has beneficial effects on brain function, such as improving learning/memory capability and promoting neurogenesis. Therefore, the second objective of this study is to examine the effects of exercise on the learning and memory of the LPS-treated animals. Treadmill exercise paradigm was selected, because the intensity and duration of exercise can be controlled. Half of the animals received 4 doses of LPS (1 mg/kg/week, i.p.) treatments, the other half received saline (Sal) injections. The LPS and Sal groups were further divided into exercise (Ex-LPS, Ex-Sal) and non-exercise (LPS, Sal) groups. Those mice received exercise training were trained for 2 weeks prior to the injections of 4 doses of LPS (1 mg/kg/week, i.p.) or saline. Two days after the end of the exercise training, half of the animals were subjected to Morris water maze to assess spatial learning ability. The other half of the mice were killed and their brains were removed and prepared for morphological analyses. Immunohistochemical evidence showed that microglia activation was found in the hippocampus, entorhinal cortex, and amygdala in LPS and Ex-LPS groups. No astrocyte activation was evident in any of the 4 groups. LPS induced a blood-brain barrier leakage, as assessed by Evans blue extravasation, which can be attenuated by five weeks of exercise. Furthermore, my results revealed that mice received 4 doses of LPS administration performed worse than the saline-treated group in the Morris water maze. Mice treated with LPS had increased latency and path length on finding the training block. The swimming speed was similar between the LPS and saline groups. Five weeks of exercise training did not rescue the LPS-induced learning and memory impairment. Taken together, my study suggests that chronic peripheral inflammation can induce CNS microglia activation, BBB leakage, and learning and memory deficit. Although 5-week exercise can lessen the LPS-induced microglia activation and BBB disturbance, it does not restore the LPS-elicited learning and memory impairment.

論文目次 目錄

致謝…………………………………………………………………..3
中文摘要…………………………………………………………. 4~6
英文摘要…………………………………………………………..7~9
目錄……………………………………………………………….10~11
圖目錄……………………………………………………………12~13
縮寫檢索表………………………………………………………14~16
第一章 緒論………………………………………………………....17
第一節 中樞神經系統的發炎反應………………………...18~23
第二節 微小膠細胞與中樞神經系統發炎………………...23~26
第三節 血腦障壁與中樞神經系統發炎之關連…………...26~27
第四節 脂多醣……………………………………………...27~29
第五節 大腦發炎與學習記憶能力………………………...29~30
第六節 運動訓練與腦功能……………………………….. 30~31
第二章 研究目的………………………………………………...32~33
第三章 材料及方法…………………………………………………34
第一節 實驗動物………………………………………………35
第二節 實驗設計…………………………………………..35~36
第三節 莫利斯水津迷宮測試……………………………..36~37
第四節 灌流取腦…………................................................. 37~38
第五節 腦組織的抗凍處理……………………………….38~39
第六節 冷凍切片………………………………………….39~40
第七節 免疫組織染色法……………………….................40~42
第八節 封片………………………………...............................42
第九節 伊凡藍染劑的製備與動物處理………………….42~43
第十節 統計分析……………………………….......................43
第四章 實驗結果…………………………………………………..44
體重變化情形…………………………………………………45
微小膠細胞與星型膠細胞之型態學方面的分析………...45~46
利用伊凡藍染劑來觀察血腦障壁的完整性………………….46
莫利斯水津迷宮測試………………………………………46~47
第五章 討論……………………………………………………..48~54
第六章 結論……………………………………………………..55~56
第七章 參考文獻………………………………………………..57~67
第八章 圖………………………………………………………..68~88



圖目錄

圖一. 實驗設計…………………...…………………………………69
圖二. 各組小鼠在實驗期間的體重變化曲線圖…………………...70
圖三. 使用CD11b偵測微小膠細胞在齒回(dentate gyrus)之分布
情形…………………………………………...........................71
圖四. 使用CD11b偵測微小膠細胞在CA區之分布情形……….72
圖五. 使用CD11b偵測微小膠細胞在視丘(thalamus)之分布情形73
圖六. 使用CD11b偵測微小膠細胞在前額皮質(prefrontal cortex)
之分布情形……………………………………………………74
圖七. 使用CD11b偵測微小膠細胞在內嗅皮質(entorhinal cortex)
之分布情形…………………………………………………...75
圖八. 使用CD11b偵測微小膠細胞在杏仁核(amygdala)之分布情
形…………………………………………...............................76
圖九. 使用GFAP偵測星形膠細胞在齒回(dentate gyrus)之分布
情形……………………………………………………….77
圖十. 使用GFAP偵測星形膠細胞在CA區之分布情形………..78
圖十一. 使用GFAP偵測星形膠細胞在視丘(thalamus)之分布情
形…………………………………………………………79
圖十二. 使用GFAP偵測星形膠細胞在前額皮質(prefrontal cortex)
之分布情形………………………………………………..80
圖十三. 使用GFAP偵測星形膠細胞在內嗅皮質(entorhinal cortex)
之分布情形………………………………………………..81
圖十四. 使用GFAP偵測星形膠細胞在杏仁核(amygdala)之分布
情形………………………………………………………..82
圖十五. 使用伊凡藍染劑偵測CA1區之血腦障壁破損的情況….83
圖十六. 使用伊凡藍染劑偵測CA2區之血腦障壁破損的情況….84
圖十七. 使用伊凡藍染劑偵測CA3區之血腦障壁破損的情況….85
圖十八. 使用伊凡藍染劑偵測繖區(fimbria)之血腦障壁破損的情
況…………………………………………………………..86
圖十九. 莫利斯水津迷宮-訓練測試……………………………….87
圖二十. 莫利斯水津迷宮-偵查測試(probe test)…………………...88

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