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系統識別號 U0026-0812200910440207
論文名稱(中文) 以cDNA微陣列技術篩選大白鼠海馬迴中與抑制性躲避學習與記憶相關的基因
論文名稱(英文) Searching for Memory-related Genes in the Rat Hippocampus after Inhibitory Avoidance Learning by cDNA Microarray Techniques
校院名稱 成功大學
系所名稱(中) 生理學研究所
系所名稱(英) Department of Physiology
學年度 91
學期 2
出版年 92
研究生(中文) 林雅屏
研究生(英文) Ya-Ping Lin
電子信箱 lyp0205@ccmail.ncku.edu.tw
學號 s3690402
學位類別 碩士
語文別 英文
論文頁數 88頁
口試委員 召集委員-簡伯武
口試委員-劉校生
指導教授-黃阿敏
中文關鍵字 抑制性躲避學習  cDNA微陣列 
英文關鍵字 cDNA microarray  inhibitory avoidance learning 
學科別分類
中文摘要   記憶依據其形成及維持的時間可以分成兩種不同的形式:短期記憶及長期記憶。短期記憶只需要已存在的分子短暫的活化就能形成;相反的,長期記憶的形成則需要有新的核醣核.酸分子及蛋白質合成。然而長期記憶形成究竟需要啟動哪些基因表現目前仍然不甚清楚。為了能大規模地篩選與長期記憶形成有關的基因,並進而推測可能的分子機制,我們利用了cDNA 微陣列技術來探討長期記憶形成的過程中,核醣核.酸分子表現的變化。本實驗所使用的是單向抑制躲避學習行為模式,這是一個與海馬迴有關的學習行為模式。我們首先將動物隨機分成五組,在行為測試之後,抽取海馬迴組織的核醣核.酸,由百恩諾公司進行cDNA 微陣列分析。結果顯示,至少有450 多個基因在學習過後與控制組相較起來,能達到兩倍以上的表現差異。而我們有興趣的基因表現模式為:在學習之後3 小時表現即增加,持續至24 小時,而在naive 及學習1週則回到正常值,這樣的基因共有20 個,接著以北方轉漬法來確認cDNA 微陣列分析是否正確。北方轉漬法共分析7 個基因,即三磷酸腺.合成.α次單元體(ATP5a1)、蘋果酸去氫.(Mor1)、蛋白去磷酸.調控次單元體(Ppp2r1a)、菸草醯腺嘌呤雙核.去氫.黃素蛋白(Ndufv1)、NADH-ubiquinone 氧化還原.、核醣體蛋白S20 及麩氨基硫過氧化.(Gpx1)。其中ATP5a1 基因若以微陣列所使用的樣本分析,在學習後3、6 及24 小時可看到在學習組的老鼠基因表現增加。但如果以另外四對獨立的樣本分析,則在學習組的老鼠表現反而減少,並於24 小時時間點達到顯著變化。Mor1, Ndufv1 及Ppp2r1a 在四對獨立樣品也有相似的差異。若再以另外四對樣本則只有Ndufv1 能被重複確認。此外,其餘三個基因,則在學習及控制組無差異。由於發現已確認的基因大部分在學習之後24 小時達到顯著差異,我們接著以這個時間點,抽取mRNA,由陽明大學微陣列及基因表現核心實驗室進行cDNA 微陣列分析。結果顯示有112個基因在學習之後較控制組達兩倍以上的增加,而有165 個基因則是減少,這些基因功能大多與能量代謝、訊息傳遞及轉譯轉錄調控有關。此外,我們亦以大鼠的基因晶片做微陣列分析,總共有五十多個基因在學習組以及控制組有表現差異。這部分挑選六個基因以即時合成.鏈鎖反應以及另外七對大鼠樣品進行確認,結果顯示其中NGCP 基因僅可在另外兩對樣品中看到學習組老鼠表現增加,而CRSP 基因只在另外三對樣品中看到學習組老鼠表現增加,其餘的樣品則並未看到增加。以上的結果顯示,利用cDNA 微陣列技術篩選與記憶相關的基因表現,雖然可以大規模篩得許多表現有變化的基因,然而後續的確認方法並無法完全確認微陣列所得的結果。其原因可能包括cDNA 微陣列技術本身,實驗的設計與個體的差異,因此這些篩得的基因是否確實與記憶相關仍有待確認。
英文摘要 Memory can be divided into two different forms based on the duration: short-term memory (STM) and long-term memory (LTM). Unlike short-term memory, which only needs transient activation of pre-existing molecules, long-term memory is dependent on de novo mRNA and protein synthesis. However, the spectrum of genes involved in long-term memory formation is still unclear. To identify the genes contributed to long-term memory formation and predict the putative molecular mechanisms, we have used the cDNA microarray techniques to assess changes in gene expression after one-trial inhibitory avoidance learning, a paradigm that can form long-term memory and is relatively associated with the hippocampus. Animals were assigned randomly into five groups: naïve, 3 hr, 6 hr, 24 hr and 1 week (n = 2 per group, including learned samples and shock controls). Hippocampal total RNAs were isolated and subjected to microarray analyses. More than 450 unique cDNA clones were found 2-fold up-regulated in the learned samples. A cluster of genes, 20 in total, which fold changes in the 3, 6, and 24hr-learned groups were significant when compared with those in naïve and the 1 week-learned groups, were selected for further validation. Seven genes of this cluster, ATP synthase 5a1 (Atp5a1), malate dehydrogenase (Mor1), NADH dehydrogenase flavoprotein 1 (Ndufv1), protein phosphatase 2 regular subunit A (Ppp2r1a), NADH-ubiquinone oxidoreductase 20 KDa subunit, ribosomal protein S20 and glutathione peroxidase 1(Gpx1), were examined by Northern hybridization. Results have shown that the expression levels of Atp5a1 in the learned samples were higher than shock controls at 3, 6, and 24 hr if using the samples that were used for the microarray analysis. However, the level of ATP5a1 gene was found to be down-regulated, especially at 24 hr (P value = 0.006) in learned samples when four pairs of independent samples were used. Similarly, the expression levels of Mor1, Ndufv1 and Ppp2r1a in learned samples also decreased significantly than in shock controls at 24 hr (P value = 0.03, 0.003, 0.003 respectively) in this set of samples. Among these four genes, only Ndufv1 can be reconfirmed by another set of RNA samples. The discrepant results may be contributed from the microarray technique itself or the individual difference of the rat samples. Since more genes were found to be differentially expressed in the samples from 24 hr after learning, another two microarray chips with modified methods were performed for this time point. Approximately 112 up-regulated genes and 165 down-regulated genes were identified. Finally, we also used the rat chip to analyze differential gene expression and found that 28 genes were up-regulated in the learned samples and 27 genes were down-regulated. Six genes were examined by real-time RT-PCR using seven pairs of independent samples. Among these genes, the expression level of neuroglycan C precursor gene (NGCP) was found to be higher in the learned samples in only two pairs of rats and the cofactor required for Sp1 transcriptional activation (CRSP) was found to be higher in the learned samples only in three pairs of rats. Taken together, although a lot of memory-related genes can be quickly screened by the microarray studies, not all of these genes can be reconfirmed by independent samples using subsequent validation methods. The discrepancy may be resulted from the microarray technique itself, the experimental designs and individual difference of rat samples. Whether these genes were indeed related to memory formation have to be further confirmed.
論文目次 Acknowledgments.………………………………………………………………I
Table of Contents………………………………………………………….…III
List of Tables…………………………………………………………………V
List of Figures…………………………………………………………….…VI
Abstract in Chinese……………………………………………………………1
Abstract………………………………………………………………………….3
Introduction………………………………………………………….…………5
Material and Methods…………………………………………………………16
Animals…………………………………………………………………16
Inhibitory avoidance learning task………………………….…16
Tissue dissection and total RNA or mRNA isolation…………18
Microarray analysis…………………………………………………20
Northern blot analysis………………….…………………………23
Minipreparation of plasmid DNA…………………………….……26
Reverse transcription real-time polymerase chain reaction26
Statistics………………………………………………………….…27
Results (PartI)………………………………………………………….……29
Retention performance of rats in the one-trial inhibitory
avoidance learning task……………………………………………29
Microarray analysis…………………………………………………30
Northern hybridization analysis…………………………………31
(PartII)………………………………………………………….……33
Retention performance of rats in the one-trial inhibitory
avoidance learning task……………………………………………33
Microarray analysis…………………………………………………33
Real-time PCR analysis…………………………………….………35
Discussion………………………………………………………………………37
References………………………………………………………………………47
Appendix…………………………………………………………………………84
About the author………………………………………………………………88
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