臺灣博碩士論文加值系統

在哺乳類轉錄因子中的ATF/CREB家族是一大群含有基本的亮胺酸拉鍊 (basic Leucine zipper, bZip)結構的蛋白所組成。他們可以根據胺基酸序列的相似性被分類成ATF1-ATF6。其中Atf3是一種壓力誘導的基因。在大部分的細胞中，其信使核糖核酸 (mRNA)表現量很低，但是在細胞暴露在壓力訊號之下時，其信使核糖核酸會快速地被壓力誘導且轉錄且表現量會有巨幅的上升。壓力誘導Atf3可以透過許多不同的訊號傳導路徑，例如說p53以及ATF2的訊號。而ATF3本身既是轉錄活化因子 (activator)和轉錄抑制子 (repressor)。當ATF3是同型二具體(homodimer)時，為一個抑制子；然而當ATF3與c-JUN/JunD形成異型二具體 (heterodimer) 時，則已經被證明是轉錄的活化因子。在先前研究當中，發現ATF3在海馬迴有大量表現，然而目前Atf3在記憶形成中，所扮演的功能尚未釐清。為了研究記憶形成中Atf3的基因功能為何，我利用Atf3基因剔除(knockout, KO)小鼠來進行恐懼制約 (fear conditioning)、莫氏水迷宮 (Morris water maze)和旋臂迷宮 (radial arms maze)測試。首先先對Atf3 基因剔除小鼠和野生型 (wildtype)小鼠進行外觀、運動能力以及感官功能進行比較。實驗結果發現Atf3基因剔除小鼠和野生型小鼠無顯著差異。接著我進行了延宕恐懼制約 (Delay fear conditioning, DFC)及痕跡恐懼制約 (Trace fear conditioning, TFC)。實驗結果發現，Atf3基因剔除小鼠在記憶提取中，包含情境測試 (Contextual test)和聲音測試 (Tone test)，都表現出比野生型小鼠較為高比例的僵直行為 (Freezing)。為了瞭解ATF3是不是只和壓力誘導的記憶相關，因此我利用了莫氏水迷宮以及旋臂迷宮來當作無壓力的平台來進行測試。其結果為Atf3基因剔除小鼠在無壓力的測試實驗中展示出和野生型小鼠相似的表現。在細胞層次中，我們利用高基染色法 (Golgi staining)並在六十以及一百倍的顯微鏡中計數經由染色呈現的樹突突棘 (dendritic spines)數目。我們發現在Atf3基因剔除小鼠和野生型小鼠在未經訓練的組別 (naïve group)中展現相似的突棘數目。有趣的是在經過痕跡恐懼制約訓練之後，Atf3基因剔除小鼠和野生型小鼠的突棘數目都有顯著性的提高。而Atf3基因剔除小鼠的突棘數目是野生型小鼠的1.67倍之高。這些實驗顯示了，Atf3在抑制壓力誘導的恐懼記憶中扮演專一且重要的角色。而壓力誘導的恐懼記憶是創傷性壓力症候群 (PTSD) 患者的患病主要原因之一。因此未來可藉著抑制ATF3的表現以治療PTSD症狀的方法。

The mammalian ATF/CREB family of transcription factors represents a large group of basic region-leucine Zipper proteins (bZip). These proteins can be grouped into six subgroups according to their amino acid similarity: ATF1 to ATF6. Atf3 (Activating Transcription Factor 3) is a stress inducible gene. Its mRNA level is low in most cells, but greatly increased upon the exposure of cells to stress signals and its induction is immediate and transient. Stress signals induce Atf3 through complex mechanisms involving multiple pathways, such as the p53 and ATF2 signaling. ATF3 serves as both transcription activator and repressor. ATF3 homodimer is a transcriptional repressor; however, heterodimeric complex of ATF3 with c-Jun (or JunD) has been demonstrated to function as a transcriptional activator. In previous studies showed, the ATF3 is highly expression in the hippocampus. However the Atf3 gene function in learning and memory is not clear yet. In order to investigate the Atf3 gene function in memory formation, I used the Atf3 knockout (KO) mice to test them on fear conditioning, Morris water maze (MWM) and radial arms maze (RAM). First I compared the Atf3 KO mice with their wildtype (WT) littermates in morphology, locomotor activity and sensory function. Results showed no significant difference between the Atf3 KO mice and the WT mice. Next I performed Fear conditioning tasks, including Delay Fear Conditioning (DFC) and Trace Fear Conditioning (TFC). The Atf3 KO mice exhibited higher freezing percentage in memory retrieval, including contextual and tone test than WT mice. To understand whether the ATF3 is specifically associated with performance of stress-induced memory, I used the MWM and RAM as non-stressful models to test the Atf3 KO. The Atf3 KO mice displayed similar performance as WT mice on non-stress memory task. And at the cellular level, I used the Golgi staining to measure the numbers of spine at 60X and 100 X magnifications. I found that the dendritic spines of WT and Atf3 KO mice are similar in naïve group. Interestingly, the spine numbers of WT and Atf3 KO mice are significant increase. And the most important thing is the spine number of Atf3 KO mice is increasing 1.67 fold than WT littermates. These results indicated the Atf3 played a specific and important role in suppressing stress-induced fear memory. And the highly stressful fear memory is similar with the major risk of PTSD (post-traumatic stress disorder). Thus, if the ATF3 expression were knockdown by shRNA, may be able to reduce the symptoms of PTSD. It is also a great research direction to study.

Abstract…………………………………………………………… ……………………………….I
中文摘要…………………………………………………………………………………...…………II
Index………………………………………………………………………………….. ……………..0
1. Introduction…………………………………………………………………… ………………1
a. The ATF/CREB family………………….………..…………….……………… …………….1
b. The Atf3 gene and structure of the ATF3 protein………………...………………. ………….1
c. Induction and regulation of the Atf3………………...…………………………… …….…….2
d. Stages of memory formation…………………………………….…………………. ………..3
e. The Hippocampus and Hippocampal-dependent Learning/Memory………………… .……..4
f. Aim of this thesis……………………………………………………………………… ……..7
2. Experimental design…………...……….………………………………………… ..……..8
3. Methods and materials……………………………………………………..……9
a. Animals……………………………………………………………………………..…...…….9
b. Genotyping of the Atf3 knockout mice…………………………………………….………..…9
c. Locomotor activity test……………………………………………………………………...….9
d. Sensory function test………………………………………………………………...…...…….9
e. Fear conditioning…………………………………………………………………… ………10
f. Morris water maze……………………………………………………………………..……...11
g. Radial arms maze…………………………………………………………………..…………11
h. RNA extraction………………………………………………………………………..…...…12
i. Real-time Quantitative PCR………………………………………………………….....…….13
j. Golgi staining……………………………………………………...……………………...…...14
k. Statistics………………………………………………………………………………...……..15
4. Results……………………………..……………………….…………….………16
5. Discussion…………………………………………………….…………….……20
6. Figures…………………………………………………………………..…….…24
7. Table..……………………………………………………………………… .…..55
8. References…………………………………………………………… ……...….56

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