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系統識別號 U0026-2007201000363900
論文名稱(中文) 生命早期壓力經由表觀遺傳調控成年後恐懼制約記憶的形成
論文名稱(英文) Epigenetic regulation of early life stress on adult fear conditioning
校院名稱 成功大學
系所名稱(中) 行為醫學研究所
系所名稱(英) Institute of Behavioral Medicine
學年度 98
學期 2
出版年 99
研究生(中文) 鄭令宜
研究生(英文) Ling-Yi Cheng
電子信箱 lynnc815@gmail.com
學號 s8696405
學位類別 碩士
語文別 英文
論文頁數 33頁
口試委員 指導教授-游一龍
口試委員-楊延光
口試委員-蕭富仁
中文關鍵字 超基因學  母親離合關係  恐懼制約  組織蛋白去乙醯基作用 
英文關鍵字 Epigenetics  maternal separation  fear conditioning  histone deacetylation 
學科別分類
中文摘要 目前已經有許多研究發表指出「早期生活壓力」是影響晚期行為的一項重要因素。然而卻鮮少有研究利用「超基因學」理論來解釋其發生的機轉。此研究中,我們企圖藉由干擾DNA甲基化及/或組織蛋白去乙醯基作用來研究「早期生活隔離壓力」對於成年期恐懼制約記憶的影響。研究方法為將幼鼠在出生後第二天到九天,每天以屏障物將幼鼠與其兄弟姐妹隔離一個小時,藉此形成「生命早期壓力」。而後藉由恐懼所引發的驚嚇反應(FPS)範例來評估成鼠的恐懼制約。研究結果顯示,相較於未經歷隔離壓力的成鼠,曾經曝露在初生期隔離壓力者對於FPS測試具有較低的制約反應。我們進一步探討是否可以藉由給予組織蛋白去乙醯基作用抑制劑來逆轉這種反應。研究方法為在幼鼠進行隔離之前,以腹腔內注射的方式給予組織蛋白去乙醯基作用抑制劑- Valproic acid(VPA;泡製於0.9% 生理食鹽水中)。劑量分別為高劑量(300mg/kg)、中劑量(100-200-300mg/kg)或低劑量(100-200mg/kg),而控制組則以腹腔內注射的方式給予等量的生理食鹽水。此項研究結果顯示,與控制組相比較,接受VPA治療的組別具有較高的恐懼制約反應,也就是可以恢復因壓力導致恐懼所引發的驚嚇反應降低。我們的結論是因為早期生活壓力而導致恐懼所引發的驚嚇反應降低可能是跟壓力造成組織蛋白去乙醯基作用有關。
英文摘要 Early life stress has been highlighted in numerous studies as an important influence on later behaviors but seldom has epigenetics been implicated as the mechanism via which this process takes place. In this study we attempted to investigate alterations in DNA methylation and/or histone deacetylation associated with an early life isolation stress and their impact upon fear memory in adulthood. Daily isolation from the dam and siblings from day 2 to 9 post partum (1 hr/day) was utilized as the method of early life stress and a fear potentiated startle (FPS) paradigm was used to examine fear conditioning in adult rats. Our findings revealed that rats exposed to neonatal isolation stress had a diminished conditioning aptitude in the fear potentiated startle test compared to their siblings that had not experienced isolation stress. We further explored whether this effect could be reversed by valproic acid, a histone deacytylase inhibitor. Pups were injected intraperitoneally (i.p.) with valproic acid in high (300mg/kg), medial (100-200-300mg/kg), or low (100-200mg/kg) dose in 0.9% saline solution prior to their isolation. Control groups were injected i.p. with an equivalent volume of saline solution. Results indicated that the VPA-treated groups had a higher fear conditioning aptitude, in comparison to that of the saline-treated group, indicating a reversal of stress-decreased fear potentiation. We conclude that lowered startle potentiation caused by early life stress may be due to stress-induced histone deacetylation.
論文目次 中文摘要………………………………………………………………………………………2
Abstract……………………………………………………………………………………….3
Acknowledgements…………………………………………………………………………...4
Table of Contents……………………………………………………….…………………….6
Introduction…………………………………………………………………………………..7
Materials and methods……………………………………………………………………...11
1. Animal Care and Housing…………………………………………………………..11
2. Drugs………………………………………………………………………………..11
3. Stress Paradigms……………………………………………………………………12
4. Experimental Paradigms…………………………………………………………....15
5. Immunoassays………………………………………………………………………17
6. Statistical Analysis………………………………………………………………….18
Results…………………………………………………………………………………..…...19
1. Behavioral Data: FPS……………………………………………………………..19
2. VPA stress-lowered fear potentiation……………………………………………...20
3. Serum corticosterone level of VPA-treated animals……………………………….23
4. Estradiol…………………………………………………………………………...25
Discussion……………………………………………………………………………………26
Supplementary Data: Baseline Figures……………………………………………………28
References…………………………………………………………………………………...31
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