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系統識別號 U0026-0812200915251943
論文名稱(中文) PI3K於杏仁核在恐懼記憶再復發扮演必要角色
論文名稱(英文) PI-3 Kinase Activation in the Amygdala is Crucial for the Reinstatement of Fear Memory
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 97
學期 2
出版年 98
研究生(中文) 曾裕洲
研究生(英文) Yu-Chou Tseng
電子信箱 s2696405@mail.ncku.edu.tw
學號 s2696405
學位類別 碩士
語文別 英文
論文頁數 92頁
口試委員 指導教授-簡伯武
召集委員-吳豐森
口試委員-陳柏熹
中文關鍵字 PI3K  恐懼記憶  杏仁核 
英文關鍵字 fear memory  PI3K  Amygdala 
學科別分類
中文摘要 於2007年世界衛生組織 (WHO)的報告中提到,世界各地每小時就有140位人因為交通意外而喪命,交通意外不只奪走許多寶貴生命,更造成許多家庭的破碎,這些人(生還者和罹難者家屬)都會因此事件而增他們獲得創傷後壓力症候群的機率(Post-Traumatic Stress disorder,PTSD)。除此之後,許多會對於人造成身心壓力的意外、創傷(例如:性侵害和家庭暴力),都可能提高得到創傷後壓力症候群的機率,但現在並沒有能有效治療創傷後壓力症候群的方法。目前對於創傷後壓力症候群(PTSD)的有效治療,如何維持恐懼記憶消除(extinction)是一大挑戰,但理論上可透過抑制恐懼記憶的再復發 (reinstatement)來達成。使用古典恐懼制約(Classical fear conditioning)模式來研究PTSD的相關機制,其原理利用無傷害性刺激原 (conditional stimulus,CS)和嫌惡性刺激原 (unconditional stimulus,US)的配對訓練,使大鼠形成對CS的恐懼制約記憶。我們的結果顯示經過恐懼記憶消除訓練的大鼠再次暴露於US,會造成大鼠腦中杏仁核phosphatidylinositol-3 kinase (PI-3 kinase)的活化。在恐懼記憶學習中,CS和US沒有配對的控制組大鼠,在經過恐懼記憶消除及再復發訓練後,腦中杏仁核PI-3 kinase活化並無增加,顯示PI-3 kinase的活化對於恐懼制約學習具有專一性。此外,我們也發現這樣的活化現象侷限於杏仁核,而不是海馬迴或是小腦。恐懼記憶再復發訓練前,於兩側杏仁核微量注射PI-3 kinase抑制劑可以阻止恐懼記憶的再復發,相同劑量的PI-3 kinase抑制劑也可抑制杏仁核的Akt磷酸化。透過利用c-fos當作測量神經活性的指標以及免疫化學染色和免疫螢光染色實驗,我們發現大鼠單獨處理US的訓練,在杏仁核c-fos有表現上升的現象,說明在恐懼記憶再復發後杏仁核的神經活性上升,再次顯示杏仁核腦區在恐懼記憶再復發形成的重要性。另外,我們利用腹腔注射β-adrenergic受體的增效劑(isopropanolol)到大鼠體內,發現可以增強恐懼記憶再復發的表現,顯示在β-adrenergic受體與恐懼記憶再復發之間有著相關性,值得我們繼續探討。透過以上實驗,我們首次證實恐懼記憶的再復發需要杏仁核中PI-3 kinase的活化。恐懼制約模式中,將大鼠再次暴露於US可模擬臨床病人恐懼記憶的復甦 (recovery),因此抑制PI-3 kinase可能提供一個新的標的來治療焦慮症候群之再復發。
英文摘要 In the report of the 2007 World Health Organization (WHO), 140 people die in traffic accident in the world per hour. Traffic accident not only takes lives away, but also causes lots of broken families. Those people involved in the accident, the survivors and the families of the victims, would increase the ability to get the post-traumatic stress disorders (PTSD). In addition, many accident and trauma (ex. sexual assault and domestic violence) that cause physical and psychologic stress would increase the chance to get the PTSD. But there is no effective treatment for the PTSD patients at the moment. The major challenge for the effective treatment of PTSD is the persistent maintenance of fear reduction that could be accomplished theoretically by blocking reinstatement. Here we show that re-exposure to the unconditioned stimulus (US) in a previously extinction rat results in an activation of phosphatidylinositol 3-kinase (PI-3 kinase) in the amygdala. Control group that received conditioned stimulus (CS) and US in an unpaired fashion followed by extinction training and US-alone trials did not present any increase, indicating that PI-3 kinase activation is specific to the learning component of the task. In addition, this activation was restricted to the amygdala, but not the hippocampus or cerebellum. Bilateral administration of PI-3 kinase inhibitors to the amygdala before US-alone presentations interfered with reinstatement at the same dose that inhibited Akt phosphorylation. By using the c-fos as the neuronal activity marker, we found that c-fos expression was increased after the US-alone trials in the amygdala with the immunohistochemistry (IHC) and immunofluorescence (IF), indicating that after the reinstatement, the neuronal activity was increased in the amygdala, demonstrating the participating of amygdala in the formation of the reinstatement. With the β-adrenergic receptor agonist (isopropanolol) intraperitoneally injected injection into the rats, an enhancement of the reinstatement expressed by the rats has been found, indicating that there is a correlation between the β-adrenergic system and the reinstatement. In conclusion, our results provide the first evidence of a requirement of PI-3 kinase activation in the amygdala for the reinstatement of fear memory. As re-exposure to the US is one of the major causes for fear recovery, inhibition of PI-3 kinase may provide a new target for the treatment of anxiety disorders.
論文目次 1. Abbreviations------------------------------------------------------------ 10
2. Introduction-------------------------------------------------------------- 11
I. Post-traumatic Stress Disorder-------------------------------- 11
II. Amygdala and fear memory---------------------------------- 13
III. Fear extinction---------------------------------------------------- 15
IV. Reinstatement of fear memory-------------------------------- 17
V. Phosphatidylinositol 3-kinase and fear memory----------- 19
VI. c-fos----------------------------------------------------------------- 22
VII. Stress hormone--------------------------------------------------- 24
VIII. β-adrenergic system-------------------------------------------- 25
Purpose-------------------------------------------------------------------- 27
3. Materials and methods------------------------------------------------ 28
I. Animals------------------------------------------------------------- 28
II. Surgery------------------------------------------------------------- 28
III. Behavioral apparatus and procedures----------------------- 29
IV. Drug administration--------------------------------------------- 32
V. Western blot analysis-------------------------------------------- 32
VI. Immunohistochemistry----------------------------------------- 34
VII. Immunofluorescence--------------------------------------------- 36
4. Results--------------------------------------------------------------------- 38
I. Association between the reinstatement of fear memory
And activation of PI-3 kinase in the amygdala.----------- -38
II. The effects of intra-amygdala administration of PI-3
kinase inhibitors on the fear reinstatement.---------------- 40
III. Lack of the effect of PI-3 kinase inhibitor on fear
reinstatement when cannula tips are not in the amygdala.---------------------------------------------------------- 41
IV. PI-3 kinase inhibitors block fear reinstatement-induced
PI-3 kinase activation.------------------------------------------- 42
V. Using the IHC measured the neuronal activity in the
amygdala after the reinstatement of fear memoery.----------------------------------------------------------- 43
VI. With the immunofluorescence of the cfos expression,
analyzed the neuronal activity in the amygdala after the
reinstatement of fear memory.--------------------------------- 44
VII. The activation of β-adrenergic receptor facilitated the
reinstatement of fear memory.--------------------------------- 45
5. Discussion ---------------------------------------------------------------- 47
6. Conclusion --------------------------------------------------------------- 50
7. Future works-------------------------------------------------------------51
8. References---------------------------------------------------------------- 52
9. Publication lists---------------------------------------------------------- 67
10. Tables----------------------------------------------------------------------68
11. Figures and figure legends-------------------------------------------- 69
Figure 1--------------------------------------------------------------------70
Anatomic localization of amygdala.

Figure 2--------------------------------------------------------------------72
Anatomy and connectivity of fear-conditioning circuits in the rat’s amygdala.
Figure 3--------------------------------------------------------------------74
The Pavlovian fear conditioning is the classical fear memory training and also the most common use of the learning of the fear memory experiments.
Figure 4--------------------------------------------------------------------76
The domain structure of the three AKT isoforms.
Figure 5--------------------------------------------------------------------77
Schematic representation of PKB activation.
Figure 6--------------------------------------------------------------------78
The c-fos gene in the signaling process within neurons.
Figure 7--------------------------------------------------------------------80
Reinstatement of fear memory is associated with activation of
PI-3 kinase in the amygdala.
Figure 8--------------------------------------------------------------------82
Effects of intra-amygdala administration of PI-3 kinase inhibitors on the fear reinstatement.
Figure 9--------------------------------------------------------------------84
Lack of the effect of PI-3 kinase inhibitor on fear reinstatement when cannula tips are not in the amygdala.
Figure 10------------------------------------------------------------------ 86
PI-3 kinase inhibitors block fear reinstatement-induced PI-3
kinase activation.



Figure 11-------------------------------------------------------------------87
With the IHC of the cfos expression, analyzed the neuronal
activity in the amygdala after the reinstatement of fear memory.
Figure 12-------------------------------------------------------------------89
With the immunofluorescence of the cfos expression, analyzed
the neuronal activity in the amygdala after the reinstatement of
fear memory.
Figure 13-------------------------------------------------------------------91
The activation of β-adrenergic receptor facilitated the reinstatement of fear memory.
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