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系統識別號 U0026-0107201223292000
論文名稱(中文) 影響情緒相關記憶獲取及再穩固化歷程的因子
論文名稱(英文) The modulating factors in the acquisition and reconsolidation of emotion-related memories
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 100
學期 2
出版年 101
研究生(中文) 莊佳穎
研究生(英文) Jia-Ying Chuang
學號 S58951277
學位類別 博士
語文別 中文
論文頁數 111頁
口試委員 指導教授-游一龍
指導教授-郭余民
召集委員-任卓穎
口試委員-廖寶琦
口試委員-梁庚辰
口試委員-王錫崗
中文關鍵字 學習記憶  僵直反應  長期增益現象  杏仁核  性別差異  古柯鹼場地制約  被動逃避學習  蛋白質合成抑制劑  阿滋海默症  血紅素  β糊蛋白  海馬迴 
英文關鍵字 Learning and memory  freezing behavior  Long term potentiation  Amygdala  Sex difference  Cocaine-induced conditioned place preference  Passive avoidance  Protein synthesis inhibitor  Alzheimer’s disease  Hemoglobin  β-Amyloid  Hippocampus 
學科別分類
中文摘要 當環境事件刺激中樞神經系統後,學習歷程開始,並且中樞神經系統開始整合這些刺激訊號。這一段學習過程很快地會歷經一個假設性的穩固化過程並將此經驗儲存在中樞神經系統直到我們需要這段記憶的資訊而再次去提取。而記憶提取通常是為了添增新的資訊或是再強化這段記憶,很多實驗研究證明這過程會使這段記憶進入不穩定的狀態,隨後這不穩定狀態記憶會自發性地經歷一個假設性的再穩固階段,並再次使這記憶穩定地儲存在中樞神經系統中。本篇論文將探討獲取學習以及再穩固化這兩個階段。第一部分,我研究小鼠表現恐懼相關記憶上之性別差異是否在學習階段就不同,其相關機制又為何? 線索制約僵直反應、電生理記錄,以及蛋白質分析將用於探討這個議題。結果顯示母小鼠在線索制約僵直反應、杏仁核LTP表現、GluR1、GluR2,以及PSD-95蛋白表達量都高過公小鼠,而雄性激素可能主導了這些差異。第二部分,研究干擾一個記憶再穩固化歷程是否同時干擾其他沒被提取出來的記憶?在這章節,小鼠依序學習古柯鹼場地制約偏好學習記憶以及被動逃避學習記憶。提取被動逃避學習記憶(或場地制約偏好記憶)之後立刻在BLA施打蛋白質合成抑制劑(anisomycin)發現兩小時後被動逃避學習記憶(或場地制約偏好記憶)的再測試表現降低了。提取被動逃避學習記憶(或場地制約偏好記憶)之後立刻在CeA施打anisomycin發現兩小時後的被動逃避學習記憶(或場地制約偏好記憶)再測試表現雖沒被影響,但是在施打5天後的再測試被動逃避學習記憶(或場地制約偏好記憶)之表現降低了。如沒提取被動逃避(或場地制約偏好)的學習記憶或提取其他學習記憶,則無論在BLA或CeA施打蛋白質合成抑制劑都不影響被動逃避學習記憶(或場地制約偏好記憶)的表現。這樣的結果暗示著杏仁核涉及調控情緒相關記憶的再穩固化過程。而在情感相關的記憶再穩固化過程,BLA對於前期的記憶再穩固化重要,而CeA則在後期的記憶再穩固化扮演重要角色。在附錄部份,我研究記憶穩固化階段異常的記憶相關疾病,阿滋海默症。我假設β糊蛋白很可能跟血球上的蛋白質進行交互作用進而引發血管相關病症最後導致AD病症的加劇。我利用阿滋海默症基因轉殖小鼠來探討血紅素以及β糊蛋白在腦中的關係。結果顯示血紅素在阿滋海默症基因轉殖小鼠會如β糊蛋白隨著年紀變大而表達量上昇,β糊蛋白與血紅素β次單位在表達位置上有高度相關性。在海馬迴引發出血後,血紅素訊號會徵集β糊蛋白聚集。這結果暗示血紅素會幫助β糊蛋白堆積。
英文摘要 When environmental events or sensory stimuli impinge upon our central nervous system, we begin to learn (acquisition process) and central nervous system begins to integrate all the incoming information. Acquisition processes soon is placed by consolidation in an attempt to consolidate such information into the central nervous system until this acquired memory is stored and later retrieved under request. Retrieving an acquired memory turns this stable memory into a labile state for incorporation of new incoming information or strengthening this memory. Labile memory then, theoretically, undergoes a spontaneous reconsolidation process and being again stably stored in the central nervous system. In present studies, two of these processes, acquisition and reconsolidation, were discussed. In part 1, whether sex difference in performance of emotional related memories is different in acquisition process was investigated. And what are promising underlying mechanisms? Fear conditioning freezing behavior test, electrophysiology, and protein assay were used in this study. Female mice show higher magnitude in cue induced freezing, amygdaloid LTP performance, GluR1, GluR2, and PSD-95 protein level compare with male mice. Gonadal hormone in male mice may be responsible for sex difference of fear condition behavioral performance. In part 2, I investigated whether disturbance of one retrieved memory by inhibition of de novo protein synthesis during reconsolidation process is also affecting other non retrieved memory. Mice were trained to sequentially acquire both cocaine-induced conditioned place preference (CPP) and step-through passive avoidance (PA) memories. Immediately following PA/CPP retrieval, intra-BLA anisomycin infusion was found to decrease subsequent PA/CPP performance in retests. Immediately following PA/CPP retrieval, intra-CeA anisomycin infusion did not acutely affect PA/CPP performance but decreased such a PA/CPP memory 5 days later. When PA/CPP retrieval procedure was omitted, intra-BLA or intra-CeA anisomycin infusion did not affect PA/CPP memory. Intra-BLA and intra-CeA anisomycin infusion alone did not affect subsequent PA/CPP memory. These results, taken together, imply that de novo protein synthesis in amygdala plays an important role in modulating reconsolidation of emotion-related memory. More importantly, de novo protein synthesis in the BLA is essential for early phase reconsolidation of retrieved emotion-related memories. Protein synthesis in the CeA is required for late phase reconsolidation of retrieved emotion-related memories. In appendix, I discussed Alzheimer’s disease, a memory related disease, which was thought abnormal in consolidation process. I hypothesize that interaction between hemoglobin and β-amyloid in mini-hemorrhagic damaged brain may facilitate Alzheimer's disease development and progression. Male double (AP/PS, Amyloid precursor protein/ Presenilin) transgenic mice was used in this study. Hemoglobin was up regulation in alzheimer’s disease mice and hemoglobin β is correlation with β-amyloid. And in in vivo study, intra-hippocampus induction of hemorrhage induce hemoglobin leakage and recruit β-amyloid protein deposition suggesting that hemorrhage may enhance β-amyloid deposition.
論文目次 總覽圖 記憶進程以及研究中假設的程序步驟 .....p1
第一章節 恐懼制約誘發僵直行為性別上表現的差異之機轉.....p2-p44
中文摘要.....p2
英文摘要.....p3
序論.....p4-p7
實驗方法與材料.....p8-p15
實驗設計與結果.....p16-p23
討論與結論.....p24-p29
圖表.....p30-p40
圖1-1 聲音-電擊恐懼制約前(baseline)與制約後聲音誘發僵直行為表現.....p30
圖1-2公小鼠跟母小鼠分別歷經單獨呈現聲音刺激或者電擊所表現的僵直反應.....p31
圖1-3 聲音-電擊恐懼制約前與制約後聲音誘發公母小鼠以及去性腺公母小鼠僵直行為表現.....p32
圖1-4 雄性激素對母小鼠以及去性腺母小鼠在恐懼制約聲音-電擊配對學習後對於聲音引起的恐懼僵直行為表現.....p33
圖1-5 側杏仁核輸入-輸出關係曲線.....p34
圖1-6 公母小鼠,以及去性腺公母小鼠,在側杏仁核的LTP初始誘發值以及維持值的表現.....p35
圖1-7去性腺公小鼠在有無Testosterone的處理下,以及去性腺母小鼠在有無Estradiol,於側杏仁核的LTP初始誘發值以及維持值的表現.....p36
圖1-8 公母小鼠以及去性腺公母小鼠在聲音-電擊配對的恐懼制約中,側杏仁核(LA)LTP相關分子的表達量.....p37-p38
圖1-9結論總覽圖.....p39-40
參考資料.....p41-p44
第二章節 情緒相關之早期及晚期記憶再穩固化歷程需要杏仁核進行新蛋白質合成.....p45-p73
中文摘要.....p45
英文摘要.....p46
序論.....p47-p49
實驗方法與材料.....p50-p54
實驗結果.....p55-p57
討論與結論.....p58-p61
圖表.....p62-p68
圖2-1 實驗流程.....p62
圖2-2 注射位置的組織學確認.....p63
圖2-3 BLA及CeA內注射蛋白合成抑制劑後被動逃避學習記憶再測試的表現.....p64-p65
圖2-4 BLA及CeA內注射蛋白合成抑制劑後古柯鹼場地制約偏好學習記憶再測試的表現.....p66-p67
圖2-5總結總覽圖.....p68
參考資料.....p69-p73
附 錄 血紅素以及β糊蛋白在阿滋海默症基因轉殖小鼠上之交互作用.....p74-p111
中文摘要.....p74
英文摘要.....p75
序論.....p76-p78
實驗方法與材料.....p79-p81
實驗結果.....p82-p86
討論與結論.....p87-p90
圖表.....p91-p104
圖A-1 基因轉殖鼠(APP/PS1)表達大量APP..... p91
圖A-2 基因轉殖鼠(APP/PS1)表達的β糊蛋白.....p92
圖A-3血紅素蛋白質表達隨著年紀而增加.....p93-p94
圖A-4 基因轉殖小鼠血紅素α次單位在皮質區域免疫組織染色訊號.....p95
圖A-5 基因轉殖小鼠血紅素β次單位在皮質區域免疫組織染色訊號.....p96
圖A-6 基因轉殖小鼠血紅素β次單位在皮質、Entorhinal,以及海馬迴區域免疫組織染色量化訊號.....p97-p98
圖A-7 14個月大的基因轉殖小鼠血紅素α以及β次單位跟β糊蛋白的表達情形.....p99
圖A-8 14個月大的基因轉殖小鼠及野生種小鼠血紅素β次單位跟β糊蛋白在皮質表達的情形.....p100
圖A-9 14個月大的基因轉殖小鼠及野生種小鼠血紅素β次單位跟β糊蛋白在海馬迴表達的情形.....p101
圖A-10 14個月大的基因轉殖小鼠及野生種小鼠血紅素β次單位跟β糊蛋白在Entorhinal皮質表達的情形.....p102
圖A-11 14個月大的基因轉殖小鼠及野生種小鼠海馬迴內引發出血後血紅素β次單位跟β糊蛋白在海馬迴表達的情形.....p103
圖A-12結論總覽圖.....p104
參考資料.....p105-p111

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