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系統識別號 U0026-0608201217042800
論文名稱(中文) 瘦素改善快速動眼期睡眠剝奪引起的認知功能障礙之機制探討
論文名稱(英文) Reversal of REM Sleep Deprivation-Induced Cognitive Deficit by Leptin Supplement
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 100
學期 2
出版年 101
研究生(中文) 張曉芙
研究生(英文) Hsiao-Fu Chang
學號 s26994118
學位類別 碩士
語文別 英文
論文頁數 81頁
口試委員 指導教授-簡伯武
口試委員-司君一
口試委員-陳柏熹
中文關鍵字 杏仁核  睡眠剝奪  恐懼記憶  瘦素 
英文關鍵字 amygdala  sleep deprivation  fear memory  leptin 
學科別分類
中文摘要 根據世界衛生組織調查顯示,全球約有29 %的人受到各種睡眠障礙的困擾。睡眠不足不僅會影響正常生理功能的運作,也會造成認知功能障礙,其中快速動眼期睡眠(rapid eye movement sleep) 被認為在記憶固化的過程中扮演重要的角色。已有研究證實,剝奪小鼠的快速動眼期睡眠會改變海馬迴神經突觸的可塑性,降低與海馬迴相關的學習記憶。但快速動眼期睡眠剝奪是否也會影響與杏仁核(amygdala)相關的恐懼記憶目前研究仍較少。
瘦素 (leptin)是一種由白色脂肪分泌的荷爾蒙,可穿透血腦障壁進入下視丘影響食慾與能量代謝。近年來更進一步發現,leptin會藉由抑制PTEN的活性而改變海馬迴神經突觸可塑性,增加空間記憶的形成。除此之外,研究指出小鼠在經過睡眠剝奪後,其體內的leptin大量減少。因此,在此實驗中我們想要探討剝奪小鼠的快速動眼期睡眠後,是否會影響恐懼記憶的形成及leptin在其中扮演的角色。
我們發現在經過24小時快速動眼期睡眠剝奪後,小鼠與杏仁核相關的線索制約恐懼記憶 (cue fear memory)及與海馬迴相關的情境制約恐懼記憶 (contextual fear memory)皆受到抑制。更進一步我們發現,在腹腔注射給予leptin後,受到抑制的記憶會被回復。恐懼記憶的形成與細胞表面AMPA受體的運輸 (trafficking)有關。經過睡眠剝奪後,小鼠杏仁核腦區細胞表面AMPA受體GluR1次單元表現量下降,但並不會改變整體GluR1的表現。然而,給予leptin後發現可回復細胞表面GluR1的表現量。此現象並不會發生在AMPA受體另一個次單元GluR2身上,顯示leptin會回復睡眠剝奪所引起的AMPA 受體GluR1運輸降低。在全細胞電位箝制法 (Whole-cell patch clamp recording)中,我們也發現睡眠剝奪後會降低突觸前神經傳遞物質釋放及抑制突觸後神經可塑性。然而,給予leptin後只可回復突觸後神經可塑性的改變。最後,我們探討leptin對於增加睡眠剝奪引起的恐懼記憶下降之分子機制,發現睡眠剝奪後,與AMPA受體運輸相關蛋白質-GSK 3與PTEN活性增加;Akt活性下降;在給予leptin後此現象皆可被回復。綜合以上結果顯示,睡眠剝奪會透過PTEN-Akt-GSK 3路徑抑制AMPA 受體運輸,使杏仁核神經元突觸可塑性下降導致恐懼記憶無法形成;然而,增加體內leptin會改變此路徑活性而回復睡眠剝奪引起的恐懼記憶形成障礙。此研究結果未來可能對治療睡眠不足引起認知功能障礙與相關疾病提供一新的治療方向。
英文摘要 Sleep deprivation alters the functions of hippocampus and amygdala at several molecular and cellular levels that may affect memory formation. Recent studies have indicated that leptin could cross the blood-brain barrier to regulate synaptic plasticity in the hippocampus by inhibiting PTEN signaling and facilitating spatial memory. Sleep deprivation reduced the level of leptin and resulted in fear contextual memory impairment. Therefore, whether sleep deprivation induced fear memory impairment is due to reduction of leptin and dis-inhibition of PTEN signaling needs to be clarified. In this study, we investigated the effect of leptin on the sleep deprivation-induced cognitive deficit. Mice were subjected to 24h sleep deprivation after fear conditioning in small platform water tank. We found that sleep deprivation resulted in both cue and contextual fear memory impairment. In parallel, surface GluR1 was reduced in amygdala after sleep deprivation. Furthermore, intraperitoneal injection of leptin to sleep-deprived mice rescued fear memory impairment and reversed surface AMPA receptor reduction. Using whole cell recording to evaluate the synaptic function of the lateral amygdala (LA), we found that the miniature EPSC amplitude and frequency were decreased in sleep-deprived mice. Besides, the AMPA/NMDA ratio was decreased and paired-pulse ratio was increased after sleep deprivation but only the AMPA/NMDA ratio could be rescues by leptin. These results indicated that both pre- and post-synaptic functions were changed in sleep-deprived mice and the post-synaptic plasticity could be rescued by leptin supplement. Moreover, we investigated whether PTEN signaling was inhibited after leptin supplement in REM sleep deprivation mice. We found that leptin could increase phospho-PTEN which inhibit PTEN function and increase phospho-Akt, phospho-GSK 3 expression after mice received REM sleep deprivation. These data indicated that leptin could reverse REM sleep deprivation induced fear memory impairment via PTEN-Akt-GSK 3 signaling pathway which could affect AMPA receptor trafficking. This process has an important role of leptin in sleep deprivation in health and disease.
論文目次 中文摘要 Abstract in Chinese..... ........1
英文摘要 Abstract in English..... ........4
致謝 Acknowledgement............ ........7
縮寫檢索表 Abbreviations................. 9
圖表索引 List of Figures and Tables...... 11
Chapter 1 Introduction..................13
Chapter 2 Specific Aim..................29
Chapter 3 Materials and Methods.........31
Chapter 4 Results.......................42
Chapter 5 Figures and Table.............53
Chapter 6 Discussion....................68
References..............................74
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