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系統識別號 U0026-0607201114273200
論文名稱(中文) 丙戊酸誘導自閉症大鼠模式中杏仁核之突觸特性
論文名稱(英文) The synaptic characteristics of amygdala in rat model of valproate induced autism
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 99
學期 2
出版年 100
研究生(中文) 詹雲涵
研究生(英文) Yun-Han Chan
學號 s26984016
學位類別 碩士
語文別 中文
論文頁數 77頁
口試委員 指導教授-簡伯武
口試委員-陳柏熹
口試委員-吳豐森
中文關鍵字 自閉症  杏仁核  丙戊酸 
英文關鍵字 autism  amygdala  valproate 
學科別分類
中文摘要 自閉症是一種神經發展性的疾病,主要病徵為社交能力障礙與溝通能力的缺乏,且常出現反覆行為與過度焦慮反應。但目前對於自閉症的致病原因仍然不明,也尚未有藥物可治療其核心症狀。先前的研究指出有數個大腦腦區的功能變化都可能導致自閉症的形成。其中杏仁核位於大腦顳葉中的邊緣系統,是負責情緒調控的中樞,並且參與了社交行為的調控,因此杏仁核區域的神經功能變化被認為與自閉症的產生有高度關聯性。在腦部影像學中發現自閉症病人杏仁核的神經功能與型態皆異於正常人。然而對於自閉症的杏仁核突觸特性是否發生了改變,目前所知仍有限。因先前研究曾利用懷孕母鼠在胚胎神經管閉合時期投與丙戊酸建立自閉症之大鼠模式,在此我們利用此模式4到5週大之子代觀察其是否表現類似自閉症的行為,隨後利用全細胞電生理紀錄杏仁核側核中突觸功能變化,最後分析行為特性與突觸功能變化間之相關。結果顯示投予丙戊酸後之子代進行社交行為的時間較短、有較多焦慮行為且恐懼記憶較難以抹除。在電生理紀錄中則發現投予丙戊酸後之子代杏仁核側核中sEPSC的頻率與mEPSC的頻率與振幅顯著增加,且刺激聽覺視丘到杏仁核的路徑產生之長期增益現象較大,顯示其杏仁核具有高度興奮性與突觸可塑性。更進一步發現其杏仁核側核的paired-pulse ratio減少但AMPA/NMDA比值並未改變,顯示突觸前功能改變可能與杏仁核側核中的高度興奮性與突觸塑性有關。過去報導自閉症患者腦中血清胺系統有所變化,而血清胺可以透過5HT1A受體抑制杏仁核中興奮性的神經傳遞,因此我們接著以腹腔注射連續七天投予5HT1A致效劑8-OH-DPAT,觀察是否可以抑制杏仁核側核的突觸興奮,並改善類似自閉症的行為。由結果顯示8-OH-DPAT可以增加社交行為的時間與恐懼記憶的遺忘,在電生理結果發現投藥後杏仁核側核mEPSC的頻率降低且paired-pulse ratio增加,顯示突觸前的神經傳遞物質釋放受到抑制。由此研究結果中,可以確定杏仁核的確在自閉症中扮演一個重要的角色,而調控杏仁核功能的藥物可以做為自閉症治療藥物開發新的標的。
英文摘要 Autism is recognized as a neurodevelopmental disorder. It is characterized by impaired social interaction, deficit in communication and repetitive behaviors. Amygdala is the brain area that involved in socio-emotional behavior and has been associated to autism. Brain imaging studies had reported changed amygdala function and morphology as well in autism. However, whether synaptic alterations happened in amygdala remains unclear. Because prenatal exposure to valproate (VPA) during a critic period for neural tube formation could lead to autistic phenotypes in their offsprings, here, we use the 4~5 weeks VPA and vehicle offsprings to observe the autistic phenotypes and evaluate the synaptic function in the lateral nucleus (LA) of the amygdala by whole cell recordings. The results showed VPA offsprings demonstrating significantly less social interaction, increased anxiety and difficulties in fear memory extinction. Moreover, in the whole cell recordings, we observed significantly increased spontaneous EPSC frequency, miniature EPSC frequency and amplitude. The long-term potentiation was also enhanced in VPA offsprings. The results provided evidence that the amygdala is hyper-excitatory and hyper-plasticity in the VPA offsprings. Meanwhile, we found the paired pulse ratio was decreased but AMPA/NMDA ratio remained unchanged. To sum up, the results suggested presynaptic mechanisms might contribute to the hyper-excitatory and hyper-plasticity noted in the LA of the VPA offsprings. Because previous reports had found alternated serotonin system balance in autism, moreover, our laboratory had showed serotonin can suppress the excitatory neurotransmission via 5HT1A receptor in the LA. Therefore, we give 5HT1A agonist, 8-OH-DPAT to the VPA offsprings through intra-peritoneal injection for 7 days. The results showed 8-OH-DPAT could increase social interaction duration and facilitate fear memory extinction, decrease mEPSC frequency and increase the paired-pulse ratio of the LA in VPA offsprings. This study had indicated the role of amygdala during development and interventions of autism. The model could be a valuable tool, beside the understanding and treatment of the disorder itself, to design therapeutic interventions to minimize the neurological and behavioral abnormalities of autism.
論文目次 第一章 緒論-------------------------------------------------------------------------------------------1
第一節 自閉症-------------------------------------------------------------------------------------2
1.自閉症的簡介----------------------------------------------------------------------------------2
2.自閉症的疾病特徵----------------------------------------------------------------------------2
3.自閉症的致病原因----------------------------------------------------------------------------3
4.自閉症相關的腦區----------------------------------------------------------------------------4
5.自閉症的藥物治療----------------------------------------------------------------------------4
6.類似自閉症行為的動物模式----------------------------------------------------------------6
第二節 丙戊酸與自閉症-------------------------------------------------------------------------8
1.丙戊酸-------------------------------------------------------------------------------------------8
2.丙戊酸與自閉症的關係----------------------------------------------------------------------8
第三節 中樞杏仁核與自閉症-------------------------------------------------------------------9
1.中樞杏仁核-------------------------------------------------------------------------------------9
2.中樞杏仁核與自閉症的關係----------------------------------------------------------------9
第四節 研究目的---------------------------------------------------------------------------------10
第二章 實驗材料與方法---------------------------------------------------------------------------11
第一節 藥品來源---------------------------------------------------------------------------------12
第二節 藥物濃度---------------------------------------------------------------------------------12
第三節 實驗動物---------------------------------------------------------------------------------12
第四節 實驗方法---------------------------------------------------------------------------------13
1.類似自閉症的大鼠行為模式建立--------------------------------------------------------13
2.腦切片之製作--------------------------------------------------------------------------------14
3.全細胞膜片箝制電生理紀錄法-----------------------------------------------------------15
4.藥物投予--------------------------------------------------------------------------------------16
5.統計方析--------------------------------------------------------------------------------------16
第三章 結果------------------------------------------------------------------------------------------18
第一節 4週大的丙戊酸子代具有類似自閉症行為---------------------------------------19
第二節 利用電氣生理學觀察丙戊酸的公鼠子代的杏仁核突觸特性------------------22
第三節 5HT1A的致效劑8-OH-DPAT可以改善類似自閉症的行為-------------------26
第四章 結論------------------------------------------------------------------------------------------30
第五章 討論------------------------------------------------------------------------------------------33
第一節 自閉症動物模式的驗證---------------------------------------------------------------34
第二節 丙戊酸的子代杏仁核具有高度興奮性與突觸可塑性---------------------------35
第三節 丙戊酸的子代其杏仁核的突觸前神經傳遞物質釋放量增加的機制探討-36
第四節 杏仁核為自閉症藥物治療的標的---------------------------------------------------37
參考文獻----------------------------------------------------------------------------------------------39
圖表索引----------------------------------------------------------------------------------------------49
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