臺灣博碩士論文加值系統

丙戊酸(valproic acid；VPA)是現今一種廣泛用於治療癲癇與精神疾病的臨床用藥，但是在一些臨床的證據卻顯示在一些患有癲癇的孕婦在服用VPA之後，其體內胎兒出生後會有認知缺陷、社交障礙和焦慮行為等類自閉症行為。然而，在出生後胎兒也可能會因為外在的環境因子造成發育時期的基因表現受到不正常的調控，造成後天神經發育行為的偏差。現今，造成神經行為異常機制到目前還不清楚。因此本篇的研究目的是利用出生後七天公鼠(P7)腹腔注射VPA誘導產生焦慮行為。探討其在不同時期，VPA對大腦發育的影響機制與行為。西方點墨法分析海馬迴區H3K9乙醯化情形，發現腹腔注射VPA增加海馬迴區H3K9乙醯化蛋白量。在高架十字迷宮的結果顯示，二、四、六和八週大老鼠給予腹腔注射VPA處理組相較於控制組具有顯著的焦慮行為。以開放場域測試(open field test)也發現VPA處理的大鼠具有較高的焦慮程度，並且有異常的運動行為。在強迫游泳實驗測試(forced swimming test)，發現VPA處理大鼠在水中不動(immobility)的時間較控制組長，顯示VPA處理組具有較抑鬱的行為。利用免疫組織化學染色實驗觀察海馬迴區BrdU和Ki67的表現的確有顯著性的上升，表示出生後暴露VPA會誘導老鼠細胞增生的情形。除此之外我們也發現VPA會調控海馬迴中分化相關基因分析海馬迴神經分化基因NeuroD和doublecortin (DCX)表現，發現此兩種神經特化的基因在VPA處理組的表現比在控制組降低。VPA 處理24小時之後，olig1與olig2寡突膠細胞的基因表現受到顯著抑制。但是，星狀膠細胞特有的GFAP基因在VPA處理組海馬迴在24小時至四週大量表現。綜合上述結果，出生後暴露丙物酸會誘導海馬迴中的細胞增生並抑制神經分化，並誘發發育時期焦慮和抑鬱的行為。

Valproic acid (VPA) is a widely used medicine to treat or prevent epilepsy and bipolar disorder. However, exposure to valproate during pregnancy causes behavioral impairments, like cognitive delay, social interaction, anxious behaviors and interests which is related to symptoms of autistic spectrum disorder. The molecular mechanism remains largely unknown. In our laboratory, we used the model of male rat pups receiving 200 mg/kg of VPA by intraperitoneal injection (ip) at postnatal day 7 (P7). The results from elevated plus-maze test at 2,4 and 6 weeks post injection showed the VPA-injected rats exhibited impaired social interaction and anxiety. Through the open field test, we found that VPA-treated rats displayed an anxious behavior and abnormal locomotion. From the forced swimming test, The VPA-injected rats increase immobility time and depressive behavior. Given the fact that cortex and hippocampus are associated with autistic behaviors, we examined cellular and molecular alterations in the hippocampus of rat at 24 h, week 2, 4, and6. An increased level of acetylated histone H3 was detected at 24 h in hippocampus of rat pups which receiving VPA injection when compared to vehicle-treated rats. BrdU+ -cells or Ki67+ -cells in the hippocampus of rats were also increased at the four observed time point after VPA exposure. In addition, neuronal differentiation gene NeuroD and neuronal migration protein doublecortin were downregulated in the hippocampus of VPA-treated rats at the four detected time points. Olig1 and Olig2 gene expression was also reduced at 24 h after VPA injection, but GFAP mRNA expression was increased in VPA-treated group. Collectively, a bolus of postnatal VPA exposure induced increased cell proliferation and reduced neural differentiation in developing hippocampus of rats with anxiety and depression.

目錄
中文摘要 2
Abstract 4
誌謝 6
目錄 7
圖目錄 9
縮寫表 10
前言 11
一、 神經發育障礙(neurodevelopment disorder ) 11
二、 VPA與神經焦慮行為 15
三、 海馬迴區與神經焦慮行為的相關性 18
四、 海馬迴區神經生成(neurogenesis)與神經行為發展 20
實驗目的 23
材料與方法 24
一、 材料 24
(一)、 動物行為材料及儀器 24
(二)、 動物實驗藥品及材料 24
(三)、 寡核苷酸購自MWG Biotech AG(Ebersberg, Germany) 25
(四)、 抗體 26
(五)、 試劑組 26
二、 方法 27
(一)、 實驗動物 27
(二)、 動物行為實驗(animal behavior test) 28
(三)、 BrdU 細胞生長分析 29
(四)、 西方點墨法(Western blotting) 31
(五)、 RNA核酸萃取 33
(六)、 核酸即時定量分析(Quantitative Real-Time Polymerase Chain Reaction, QPCR) 34
(七)、 統計分析 35
結果 36
一、 腹腔注射VPA增加海馬迴區組蛋白乙醯化修飾 36
二、 出生後暴露VPA對實驗老鼠體重變化 36
三、 出生後暴露VPA造成老鼠出現類似自閉症的行為 37
四、 出生後暴露VPA增加海馬迴區細胞增生 39
五、 出生後暴露VPA 影響海馬迴區調控細胞的分化的基因表現 40
討論 42
一、 出生前與出生後注射VPA對子代產生自閉症的差異 42
二、 VPA可能影響細胞增生、分化的途徑 43
三、 神經增生與類自閉行為的關聯 45
四、 未來研究方向 46
結論 47
參考資料 48

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