臺灣博碩士論文加值系統

發育成熟的動物，神經系統的結構並非不變的固定結構，當神經系統受到損傷後，神經元之間便會有神經塑性的現象，亦即神經元間的聯結會再度被建立，細胞間的溝通也會再度重塑。為了適應新的神經聯結，神經系統會再度啟用在發育過程中的分子及訊息傳遞。例如生長相關蛋白質（GAP-43）及一氧化氮（NO）。在探討聽覺系統的動物模式發現，利用聲音刺激經驗或是內耳破壞方式可以使腦幹聽覺核區的突觸重新聯結。因此本實驗利用破壞內耳耳蝸的方式觀察及探討發生在腦幹聽覺神經核區的突觸重新形成過程中，神經性一氧化氮合成?（nNOS）及GAP-43扮演的角色及其機制。在進行單側耳蝸破壞前，先以聲音刺激記錄手術前之腦幹聽覺誘發電位（BAEP），手術之後再以相同的聲音刺激記錄之，結果發現破壞側的BAEP波形明顯變小甚至消失，非手術側則無明顯變化，動物犧牲前再次記錄手術側的BAEP波形依舊沒有回復正常，證實單側耳蝸破壞的完整性與永久性。接著將動物的腦組織做冷凍切片，以免疫組織化學染色法觀察GAP-43、NMDA受器、nNOS及cGMP的表現，比較破壞側與非破壞側的耳蝸神經核（CN）內，不同蛋白質的表現及分佈情形之差異。結果發現，單側耳蝸破壞後，在術後第四天到第十四天時，GAP-43蛋白質會表現於破壞側CN的神經元。此外，CN內NMDA受器的表現會有重新分佈的情形，證實破壞之後CN會發生突觸重新形成的現象。本實驗發現到在單側耳蝸破壞後的CN中nNOS也會有重新分佈變化情形。利用雙重螢光染色的方式，證實表現於軸突末稍的GAP-43會投射在CN中表現nNOS的神經元上。因此實驗結果認為NO可能對於在CN中新生成的軸突擔任停滯訊息的角色，使新生成的軸突會停留在CN的神經元上。實驗也發現CN中本身的神經元會表現cGMP反應，表現cGMP和nNOS的神經元共同分佈在相同神經元內，因此不能排除NO會透過其他訊息傳遞路徑使軸突退縮回去的可能性，或擔任逆向傳遞者功能去影響神經軸突生長，進而調控神經傳導物質的釋放。因此實驗結果認為在單側耳蝸破壞後，CN中NO參與了神經可塑性的過程。
關鍵字：耳蝸神經核、一氧化氮、生長相關蛋白質、神經性一氧化氮合成?、耳蝸破壞手術、腦幹聽覺誘發電位、神經可塑性。

Several molecules playing important roles during brain development are also involved in the process of lesion-induced synaptic remodelling. Growth associated protein GAP-43 and nitric oxide (NO) are frequently mentioned. GAP-43 is a major constituent of the growth cone and responsible for guiding the growth of axons and modulating the new synaptic formation. Unilateral cochleotomy in adult animal caused a dramatic re-expression of GAP-43 in the neuropil of the ipsilateral cochlear nucleus (CN) and cell bodies of the lateral superior olive, which indicates that a reactive synaptogenesis takes place in the CN following cochleotomy. Meanwhile, NO is strongly suggested to participate in neurotransmission, neuronal development, neuronal plasticity and remodeling. This study was attempted to evaluate the effect of unilateral cochleotomy on the expression of GAP-43 and neuronal NO synthase (nNOS), and then to find out the role of NO in neuronal plasticity. C57B10/SnSc mice were used as experimental animals, and immunohistochemistry was adopted to evaluate the localization and time course of nNOS expression in cochlear nucleus. Brainstem auditory evoked potential (BAEP) was recorded to confirm the accuracy of cochlear ablation. Immunohistochemistry was performed to reveal the localization and time course of the expression of GAP-43 、NMDA receptors nNOS and cGMP in CN at various postoperative days ( POD ). The results of GAP-43 expression corresponded to those shown in literature. As for the results of nNOS expression, perikarya containing nNOS evenly were found in the ventral CN before lesion. Stained terminals were also observed on these cells. After cochleotomy, NMDA receptors and nNOS stained surround cell membrane around POD4 and then re-emerged around POD14. The expression pattern was the same as that of before surgery until POD60. Then, a transient rise of cGMP immunoreactivity was observed in the ipsilateral CN. While using the double immunoflourecent stain in this experiment, the redistribution of nNOS in the ipsilateral side CN could be detected, and GAP-43 at presynaptic terminals of neurons would only project onto these nNOS eventually. In the CN, the result was nNOS positive reside on cell bodies that were stained for cGMP immunoreactivity. These changes are suggested as new synapses formed in the CN. These findings suggest that NO may play a stopping signaling for new presynaptic axon to connect in cochlear nucleus during synaptogenesis following cochleotomy.
Key words：cochlear nucleus；nitric oxide；growth associated protein；neuronal Nitric Oxide Synthase；cochleotomy；BAEP；neuronal plasticity

目 錄
中文摘要…………………………………………………………a
英文摘要…………………………………………………………b
第一章 緒論
前 言……………………………………………………………1
文獻回顧…………………………………………………2
一、神經可塑性………………………………………………2
二、生長相關蛋白質GAP-43在神經系統的角色…………….3
三、一氧化氮在神經系統的角色……………………………4
四、聽覺傳導徑路……………………………………………5
五、耳蝸破壞後突觸重新形成之動物模式…………………7
六、一氧化氮在聽覺徑路的角色……………………………8
研究目的…………………………………………………………10
研究設計…………………………………………………………10
圖1-1~ 1-2………………………………………………11
第二章 材料與方法
一、實驗動物…………………………………………………13
二、實驗步驟…………………………………………………13
實驗流程………………..………………………………………13
腦幹聽覺誘發電位記錄………………………………………14
耳蝸破壞手術免疫組織化學染色……………………………..15
腦組織切片………………………………………………….15
神經性一氧化氮合成?免疫組織化學染色……………….16
生長相關蛋白質GAP-43免疫組織化學染色……………..17
N-甲基天門冬胺酸受器免疫組織化學染色……………….18
環狀鳥嘌核甘磷酸cGMP免疫組織化學染色…………….18
雙重染色…………………………………………………….19
三、實驗結果處理……………………………………………22
第三章 實驗結果
手術前後腦幹聽覺誘發電位…………………………………23
生長相關蛋白質GAP-43免疫組織化學染色………………24
神經性一氧化氮合成?免疫組織化學染色……………………...25
N-甲基天門冬胺酸受器免疫組織化學染色……………………27
環狀鳥嘌核甘磷酸cGMP免疫組織化學染色……………………28
雙重染色……………………………………………………………29
圖3-1~3-16……………………………………………………31
第四章 討論
耳蝸破壞後對聽覺系統的影響……………………………………….47
耳蝸破壞後生長相關蛋白質GAP-43在耳蝸神經核的表現變化…………48
耳蝸破壞前後神經性一氧化氮合成?在耳蝸神經核的表現變化…………49
NO在耳蝸神經核中突觸形成過程的功能……………………….52
單側耳蝸破壞後對橄欖耳蝸神經束造成的影響……………….55
總結……………………………………………………………56
圖4-1~4-2…………………………………………………57
參考文獻…………………………………………………………………59

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