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研究生:王咨涵
研究生(外文):Chi-Han Wang
論文名稱:癲癇重積前週邊系統神經迴路的改變因子
論文名稱(外文):Altered regulation of neural circuits in limbic structures prior to status epilepticus
指導教授:林永煬林永煬引用關係
指導教授(外文):Yung-Yang Lin
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2012
畢業學年度:101
語文別:中文
論文頁數:101
中文關鍵詞:癲癇週邊系統神經網路局部場電位神經元關連性分析頻率分析
外文關鍵詞:epilepsylimbic systemneural networklocal field potentialneuronal ensemblecoincidence analysisfrequency analysis
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癲癇的產生取決於腦神經迴路由正常轉變到異常迴路的歷程,此轉變涉及大腦活性的變化,包括神經放電模式的改變、神經族群的協調性、以及單一神經元及神經群的相關性。咸認這些神經迴路係起因於腦神經遭受某些損傷,然而,遭逢類似程度的損傷一段時間後,在人體或實驗動物都可觀察到,有些個案會產生癲癇但另一部分個案則不會。本研究嘗試在實驗動物探討癲癇重積狀態的形成前有哪些變化已經發生於相關的神經迴路。希望此研究有助於更清楚了解形成癲癇的前驅神經變化及標記。本論文由三個研究組成,概述如下:

在第一個實驗,為求了解癲癇的轉變,我們將毛果芸香鹼注射於大鼠腹腔,同時紀錄腦部海馬迴區的神經活性。藉由分析不同神經元彼此間放電模式的相關性,我們發現癲癇重積狀態發生之前會先有海馬迴神經元間相關性降低的現象。海馬迴各神經元間相關性的降低可能是一種神經元去同步化的現象。此海馬迴去同步化的現象或許可做為癲癇重積狀態的前驅徵兆。然而,海馬迴內各別神經元的放電活性則以非均質的方式在癲癇重積發生前進行放電。

於第二個實驗,我們利用多腦區紀錄的方式,量測毛果芸香鹼誘發癲癇重積前各腦區神經活性的改變。在多腦區的紀錄中,同時紀錄大腦週邊系統中的八個腦區,包括CA1,CA3,扣帶回,丘腦前核,杏仁核,內鼻皮質,下腳,及中隔區。為了評估癲癇重積前的腦部連結變化,我們採用兩特定腦區間相干性(coherence)的改變來比較不同腦區間癲癇重積前後的變化。將各腦區的相干性以網狀分析,結果發現在毛果芸香鹼的模式中,可量測到癲癇重積發生前beta波同步化的增加。此beta波同步化的增加,特別表現在丘腦前核與可仁核間的連結。因此,丘腦前核和杏仁核間的連結可能涉及癲癇重積的發生。

腦部興奮性及抑制性神經活性的不平衡可能是導致癲癇狀態的基礎。例如,γ-丁氨基酪酸(GABA)的改變可能在毛果芸香鹼模式中參與這樣的轉變過程。為了評估γ-丁氨基酪酸在癲癇重積中扮演的角色,於第三個實驗中,我們採用藥理的方式來進行探討。在給予丹祈平(diazepam)處理的動物中,快速放電神經元的放電頻率有明顯的下降,同時癲癇重積的誘發率亦降低。這個發現推測γ-丁氨基酪酸的傳遞在癲癇重積的產生上扮演重要的角色。

總結來說,本研究結果顯示在癲癇重積的發生前有一個關鍵的電生理改變:海馬迴神經元間的去同步化現象。此外,週邊系統beta同步化的增加也是癲癇重積發生前的重要表徵。再者,γ-丁氨基酪酸受體的拮抗劑可能藉由降低那些原本放電頻率較高的神經元的活性,以阻止癲癇重積現象的發生。期望後續研究能進一步釐清癲癇重積發生前之生物標誌以及毛果芸香鹼誘發癲癇的潛在機轉。

The generation of epilepsy depends on the circuit transition from normal state to abnormal state, and this transition is involved in the changes of brain activities including neuronal firing patterns, coordination of neural populations, and correlation between single neurons and neural populations. However, the determinants and regulators prior to status epilepticus (SE) are not well understood. In this dissertation, different approaches to spatio-temporal dynamics of brain were used to study the transition factors from normal state to epileptic state.

Firstly, to understand the transition of epilepsy, the neural activities in the hippocampus were measured by neuronal ensemble recording in Sprague Dawley rats treated with pilocarpine. According to the analysis of firing coincident from neuronal ensembles, a decrease of hippocampal coincidence was correlated with the development of SE. The hippocampal desynchronization might be a predicting factor of SE. However, we found a very heterogeneous change in the firing rate across putative hippocampal neurons.

Secondly, the neural activities prior to SE in pilocarpine-treated rats were recorded in multiple regions of the limbic system including the CA1, CA3, dentate gyrus, anterior nucleus of thalamus, amygdala, entorhinal cortex, subiculum, and medial septum. The synchronization between different brain regions was computed by inter-structure coherence to assess the brain connection prior to SE. According to neural network analysis, we identified the enhanced beta synchrony in the limbic system prior to the occurrence of SE. Specifically, a significant beta synchrony between the amygdala and the anterior nucleus of thalamus was found. Therefore, the neural connection between the amygdala and the thalamus might involve in the development of SE.

Thirdly, an imbalance between neural excitation and inhibition in the brain may underlie the transition from normal state to epileptic state. For example, a change in GABAergic transmission might participate in this transition process in pilocarpine model. To evaluate the involvement of GABAergic transmission, a pharmaceutical approach was used. In rats treated with diazepam, a GABAA receptor agonist, we found a decrease in the firing rate of high-spiking neurons in association with a lower rate of SE induction. This finding suggests that the GABAergic transmission plays an important role in generation of SE.

In conclusion, these results suggest that hippocampal desynchronization is a key electrophysiological change prior to the occurrence of SE. The limbic hyper-synchronization at beta oscillation is a characteristic feature in rats with SE. Moreover, a blockade of GABAA receptors might prevent the development of SE by decreasing the firing rate of high-spiking neurons. Further studies are warranted to determine the exact biomarkers prior to SE and their underlying mechanisms in pilocarpine-treated rats.

論文電子檔著作權授權書 i
論文審定同意書 ii
誌謝 iii
英文摘要 iv
中文摘要 vi
目 錄 viii
圖目錄 xiv
表目錄 xiv
縮寫表 xv
第一章 介紹 1
1.1 總覽 1
1.2 癲癇 1
1.2.1 背景介紹 1
1.2.2 癲癇種類 2
1.2.3 顳葉癲癇 2
1.2.4 顳葉癲癇的病理變化 3
1.2.5 癲癇形成的過程 3
1.3 癲癇的模式動物 4
1.3.1 急性癲癇模式 5
1.3.2 慢性癲癇模式 5
1.3.3 其他癲癇模式 6
1.4 問題:癲癇重積前的決定因子及調節因子為何? 7
第二章 癲癇重積發展前的海馬迴決定因子 8
2.1 介紹 8
2.2 材料與方法 9
2.2.1 動物 9
2.2.2 電極埋放手術 9
2.2.3 實驗流程 9
2.2.4 行為觀察 10
2.2.5 電極位置確認 10
2.2.6 棘波與局部場電位紀錄 11
2.2.7 自發性癲癇監控 11
2.2.8 資料分析 11
2.2.9 統計分析 12
2.3 結果 13
2.3.1 毛果芸香鹼誘發癲癇重積 13
2.3.2 有癲癇重積與無癲癇重積大鼠之放電變化 13
2.3.3 有癲癇重積與無癲癇重積大鼠之功能性連結差異 14
2.3.4 毛果芸香鹼注射後第二至第五週自發性癲癇觀察 15
2.4 結論 15
2.5 討論 16
2.5.1 不同癲癇時期的電生理改變 16
2.5.2 神經關連性的觀察 16
2.5.3 海馬迴紀錄的限制 17
2.5.4 海馬迴神經的異質活性 18
第三章 癲癇重積發生前週邊系統的全腦動態綜觀 33
3.1 介紹 33
3.2 材料與方法 34
3.2.1 動物 34
3.2.2 電極埋放手術 35
3.2.3 實驗流程 35
3.2.4 行為觀察 35
3.2.5 確認電極位置 36
3.2.6 局部場電位之擷取 36
3.2.7 二維行為狀態地圖的組建 36
3.2.8 腦區之間同步化的測量 37
3.2.9 Z分數的轉換 37
3.2.10 神經網路分析 37
3.2.11 統計分析 38
3.3 結果 38
3.3.1 毛果芸香鹼誘發癲癇重積 38
3.3.2 食鹽水注射基線期與癲癇前期的行為狀態地圖分析 39
3.3.3 有癲癇重積與無癲癇重積在結構間的相關性 39
3.3.4 有癲癇重積與無癲癇重積在相關性的差異 40
3.4 結論 40
3.5 討論 41
3.5.1 行為調節的同步化 41
3.5.2 癲癇重積前的週邊系統連結 41
3.5.3 丘腦與海馬迴間的關連性 42
3.5.4 多腦區紀錄的限制 42
3.5.5 癲癇中的Beta波同步化 43
第四章 癲癇重積發展前在海馬迴的調節因子所造成的興奮性/抑制性不平衡 58
4.1 介紹 58
4.2 材料與方法 59
4.2.1 實驗動物 59
4.2.2 電極埋放手術 59
4.2.3 實驗流程 59
4.2.4 灌流與組織確認 60
4.2.5 局部場電位及神經資料擷取 60
4.2.6 棘波放電分析 61
4.2.7 爆發放電分析 61
4.2.8 統計分析 62
4.3 結果 62
4.3.1 前處理gabazine和diazepam對癲癇重積發生率及潛伏時間的影響 62
4.3.2 前處理diazepam減少HS神經元的放電頻率 63
4.3.3 前處理diazepam調節爆發放電的趨性 64
4.4 結論 64
4.5 討論 65
4.5.1 海馬迴神經元在癲癇中的角色 65
4.5.2 diazepam和gabazine的影響 66
4.5.3 毛果芸香鹼誘發癲癇的癲癇發作前期變化 67
第五章 整體討論 86
5.1 結論 86
5.2 本實驗的應用價值 87
5.3 本實驗的限制與未來研究方向 87
References 89
Biography 100
Appendix 101


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