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研究生:陳勤霖
研究生(外文):Chin-Lin Chen
論文名稱:大鼠藍斑核之持續性鈉離子電流
論文名稱(外文):The persistent sodium currentin rat locus coeruleus neurons
指導教授:閔明源
指導教授(外文):Ming-Yuan Min
口試委員:楊琇雯陳志成嚴震東
口試委員(外文):Hsiu-Wen YangChih-Cheng ChenChen-Tung Yen
口試日期:2013-07-18
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:腦與心智科學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:94
中文關鍵詞:藍斑核持續性鈉離子電流自發性放電
外文關鍵詞:locus coeruleuspersistent sodium currentspontaneous firing
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藍斑核 (locus coeruleus;LC) 神經元廣泛投射於許多腦區。它是大腦正腎上腺素 (norepinephrine;NE) 的主要來源,並且扮演許多認知和生理功能的角色,如:睡眠醒覺循環、注意力、學習與記憶、疼痛和大腦新陳代謝…等。因此,探索藍斑核細胞放電的調控可以瞭解此藍斑核正腎上腺素系統的運作與認知功能的關係。在此篇報告探討的是持續性鈉離子電流 (persistent Na+ current;INaP) 有可能成為藍斑核細胞自發性放電 (spontaneous firing) 的可能原因。以30mV 到 -100mV (20 mV/s) 的斜波電位法 (ramp) 引發電流,加入河豚毒素 (tetrodotoxin;TTX) 前後的電流紀錄線 (current trace) 差異即為INaP。INaP開啟的電位大約在-50到-60 mV,電流為-103 +- 16 pA (n = 12)。INaP的活化曲線 (activation curve) 可被二狀態一級波茲曼方程式 (two-state first-ordered Boltzmann equation) 描述,得到k為6.8 +- 0.8和Vh為-24 +- 1.5 mV。以非侵入性法量測17顆細胞膜電位,得知膜電位平均為-51 +- 1.5 mV。其中10顆為非自發性放電 (non-spontaenous firing) 的細胞,其膜電位 (membrane potential;Vm) 為-54 +- 1.3 mV,而7顆會自發性放電的細胞膜電位為-47 +- 1.7 mV。平均上,細胞膜電位和INaP的開啟電位相近,若膜電位達其閾值 (threshold) 則可穩定地推動膜電位提升達到自發性放電,反之則否。在電位箝制模式 (voltage clamp mode) 或電流箝制模式 (current clamp mode) 紀錄下,可以看到藍斑核細胞膜電位在動作電位 (action potential;AP) threshold以下仍然產生規律的振盪 (oscillation),此振盪可被卡貝索酮 (carbenoxolone;CBX)抑制,表示是經connexin調控之相鄰細胞傳入的動作電流。這個振盪可以使藍斑核細胞受正電流 (positive current) 興奮後,產生相位式放電 (phasic firing)。使用力如太 (riluzole) 抑制INaP,可以完全或部分地抑制藍斑核細胞的自發性放電,並且改變動作電位波型,造成動作電位頂點 (peak) 電位下降與動作電位的去極化 (depolarize) 速度降低,甚至可讓部分細胞產生適應性放電 (adaptive firing),可見INaP對於藍斑核細胞自發性放電,動作電位完整性有很重要的地位。

Locus coeruleus (LC) neurons have widely projections to various areas of brain; they provide the forebrain the major supply of norepinephrine which is well known to play important roles in many cognitive functions, including sleep-awake cycle, alertness attention, learning and memory, pain, and brain metabolism, etc. Accordingly, investigating the regulation of LC neurons is essential to understand how LC-NE system associated brain functions are regulated. Here we reported the persistent voltage-gated sodium current (INaP) could be a major player for generating spontaneous firing in LC neurons. We recorded membrane currents responded to a voltage-ramp from 30mV to -100mV (slope = 20 mV/s) in control and in the presence of 1 μM tetrodotoxin (TTX) in LC neurons; subtracting recording in TTX from that in control condition yielded INaP, the range of activation threshold and peak amplitude of which were about -50 to -60 mV and -103 +- 16 pA (n = 12 cells), respectively. The activation curve of INaP was fitted with two-state fisrt-ordered Boltzmann equation with estimated k-value and half-activation voltage (Vh) being 6.8 +- 0.8 and -24 +- 1.5 mV, respectively. By using noninvasive membrane potential measurement to estimate resting membrane potential (Vm) without interrupting cytosol compositions of the recorded neurons and misjudging the seal quality in whole cell recording, the averaged Vm from 17 LC neurons was -51 +- 1.5 mV, 10 of them whose Vm is -54 +- 1.3 mV showed no spontaneous firing and the 7 of them with estimated Vm = -47 +- 1.7 mV could fire spontaneously. These results show that Vm and activation threshold of INaP in LC neurons are about the same value. This feature together with the high k-value of INaP could allow the self-generation of AP in LC neurons. In current clamp recording, most LC neurons showed sub-threshold voltage-oscillation, which was blocked by connexin blocker, carbenoxolone, showing the activity was generated by action currents of discharging neighboring cells flowing through gap junctions. This voltage-oscillation enable the generation of phasic firing in recorded LC neuron. Moreover, selective blocker of INaP─riluzole can fully or partially inhibit the spontaneous firing in LC neurons, abolish the repetitive firing pattern in some neurons, and change the AP waveform when injecting 100 or 200 pA from Vm at I = 0. The peak amplitude and rate of rising phase are both decreased. Also, INaP probably can enhance the oscillation amplitude due to the similar range between threshold of INaP and Vm at I = 0. In conclusion, INaP is an important factor that completes the intact firing ability in LC neurons.

中文摘要 i
Abstract ii
目錄 iv
背景介紹 1
正腎上腺素 (norepinephrine;NE) 的生成與接受器 (receptor) 1
藍斑核 (locus coeruleus;LC) 位置與細胞型態 2
藍斑核基本電生理特性 3
藍斑核細胞放電活動於意識控制的影響 5
自發性放電 (spontaneous firing) 的可能機制 6
鈉離子通道 (Na+ channel) 8
持續性鈉離子電流 (persistent Na+ current;INaP) 8
力如太 (Riluzole) 的作用 10
研究動機與目的 13
材料與方法 14
腦薄片製作 14
細胞電生理紀錄 14
電生理實驗之藥物使用 18
組織免疫染色 18
資料分析 19
實驗結果 20
藍斑核神經細胞的放電型式與離子通道 (ion channel) 之初步觀察 20
藍斑核細胞的INaP 23
細胞接觸模式 (cell-attach mode) 之非侵入性膜電位量測 24
抑制INaP於藍斑核細胞放電能力的影響 26
討論 28
膜電位與INaP於藍斑核細胞自發性放電機制的作用 28
INaP對於藍斑核細胞放電能力和動作電位 (action potential;AP) 的關係 30
隙型連結 (gap junction) 調控之振盪 (oscillation) 對於放電型式的作用 31
其他可能參與放電能力的因素 32
實驗侷限 34
結論 38
圖表 39
圖1. 藍斑核細胞群的位置 39
圖2. 藍斑核神經細胞的放電型式之初步觀察 40
圖3. 隙形連結 (gap junction)調控之振盪 (oscillation) 對於放電型式的影響 43
圖4. 藍斑核細胞的INaP 46
圖5. 細胞接觸模式之非侵入性膜電位量測 49
圖6. 40 μM riluzole可抑制INaP,並可完全或部分抑制自發性放電 52
圖7. 受Riluzole影響後的細胞放電型態可分為重複式放電 (repetitive firing)或適應式放電 (adaptative firing) 56
圖8. 在控制組情形和 40 μM riluzole情形下,以100 pA正電流引發之動作電位 (action potential;AP)的波形分析比較 59
表1. 40 μM Riluzole與1 μM TTX抑制之INaP以二狀態一級波茲曼方程式描述得到的動力學參數 55
附錄 61
a.背景介紹部分 61
附錄a圖1. 大鼠腦內NE的來源與其投射的部位 61
附錄a圖2. 藍斑核的細胞型態 62
附錄a圖3. 藍斑核細胞在核區內的位置不同,其樹突 (dendrite) 伸展方向也不同 63
附錄a圖4. T型鈣離子通道 (T-type calcium channel) 造成的反彈 (rebound) 與叢發式放電 (burst firing) 64
附錄a圖5. 過極化活化環核苷酸活化離子通道 (Hyperpolarization-activated cyclic nucleotide-gated channels;HCN channel)造成的凹陷 (sag) 65
附錄a圖6. A型鉀離子通道 (A-type K+ channel) 造成的延遲放電 66
附錄a圖7. 藍斑核細胞在不同的意識狀態有不一樣的放電頻率 67
附錄a圖8. 鈉離子通道 (Na+ channel) 之分子結構 68
附錄a圖9. 霍奇金-赫胥黎 (Hudgkin-Huxley;HH)之鈉離子通道動力學模型 69
附錄a圖10. 全細胞模式 (whole cell mode)紀錄的Na+ channel產生的電流 70
附錄a圖11. 鈉離子通道產生的電流 (全細胞模式記錄時的鈉離子瞬變電流(transient sodium current;INaT)),其活化曲線 (activation curve) 與不活化曲線 (inactivation curve) 呈現電位依賴性 (voltage dependence) 71
附錄a圖12. 細胞接觸模式的方法量測鈉離子通道產生的電流 72
附錄a圖13. 改變那離通道動力學模型中的速率常數,可增加INaP,並使自發性放電頻率增加 73
附錄a圖14. 低到高斜波電位 (ramp)與高到低ramp引發的INaP是相同的 74
附錄a圖15. 低到高ramp與高到低ramp引發的INaP是不同的 75
b.實驗侷限部分 76
附錄b圖1. 全細胞模式下量測藍斑核細胞之INaT與其活化曲線 76
附錄b圖2. 含核外側外膜箝制模式 (nucleated outdie-out patch)量測之藍斑核INaT與其活化曲線與不活化曲線 78
附錄b圖3. 動作電位的後過極化並沒有受40uM riluzole影響 81
中英對照 83
參考文獻 89


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