臺灣博碩士論文加值系統

許多研究已經指出長期運動訓練可增強學習記憶及長期增益現象(一種至今最受青睞的學習與記憶之神經生物學模式)。先前的研究報告指出，跑步機運動訓練會透過抑制老鼠杏仁體與海馬迴之血清素1A(5-HT1A)受體的活化，以及增加此二腦區腦源性神經滋養因子(BDNF)及其受體TrkB的表現，來促進動物被動迴避試驗(一種與杏仁體和海馬區域密切相關之聯結性記憶測試)的學習與記憶能力。最近我們實驗室的研究發現，跑步機運動可藉由抑制 5-HT1A受體的活化，來增強大白鼠海馬齒狀回(DG)和杏仁體側核(LA)區域高頻電刺激(HFS)所誘發的LTP。此外，我們更進一步指出BDNF-TrkB訊息路徑有參與跑步機運動訓練對LA-LTP的增強作用。然而，跑步機運動訓練是否亦可透過活化BDNF-TrkB訊息路徑，來增強DG-LTP，則不得而知。因此在本研究中，我們利用胞外電生理紀錄的技術以及藥理學的方法，探討BDNF-TrkB訊息路徑在四週跑步機運動促進雄性大白鼠DG-LTP的作用中所扮演的角色。我們的結果顯示，四週跑步機運動訓練可顯著促進雄性大白鼠HFS所誘發的DG-LTP。我們也發現，施予K252a (TrkB受體拮抗劑) 可完全消除運動訓練對DG-LTP 的促進作用，表示跑步機運動是透過活化BDNF-TrkB路徑來促進DG-LTP。此外，分別給予U73122 (磷脂酶Cγ抑制劑)和Bis I (磷酸激酶 C 抑制劑)，都可阻斷運動訓練對DG-LTP的促進作用，顯示運動訓練是經由活化BDNF-TrkB下游這些訊息傳遞分子來促進DG-LTP。相反地，分別給予wortmannin (磷酸肌醇 3-激酶抑制劑) 和PD98059 (MEK 抑制劑)，則都不會影響運動訓練對DG-LTP的促進作用。綜合上述，我們的結果顯示，BDNF-TrkB 訊息路徑及其下游的訊息傳遞分子包括磷脂酶Cγ和磷酸激酶 C皆有參與跑步機運動訓練對雄性大白鼠HFS所誘發DG-LTP的促進作用。

Many studies have indicated that chronic exercise training enhances learning and memory as well as long-term potentiation (LTP), the best-described neurobiological substrate of learning and memory to date. Previous studies have shown that treadmill exercise enhances passive avoidance (PA) memory by down-regulating the serotonin type 1A (5-HT1A) receptor system and up-regulating levels of brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) in the rodent hippocampus and amygdala, brain areas highly associated with PA memory. Our recent studies have indicated that treadmill exercise potentiates high-frequency stimulation (HFS)-induced LTP in the rat hippocampal dentate gyrus (DG) and lateral amygdala (LA) via reducing 5-HT1A receptor activation. In addition, we have further demonstrated the involvement of the BDNF-TrkB pathway in treadmill exercise-induced enhancement of rat LA-LTP. However, it is unclear whether the BDNF-TrkB pathway also mediates treadmill exercise-induced facilitation of rat DG-LTP. In the present study, we used the extracellular electrophysiological recording technique and pharmacological methods to determine the role of the BDNF-TrkB pathway in four-week treadmill exercise-induced facilitation of DG-LTP in male rats. Our results revealed that four-week treadmill exercise facilitated HFS-induced DG-LTP in male rat slices. Moreover, bath perfusion of the TrkB inbihibor K252a abolished exercise-induced facilitation of DG-LTP, suggesting that the facilitating effect of treadmill exercise was mediated by the BDNF-TrkB pathway. Furthermore, the phospholipase C-γ (PLCγ) inhibitor U73122, and the protein kinase C (PKC) inhibitor Bis I completely blocked the exercise-induced facilitation of DG-LTP, indicating that exercise acted through PLCγ and PKC to facilitate DG-LTP. In contrast, bath perfusion of the phosphatidylinositol-3 kinase (PI3K) inhibitor wortmannin or the MEK inhibitor PD98059 has little effect on exercised-induced facilitation of DG-LTP. In summary, our results demonstrate that treadmill exercise acts through the BDNF-TrkB pathway and its downstream signaling molecules including PLCγ and PKC to facilitate DG-LTP in male rats.

Abstract in Chinese……………………………………………………...I
Abstract………………………………………………………………...III
Acknowledgement………………………………………………………V
Table of Contents………………………………………………………VI
List of Figures......................................................................................VIII
Abbreviations…………………………………………………………...X
Introduction……………………………………………………………..1
Exercise participates in learning and memory and synaptic plasticity………….1
Role of brain-derived neurotrophic factor (BDNF) in neuronal plasticity and memory…………………………………………………………………………..2
Effect of exercise on BDNF and TrkB expression levels………………………....4
Rationale and the specific aim of this study……………………………………...5
Materials and Methods…………………………………………………6
Animals…………………………………………………………………………...6
Treadmill exercise protocol………………………………………………………6
Slice preparation…………………………………………………………...…….6
Extracellular electrophysiological recordings.......................................................7
Drugs and chemicals……………………………………………………………..8
Statistical analysis…………………………………………..……………………8
Experimental Design……………………………………………………………..8
Results…………………………………………………………….…….11
Four-week treadmill exercise facilitates HFS-induced DG-LTP.………….…...11
Bath perfusion of K252a abolishes exercise-induced facilitation of DG-LTP…………………………………………………………………………11
Bath perfusion of U73122 abolishes exercise-induced facilitation of DG-LTP…………………………………………………………………………12
Bath perfusion of Bis I abolishes exercise-induced facilitation of DG-LTP…………………………………………………………………...…….12
Bath perfusion of wortmannin does not block exercise-induced facilitation of DG-LTP................................................................................................................13
Bath perfusion of PD98059 does not block exercise-induced facilitation of DG-LTP…………………………………………………………………………13
Discussion……………………………..………………………………..14
Four-week treadmill training facilitates DG-LTP thorough BDNF-TrkB signaling transduction……………………………………………………………………..14
Role of the PLCγ-PKC pathway in treadmill exercise-facilitated DG-LTP………………………………...……………………………………….15
Role of PI3K-Akt and MAPK pathways in treadmill exercise-induced DG-LTP facilitation………………………………………………………………………16
Conclusion……………………………………………………...………18
References…………………………………..…………………………..31
About the Author……………………...……………………………….39

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