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系統識別號 U0026-0907201212373100
論文名稱(中文) 長期運動改善中樞調控血壓功能並促進線索性恐懼學習
論文名稱(英文) Chronic exercise improves the central regulation of blood pressure and facilitates the cued fear learning
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 100
學期 2
出版年 101
研究生(中文) 徐袁章
研究生(英文) Yuan-Chang Hsu
學號 s58941280
學位類別 博士
語文別 英文
論文頁數 139頁
口試委員 指導教授-任卓穎
口試委員-陳洵瑛
召集委員-郭余民
口試委員-游一龍
口試委員-梁庚辰
口試委員-王鐘賢
中文關鍵字 運動  壓力  心臟血管功能  學習與記憶 
英文關鍵字 Exercise  Stress  cardiovascular performance  Learning and memory 
學科別分類
中文摘要 目的 壓力已知為心臟血管疾病的危險因子之一,但規律性運動可降低心臟血管疾病之發病率或減緩其嚴重性。除了已知腦幹為調控心血管系統的中心之外,下視丘也在中樞調控心臟血管系統中扮演重要的角色。因此規律性運動用以對抗壓力所造成的心血管反應及其交互作用,可能發生在中樞調控心臟血管系統。有許多文獻指出,長期運動能增加自發性高血壓大白鼠下視丘中的GABA蛋白及活性,而降低高血壓的病症。運動可能改善在休息或處於壓力的條件下之心臟血管的表現,這可能一部分源自於下視丘的改變。此外,運動可能讓動物對恐懼記憶有更好的學習能力,這可能源自於對壓力引發的反應有更好的適應力。因此,本研究在第一部分假設長期運動訓練能改善心臟血管的功能,這改善的方式可能源自於下視丘的GABA活性的改變。第二部分則假設長期運動改變下視丘及腦幹之神經活性,進而降低大白鼠在面臨急性壓力時所造成的心臟血管反應。第三部分,假設長期運動能透過加速對線索的辨識及恐懼刺激後的平靜反應,可改善大白鼠對線索性恐懼記憶的學習能力。


方法 將大白鼠並為控制組與運動組,後者進行八週中度之跑步機運動訓練。將無線電發報器植入大鼠之腹主動脈內以測量血壓、心跳、自律神經活性和感壓反射靈敏度。如搭配將藥物投以顱內注射至下視丘之室旁核與下丘腦後區,此法亦可測得內生性GABA神經活性。接著收集下視丘的檢體進行GABA相關蛋白的表現與GABA神經元的數目之測定。此外,我也會針對監測大鼠對束縛性壓力所引起的心臟血管之反應,以及下視丘c-Fos蛋白於不同時間點之表現進行測定。最後,在大鼠恐懼驚跳反應的訓練與測試階段,我將以前述生物遙測系統來監測即時的血壓變化。


結果 第一部分:長期中度跑步機運動會降低平靜狀態的血壓、心跳(心血管參數)、與交感神經活性,但增強副交感神經活性及感壓反射靈敏度(中樞調控心血管的神經活性)。此外,長期中度運動縮小下視丘的神經元及其樹突範圍。但是下視丘的GABA相關蛋白(nNOS, GAD67 and gephyrin)的表現量。第二部分:長期中度跑步機運動會:1)在壓力給予時和壓力給予後,降低壓力所提昇的血壓、心跳與交感神經活性但增強感壓反射靈敏度;2)在壓力給予後,使血漿皮質固醇及下視丘的c-Fos 濃度,加速恢復至基礎值並使腦幹的神經活性延遲恢復至基礎值。第三部分:長期中度跑步機運動促進大鼠對恐懼驚跳反應的學習能力。長期中度運動增加對光線(制約性刺激)所引起的血壓迅速上升,且加速交感神經活性在電擊(非制約性刺激)後之恢復,此外,在恐懼驚跳反應的訓練階段中,不論對照組或運動組所表現的二種血壓相關的參數(PCS/PA 和 STUS/ST0)彼此皆為顯著負相關。最後,不論阻斷線索性學習或是干擾電擊後的平靜反應,都會讓運動所提昇的恐懼驚跳反應消失。


結論 長期中度運動訓練會增強血壓正常的大鼠之下視丘中室旁核和下丘腦後區的GABA系統造成下視丘神經元萎縮,進而降低平靜狀態下清醒大鼠的血壓、心跳和交感神經活性。在壓力給予中、和壓力給予後,長期中度運動訓練皆能透過降低交感神經活性,並提高感壓反射靈敏度,而降低壓力引起的心血管反應。最後,改善線索性學習及加速電擊後之交感神經活性的恢復,有助於運動促進大鼠對嫌惡記憶的學習能力。整體來說,這些數據支持長期中度運動,能改善中樞調控血壓的能力,並促進線索性恐懼學習。
英文摘要 Objective: Stress is a well-known cardiovascular disease risk factor, while regular exercise exerts beneficial effects in the prevention of cardiovascular diseases. Regular exercise thus exerts counteracting effects on stress-evoked cardiovascular responses and such interactions may happen in the central control machinery in the brain. In addition to the well-known cardiovascular center in the medulla, the hypothalamus should also play an important role in the central control of cardiovascular performance. Results from many spontaneously hypertensive rat studies indicate that exercise training should effectively ameliorate the cardiovascular defects via increasing GABAergic proteins and activities. It is likely that the exercise-improved cardiovascular performance in both resting and stress-evoked conditions is partially mediated by hypothalamic adaptations. Moreover, the exercise-adapted animals may show superior performance in fear leaning and memory, if their stress-evoked responses are indeed well-adjusted. In this study, we hypothesized that chronic exercise i) induced cardiovascular resetting effects, which might be mediated by elevating GABAergic activities in the hypothalamus; ii) suppressed the stress-evoked cardiovascular responses and accelerated the post-stress recovery process, which might be mediated by altered central control in both hypothalamic and medullar areas, and iii) improved the conditioned fear learning and memory, which might be mediated by both faster cue identification and rapid post-shock recovery.

Methods: Rats were divided into sedentary and exercise groups; the latter was subjected to 8-week treadmill running at moderate intensity. A biotelemetry system was used to measure blood pressure, heart rate, autonomic nervous activities, baroreflex sensitivity, and endogenous GABAergic activities in the paraventricular nucleus and the posterior hypothalamic area. Hypothalamic specimens were collected for quantifying GABA-related proteins and GABAergic neurons. Additionally, the time-dependent cardiovascular responses and local c-Fos reactivity changes were measured in rats exposed to an immobilization stress. Finally, I used this telemetric system to monitor cardiovascular parameters real-time during training and testing sessions of the fear-potentiated startle. The exercise effects on fear learning and memory were compared between sedentary and exercise groups.

Results: Part I: Chronic moderate exercise reduced resting blood pressure, heart rate, sympathetic activity and enhanced parasympathetic activity and baroreflex sensitivity. It also elevated the resting level of hypothalamic GABAergic activities, increased the percentage of GABAergic neurons in the hypothalamus and upregulated the hypothalamic protein levels of nNOS, GAD67 and gephyrin, but not GABAA receptor. Consistently, exercise group showed reduced hypothalamic neuron soma and dendritic field. Part II: Chronic exercise i) suppressed the stress-evoked BP, heart rate and sympathetic activity during stress and post-stress periods; ii) increased the stress-induced baroreflex sensitivity during stress and post-stress periods; iii) accelerated the recovery of stress-evoked elevations of plasma corticosterone and hypothalamic neuron c-Fos during the post-stress period; iv) delayed the recovery of stress-evoked medullar c-Fos level during the post-stress period. Part III: Chronic moderate exercise improved the performance of fear-potentiated startle. It also increased light (CS)-induced rapid blood pressure elevations and accelerated the recovery of electric shock (US)-evoked sympathetic tone elevations. Moreover, these two blood pressure-related parameters (PCS/PA and STUS/ST0) were negatively correlated with each other in the training session trials. Finally, the blocking of cued learning or the interference of post-shock calmness abolished the exercise-facilitated performance of fear-potentiated startle.

Conclusion: Chronic treadmill running in normotensive rats augmented the GABAergic system in both paraventricular nucleus and posterior hypothalamic area, resulting in lower resting blood pressure, heart rate and sympathetic tone under conscious unrestraint conditions. Additionally, exercise reduced the dendritic field of hypothalamic neurons and suppressed the stress-evoked cardiovascular responses via differentially altering hypothalamic and medullar neuron activities during stress and post-stress periods. Finally, exercise facilitated aversive memory via improving cued learning and accelerating post-shock recovery of sympathetic tone. Taken together, these data suggest that chronic exercise improves the central regulation of blood pressure and facilitates the cued fear learning.
論文目次 Abstract…………………………………………………………………......................1
Chinese abstract………………………………..……………………....................……4
Acknowledgement………………………………………………………......................7
Contents……………………………………………………....................……...….......9
Table contents…………………………………………………...................………....14
Figure contents…………………………………………………....................…..…...15
Appendixes contents…………………………………………....................……........17
Abbreviations……………………………………………………………...................18

Part I Chronic exercise resets the resting blood pressure to lower levels by upregulating the hypothalamic GABAergic system
I-1. Introduction…………………………………………………………………...…20
I-2. Hypothesis and Experimental Design………………………….………………..23
I-3. Materials and Methods…………………...…………………………………...…24
1.3.1. Animals……………………………………………………………….…….24
1.3.2. Treadmill exercise protocol……………………………………………...…24
1.3.3. Measurement of cardiovascular parameters…………………………….…..25
1.3.4. Spectral analysis……………………………………………………….……26
1.3.5. Experiments of hypothalamic microinjection………………………....……27
1.3.6. Measurement of citrate synthase activity……………………………..….…27
1.3.7. Measurement of plasma corticosterone level………………………….……28
1.3.8. Immunoblotting of nNOS, GAD67, GABAA receptor, and gephyrin………………………………………………………………..……28
1.3.9. Immunostaining of hypothalamic neurons…………………………….……29
1.3.10. Statistical analysis…………………………………………………....……29
I-4. Results……………………………………………………...……………………30
1.4.1. Effects of exercise training on aerobic capacity, corticosterone
level, resting BP and HR, and the neural control………………………….…30
1.4.2. Effects of exercise training on the expression of GABA-related
proteins and percentage of GABAergic neurons in the hypothalamus………30
1.4.3. Effects of exercise training on endogenous GABAergic activities
in PVN and PHA…………………………………………………………..…31
1.4.4. Effects of exercise training on the recovery of BP, HR, and neural
control factors after acute moderate exercise…………………...……………31
I-5. Discussion………………………………………..…………………..….……….33
1.5.1. Effects of AME and CME on cardiovascular performance………..……….33
1.5.2. Effects of CME on hypothalamus in SHR……………………...….……….34
1.5.3. Effects of CME and stress on cardiovascular performance………………...35
1.5.4. Effects of CME on neuronal morphology in cardiorespiratory areas……....36
Part II Exercise Training Suppresses the Stress-evoked Cardiovascular Responses: the Role of Central Adaptations
II-1. Introduction…………………………………………………………...…….…..39
II-2. Hypothesis and Experimental Design…………………………………………..42
II-3. Materials and Methods………………………………………..……………...…43
2.3.1. Animals………………………………………………….……………….…43
2.3.2. Treadmill exercise protocol……………………………………………....…43
2.3.3. Stress exposure…………………………………………………………...…44
2.3.4. Measurement of cardiovascular parameters…………………………...……44
2.3.5. Spectral analysis……………………………………………………….……45
2.3.6. Measurement of citrate synthase activity………………………………...…46
2.3.7. Measurement of plasma corticosterone level…………………………….…46
2.3.8. Morphometric measurements of hypothalamic neurons……………....……46
2.3.9. Immunohistochemistry of hypothalamic neurons………………….…….…47
2.3.10. Statistical analysis……………………………………………….………...48
II-4. Results………………………………………………………………..…………49
2.4.1. Effects of exercise training on body weight, aerobic capacity, corticosterone
level, resting BP and HR, and the neural control………………….…………49
2.4.2. Effects of exercise training on hypothalamic neuron morphology…………49
2.4.3. Effects of exercise training on the recovery of BP, HR, and neural control
factors during the stress and post-stress periods………………………..……50
2.4.4. Effects of exercise training on the recovery of corticosterone level during the
post-stress period………………………………………………. ……………51
2.4.5. Effects of exercise training on the recovery of local c-Fos reactivity during the post-stress period…………………………………………………………51
II-5. Discussion……………………………….…………………………..…….……53
2.5.1. How do the underlying mechanisms of CME suppress stress-evoked cardiovascular responses…………………………...……………..…….……53
2.5.2. Effects of CME on neuronal morphology in cardiorespiratory areas….…...54
Part III Exercise training enhances conditioned fear learning via improving cued acquisition and post-shock recovery
III-1. Introduction……………………………………………………….... …...….....57
3.1.1 Blood pressure and the conditioned fear learning and memory………….….57
3.1.2 Exercise and the conditioned fear learning and memory…………...….…....59
III-2. Hypothesis and Experimental Design………………………….....……….…...61
3.2.1. Blood pressure and the conditioned fear learning and memory…….……....61
3.2.2. Exercise and the conditioned fear learning and memory…………….….….61
III-3. Materials and Methods……………………………………….………..……….62
3.3.1. Animals………………………………………………….………………….62
3.3.2. Treadmill exercise protocol……………………………………………....…62
3.3.3. Real-time BP Measurement and BP Spectral Analysis…………………..…63
3.3.4. Measurement of citrate synthase activity………………………………...…64
3.3.5. Behavioral Apparatus and Procedures for Fear-Potentiated Startle….….….64
3.3.6. Cannula Implantation and Intracranial Drug Delivery………. ………....….65
3.3.7. Block of amygdalar acquisition by microinjection of K252a………. .…….66
3.3.8. Noise interference procedures for fear-potentiated startle………. …….…..67
3.3.9. Statistical analysis……………………………………..……….………..….67
III-4. Results…………………………………………………………………….……68
3.4.1. Performance of fear-potentiated startle…………………………………..…68
3.4.2. BP-related parameters during learning trials of the training session……….68
3.4.3. BP-related parameters in the training session and the performance of
fear-potentiated startle…………………………………………………..……71
3.4.4. PCS/PA values during the testing session and the performance of
fear-potentiated startle……………………………………………………..…72
3.4.5. Pharmacological interventions to elucidate fear-conditioned learning pathways in the fear-potentiated startle………………………………………73
3.4.6. Effects of exercise training on the performance of fear-potentiated startle. ……………………………………………………….……………….74
3.4.7. Effects of exercise training on BP-related parameters during learning trials of
the training session……………………………………………………..…….75
3.4.8. Pharmacological and noise interventions to elucidate fear-conditioned learning mechanisms in the fear-potentiated startle………………..……..….76
III-5. Discussion………………………………………………………………...……78
3.5.1. Blood pressure and the conditioned fear learning and memory………....….78
3.5.2. Exercise and the conditioned fear learning and memory………….….…….81
References……………………………………………………………………………84
Tables…………………………………………………………...................................94
Figures…………………………………………………………..................................98
Appendixes…………………………………………………….................................124
Curriculum vitae……………………………………………….................................137
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