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研究生:蕭逸澤
研究生(外文):Yi-Tse Hsiao
論文名稱:Hypocretin與theta oscillations在壓力及壓力誘發之睡眠變化中所扮演的角色,以及Cannabidiol (CBD)對壓力引發睡眠失調之作用
論文名稱(外文):Roles of hypocretin, theta oscillations, and cannabidiol in stress and stress-induced sleep alterations
指導教授:張芳嘉
指導教授(外文):Fang-Chia Chang
口試委員:詹東榮簡伯武黃玉書徐崇堯
口試日期:2012-12-22
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:獸醫學研究所
學門:獸醫學門
學類:獸醫學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:英文
論文頁數:228
中文關鍵詞:壓力睡眠下丘泌素大麻二酚θ波中縫核杏仁核
外文關鍵詞:stresssleephypocretincannabidiolthetaraphe nucleusamygdala
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壓力影響生理和心理健康。許多因素(例如:生活環境和藥物治療)讓研究人員難以釐清壓力如何影響生理和心理健康。因此這篇實驗利用控制良好的環境和實驗動物(大鼠)來研究壓力引起的行為以及相關機制。我們研究神經傳遞物質:下丘泌素(hypocretin, hcrt)或稱食慾素(orexin)的壓力調控功能。論文中有三個研究主題:壓力造成腦波θ波的改變、壓力造成睡眠失調、以及大麻二酚(cannabidiol, CBD)減緩焦慮的機制。

Hcrt上升會造成壓力相關反應。腦波θ波是大鼠遭遇壓力時主要的腦波。Hcrt受體(hcrtR-1和hcrt-R-2)在抑制θ波的腦區—內中縫核(median raphe nucleus, MRN)相當豐富。這可能代表hcrt能調控壓力引起的θ波。在第一部分的實驗是釐清hcrt引發θ波之機轉和MRN在其中扮演的角色。我們的實驗結果顯示對大鼠足電刺激會增加θ波而hcrt受體拮抗劑(TCS1102)會抑制足電刺激引發的θ波。微量注射hcrt-1 (1 and 10 μg) 或 hcrt-2 (10 μg)到MRN中模擬了足電刺激升高θ波之作用。同時注射GABAA受體拮抗劑bicuculline至MRN可以阻斷hcrt或足電刺激引發的θ波。100 Hz的MRN電刺激也抑制了足電刺激的θ波。我們的資料顯示θ波和焦慮感正相關,所以我們再假設抑制θ波可以減緩焦慮。我們利用架高十字迷宮(elevated plus maze, EPM)來測量大鼠焦慮程度。θ波被bicuculline或MRN電刺激抑制後,大鼠進入EPM的open arm時間和比率增高;這些結果代表了壓力會引起hcrt的釋放,經過MRN中GABA神經,減緩了MRN抑制θ波的作用,最後造成θ波增加。除此之外,刺激MRN減少θ波後可減少大鼠焦慮。

壓力同時也是造成睡眠問題的主要原因之一。Hcrt可以增加醒覺,同時也是壓力神經傳遞物。另外,MRN同時調控恐懼反應和睡眠。不過壓力是否會造成hcrt在MRN增加而抑制了睡眠目前不是很了解。我們的結果顯示足電刺激抑制了快速動眼睡眠(rapid eye movement, REM)且微量注射TCS1102到MRN減緩了REM睡眠抑制。hcrt-1 (1 and 10 μg) 或 hcrt-2 (10 μg)注射到MRN模擬了足電刺激引起的睡眠改變。足電刺激也會使hcrt-1和hcrt-2在外側下視丘免疫陽性的神經細胞增加。而注射bicuculline抑制了足電刺激或者hcrt引起的REM睡眠減少。這些結果可能代表了hcrt在MRN中經由GABA神經而抑制REM睡眠。

CBD是大麻中活性主成分且有抗焦慮作用。影像學研究顯示CBD活化了杏仁核(amygdala)而有抗焦慮作用。不過CBD是否可以改善壓力造成的睡眠障礙並不清楚。因為焦慮的產生有時是因為有數天持續的壓力造成,所以我們利用連續四天重複合併測驗(repeated combination test, RCT)也就是50分鐘的曠野測試(open field, OF)接著10分鐘EPM。四天測驗中,大鼠在OF中心的時間以及EPM open arm的時間會漸漸越來越少。CBD注射到杏仁核中心核後(central nucleus of amygdale, CeA)增加了大鼠在OF中心和在EPM open arm的時間,代表了CBD有抗焦慮作用。RCT會抑制入眠後的一小時的非快速動眼睡眠(non-REM, NREM)和第4-10小時的REM睡眠。CBD改善了RCT造成的REM睡眠減少但是對NREM效果不顯著。實驗的結果顯示CBD藉由減緩焦慮而改善了REM睡眠。

總體來說,我們的結果顯示:REM睡眠減少是短暫壓力(例如:足電刺激)最主要造成的影響、壓力造成hcrt在MRN的釋放增加所以使θ波升高,且也抑制了REM睡眠、抑制θ波產生可以減緩焦慮、CBD透過CeA減緩焦慮而改善壓力引起的REM睡眠減少。


Abstract
Stress impairs physical and mental health. Multi-factors, such as living environments, make investigators difficult to clarify how stress affects health. Thus this study utilized well-controlled environments and experimental animals (rats) to elucidate stress-induced behaviors and the related underlying mechanisms. We investigated the stress-related functions of a novel neurotransmitter, hypocretin (hcrt). Three main issues have been investigated in current dissertation, including: the stress-induced alteration of theta frequency in the electroencephalograms (EEGs), stress-induced sleep disturbances, and the mechanism of a potential anxiolytic, cannabidiol (CBD).
Increased hcrt mediates stress-related responses. Theta frequency of EEGs is predominant during stress in rats. Hcrt receptors are abundant in the median raphe nucleus (MRN) which is a brain region desynchronizing hippocampal theta oscillation, suggesting a possible role of hcrt in modulating theta rhythm. First part of experiments clarified the involvement of hcrt in the stress-induced theta waves and the role of the MRN. Our results indicated that the intensity of theta waves was enhanced by the footshock and that TCS1102 (hcrt receptor antagonist) suppressed the footshock-induced theta waves. Administration of hcrt-1 (1 and 10 μg) and hcrt-2 (10 μg) directly into the MRN simulated the effect of footshock and increased theta waves. Co-administration of GABAA receptor antagonist, bicuculline, into the MRN blocked the increase of theta waves induced by hcrt or footshocks. Electrical stimulation of MRN also suppressed footshock-induced theta waves. We hypothesized that suppression of theta waves reduces anxiety. We exploited the elevated plus maze (EPM) to measure the anxiety level of subjects. After suppression of theta waves by either bicuculline or electrical stimulation, the duration in open arms increased. These results suggested that stress enhances the release of hcrts, activates GABAergic neurons in the MRN, blocks the ability of MRN to desynchronize theta waves, and subsequently increases the intensity of theta rhythm. Furthermore, stimulation of MRN blocked theta waves, which in turn reduced anxiety levels.
The MRN modulates fear responses and also regulates sleep, but it is unclear whether stress-induced hcrts in the MRN disrupt sleep or not. Our data demonstrated that the footshock reduced rapid eye movement (REM) sleep and microinjection of TCS1102 into the MRN blocked the decrease of REM sleep in rats. Administration of hcrt-1 or hcrt-2 to the MRN mimicked the footshock-induced sleep alterations. Co-administration of bicuculline suppressed the decrease of REM sleep, induced either by footshock stimuli or administration of hcrts. These observations suggest that hcrt in the MRN is involved in the stress-induced reduction of REM sleep and this action is mediated by the GABAergic neurons in the MRN.
CBD, an active component of marijuana, is reported to have the anxiolytic effect. Image studies showed that CBD decreases anxiety by activation of the amygdala. However, the ability of CBD to improve stress-induced sleep disturbances is unclear. We employed the repeated combination tests (RCT), consisting of a 50-minute open field (OF) and a subsequent 10-minute EPM, for four consecutive days to simulate the development of anxiety. Time spent in the centre arena of OF and during open arms of the EPM was substantially decreased in latter days of RCT, whereas microinjection of CBD into the amygdala blocked the reduction, further confirming its anxiolytic effect. The suppression of REM sleep during hours 4-10 were observed after the RCT. CBD efficiently blocked anxiety-induced suppression of REM sleep.
In summary, our results have shown that REM sleep reduction is the main sleep disturbance induced by the acute stress, such as the inescapable footshock. Stress increases hcrt in the MRN which results in increase of theta rhythms and subsequently decreases REM sleep. Desynchronization of theta waves reduces the anxiety level of rats. Moreover, CBD in the amygdala reduces anxiety and reverses the REM sleep reduction induced by stressors.


TABLE OF CONTENTS
中文摘要 i
Abstract iv
CHAPTER 1 1
GENERAL INTRODUCTION 1
1.1 Hcrt causes sleep disturbance after stressful experience 4
1.2 Hcrt contributes to the stress-induced theta generation 6
1.3 Treatments for anxiety disorders 6
1.3.1 Manipulation of theta waves interrupts brain functions 6
1.3.2 A potential anxiolytic: CBD 7
1.4 Specific Aims 8
CHAPTER 2 9
ACTIVATION OF GABAERGIC INDIRECT PATHWAY BY HYPOCRETIN IN THE MEDIAN RAPHE NUCLEUS (MRN) MEDIATES STRESS-INDUCED THETA RHYTHM IN RATS 9
2.1 ABSTRACT 9
2.2 INTRODUCTION 11
2.3 MATERIAL AND METHODS 14
2.3.1 Drugs 14
2.3.2 Animals and surgeries 14
2.3.3 Apparatus and recoding 16
2.3.4 Experimental protocols 17
2.3.5 Statistical analysis 18
2.4. RESULTS 19
2.4.1 The effects of IS stimuli on the theta power 19
2.4.2 The role of MRN hypocretin in the IS stimuli-induced enhancement of theta waves 20
2.4.3 Activation of GABAergic activity in the MRN modulates IS stimuli-induced enhancement of type-2 theta waves 21
2.4.4 Histological analysis of MRN lesion after multiple microinjections 22
2.5. DISCUSSION 40
2.6. CONCLUSIONS 44
CHAPTER 3 45
DISRUPTION OF FOOTSHOCK-INDUCED THETA RHYTHMS BY STIMULATING MEDIAN RAPHE NUCLEUS REDUCES ANXIETY IN RATS 45
3.1 ABSTRACT 45
3.2 INTRODUCTION 47
3.3 MATERIAL AND METHODS 50
3.3.1 Drugs 50
3.3.2 Animals and surgeries 50
3.3.3 Behavioral tests 53
3.3.4 Experimental protocols 54
3.3.5 Statistical analysis 55
3.4 RESULTS 56
3.4.1 Type-1 theta power increased when rats explored in the footshock box 56
3.4.2 Inescapable footshock stimuli enhanced the type-2 theta power 57
3.4.3 The effects of MRN stimulation and bicuculline administration 58
3.4.4 The results of EPM task 59
3.5 DISCUSSION 73
CHAPTER 4 79
HYPOCRETIN (OREXIN) IN THE MEDIAN RAPHE NUCLEUS MODULATE INESCAPABLE FOOTSHOCK-INDUCED SLEEP ALTERATIONS IN RATS 79
4.1 ABSTRACT 79
4.2 INTRODUCTION 81
4.3 MATERIAL AND METHODS 83
4.3.1 Substances 83
4.3.2 Animals 84
4.3.3 Surgery 84
4.3.4 Apparatus and recoding 85
4.3.5 Experimental protocol 87
4.3.6 Immunohistochemistry (IHC) 88
4.3.7 Statistical analysis 89
4.4 RESULTS 90
4.4.1 Sleep alterations after IS 90
4.4.2 TCS1102 reduced IS-induced sleep alterations 90
4.4.3 Microinjection of hcrt-1 and hcrt-2 suppressed REM sleep 92
4.4.4 Sleep architecture altered by hcrts 92
4.4.5 The IHC revealed hcrt-1 and hcrt-2 IR following IS 93
4.4.6 Histological analysis of MRN lesion after multiple microinjections 94
4.5 DISCUSSION 109
4.6 CONCLUTION 113
CHAPTER 5 114
GABAERGIC NEURONS IN THE MEDIAN RAPHE NUCLEUS (MRN) MODULATE FOOTSHOCK-INDUCED RAPID EYE MOVEMENT (REM) SLEEP DISTURBANCE IN RATS 114
5.1 ABSTRACT 114
5.2 INTRODUCTION 116
5.3 MATERIAL AND METHODS 117
5.3.1 Substances 117
5.3.2 Animals 118
5.3.3 Apparatus and Recoding 119
5.3.4 Experimental Protocol 121
5.4 RESULTS 122
5.4.1 The influence of IS on sleep 122
5.4.2 The effect of Bicuculline on post-IS sleep 123
5.4.3 The effects of microinjecting bicuculline+hcrt into the MRN 123
5.5 DISCUSSION 137
CHAPTER 6 140
EFFECT OF CANNABIDIOL ON SLEEP DISRUPTION INDUCED BY THE REPEATED COMBINATION TESTS CONSISTING OF OPEN FIELD AND ELEVATED PLUS-MAZE IN RATS 140
6.1 GRAPHICAL ABSTRACT 140
6.2. INTRODUCTION 143
6.3 MATERIALS AND METHODS 146
6.3.1 Substances 146
6.3.2 Animals 146
6.3.3 Apparatus and recording 148
6.3.4 Behavioral tests 149
6.3.5 Experimental procedures 151
6.3.6 Statistical analysis 153
6.4 RESULTS 154
6.4.1 Behavioral measures of the repeated combination tests (RCT) 154
6.4.2 Effects of CBD on repeated combination tests-induced behaviors 157
6.4.3 Sleep alterations induced after repetitive exposure to the combination tests 159
6.4.4 CBD blocked RCT-induced suppression of REM sleep 161
6.5. DISCUSSION 178
CHAPTER 7 187
DISCUSSION and CONCLUSIONS 187
REFERENCE 198

LIST OF ILLUSTRATIONS
Figure 1. A diagram of experimental protocol. 23
Figure 2. The intensity of EEG spectra obtained from undisturbed baseline and PFS+IS stimuli. 25
Figure 3. The intensity of EEG spectra obtained from undisturbed baseline, 28
Figure 4. Summary for the alterations of delta, type-1 theta, type-2 theta, alpha, and beta powers after IS stimuli. 30
Figure 5. A: Summary for the alterations of type-2 theta power after microinjection of TCS1102. 32
Figure 6. Summary for the effects of bicuculline on the enhancement of type-2 theta power induced by IS stimuli and hcrts. 34
Figure 7. A: Left side: the histological slide of the median raphe nucleus (MRN). 36
Figure 8. A hypothetical diagram. 38
Figure 9. A diagram of experimental protocol. 61
Figure 10. Summary for the alterations of spectral powers after manipulations of MRN activity. 63
Figure 11. The intensity of EEG spectra obtained from undisturbed baseline and inescapable footshock. 65
Figure 12. The intensity of EEG spectra obtained from the baseline when rats were in their home cage and during footshock+100 Hz MRN stimulation. 67
Figure 13. Desynchronization of footshock-induced theta waves reduced anxiety in the EPM task. 69
Figure 14. Examples of tracing for the rat’s movement in the EPM. 71
Figure 15. The effects of IS on sleep alterations. 95
Figure 16. The influences of non-selective hcrtR antagonist (TCS1102) on IS-induced sleep alterations. 97
Figure 17. The effects of sleep patterns after administration of hcrt-1 in the MRN. 99
Figure 18. The effects of sleep patterns after administration of hcrt-2 in the MRN 101
Figure 19. The expression of hcrt neurons in the LHA after IS 103
Figure 20. A. The diagram for the experimental protocol. 105
Figure 21. The effects of footshock on sleep alterations. 125
Figure 22. The influences of GABAA receptor antagonist (bicuculline) on footshock-induced sleep alterations. 127
Figure 23. The effects of sleep patterns after administration of bicuculline+hcrt-1 in the MRN 129
Figure 24. The effects of sleep patterns after administration of bicuculline+hcrt-2 in the MRN 131
Figure 25. A summary diagram 133
Figure 26. A: The diagram for the experimental protocol. 163
Figure 27. The OF of RCT decreases the time spent during the centre arena and CBD increases rats’ exploration in the central arena 165
Figure 28. The effects of CBD on the time rats spend in the open arms 167
Figure 29. The level of anxiety determined by urination and defecation after exposing to the RCT. 169
Figure 30. The alterations of NREM sleep and REM sleep after the RCT 171
Figure 31. The effects of CBD on RCT-induced sleep alterations 173
Figure 32. The subcortical regions that control theta waves 193
Figure 33. The mechanism of subcortical regions that control theta waves, stress, and REM sleep 195


LIST OF TABLES

Table 1. Effects of IS, DMSO, TCS1102+IS, hcrt-1 and hcrt-2 on the sleep-wake architecture parameters of rats. 107
Table 2. Effects of PFS, footshocks, bicuculline, bicuculline+footshock, bicuculline+hcrt-1 and bicuculline+hcrt-2 on the sleep-wake architecture parameters of rats. 135
Table 3. Parameters (immobilization time, total distance of movement, movement distance in the centre arena, and velocity in the centre arena) detected from the OF in three groups 175
Table 4. Effects of RCT, CBD and sleep deprivation on the sleep-wake architecture parameters of rats 177



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