臺灣博碩士論文加值系統

中文摘要
日變節律(circadian rhythm)，存在於地球上的各類生物中，即便是內生性時鐘(internal clock)，其節律與週期也都與自然界息息相關。調控日變節律的基因，如Per1 (Period1)、Per2、Per3、Clock、Bmal1、Cry1 (Cryptochrome1)、Cry2、CK1ε (Casein kinase 1 ε)等，會隨外界正常的亮暗週期或內生性時鐘做約略二十四小時一次的規律性循環，亦或是單純參與日變節律的調控，我們稱之為日變節律相關基因(circadian rhythm related genes)。從了解哺乳類的生物時鐘位於視叉上核(suprachiasmatic nucleus, SCN)，至日變節律相關基因的研究，學者們發現了日變節律影響的層面相當廣泛而深遠。因此，本論文的目的便是要去觀察在不同亮暗間歇的情況下，對於大鼠日變節律性與日變節律相關基因的影響。
現今研究哺乳類日變週期在行為上的表現多採用動物跑滾輪(wheel running)或是紅外光閘阻斷(infrared detector)的方式偵測，而本實驗是採用影像擷取的方式來記錄大鼠日變節律性。利用Sprague-Dawley大鼠，以具夜視功能的紅外光攝影機拍攝大鼠亮暗活動的情形，可同時記錄四~六隻各自獨立飼養的大鼠，並以移動的距離作為參數。在正常的12小時光亮-12小時光暗(12L-12D)的情形下，可以記錄分析出大鼠活動力具有日變節律性，而在全暗(constant dark)的環境下，也能觀測到動物的行為依內生性時鐘而自由運行(free running)的情形。此外，利用光線造成內生性時鐘向後延遲(phase delay)的實驗也能呈現，故可證明利用影像擷取的方式，能正確觀測動物活動性的日變週期。
本論文的另一主題是探討不同於一般實驗用的亮暗週期，如8L-8D，6L-6D，4L-4D，2L-2D，24L下，亮暗間歇對動物的影響。除動物行為的觀測，也在不同時間點犧牲動物，並取其下視丘(hypothalamus)與小腦(cerebellum)，以觀測日變節律相關基因的表現。利用抽取組織RNA，反轉錄為cDNA並藉RT-PCR (reverse transcriptase-polymerase chain reaction)的方式放大基因表現。
結果發現在8L-8D下，動物活動力在光亮期皆較低落，主要活動力上升的時間點則延後至第一次主觀性黑夜(subjective night)的光暗後期及第二次主觀性黑夜的光暗初期；相較於正常週期，小腦的部份，rPeriod1、rPeriod3、rClock、rBmal1、rCry1、rCK1ε在連續三次8L-8D的亮暗週期中，第三次亮暗週期的基因表現皆低於前兩次，rPeriod1在第二次亮暗週期時會增加，rPeriod2在第二次主觀性白天(subjective day)的光暗初期會增加，而第二次主觀性黑夜的光亮期會抑制，rPeriod3在前兩次光暗期會增加，第三次光暗期會抑制，rBmal1在第一次光亮期與第三次亮暗週期時會抑制，第二次光暗初期會增加，rCry1在第二次光暗期會增加，第三次亮暗週期會抑制，rCry2在第一次光暗後期會上升，在第二次光暗期與第三次光亮期會受到抑制，rCK1ε在第一次光暗後期與第二次亮暗週期時會增加，在第三次亮暗週期時會抑制。在6L-6D的情形下，動物主要活動力時間由正常亮暗週期下十二小時的光暗期縮短至此時區主觀性黑夜的六小時光暗期；相較於正常週期，下視丘rPeriod2相位延遲(phase delay)約六小時，rPeriod3則呈現相位提前(phase advance)的情形，rClock在主觀性白天光暗期受到抑制，rBmal1、rCry1皆有趨於平緩的情形，rCry1、rCry2在主觀性黑夜的高峰會受到抑制，rPeriod1、rCK1ε則無明顯改變；小腦的部份，rPeriod1、rPeriod2、rCry1有相似的雙波峰，在兩次光暗的初期，表現都達高峰，rPeriod3的雙波峰則在第一次光暗初期與第二次光暗後期，rClock、rBmal1、rCry2、rCK1ε則在第一次光暗初期有高峰。在4L-4D的情形下，動物主觀性黑夜的光亮期，活動力明顯受到抑制，主觀性白天的光暗期，活動力有些許上升；與正常週期相比而言，下視丘rPeriod2高峰提早至主觀性白天的第一次光暗期，rClock原於主觀性黑夜第二次光暗後期上升的波峰點與光亮後的下降點，在此時區各受到抑制與增加的現象，rBmal1則呈現相位提前的情形，rCry1、rCK1ε皆有趨於平緩的趨勢，rCry2則無明顯改變；小腦的部份，rPeriod1有趨於平緩的情形，rPeriod2於主觀性白天的第一次光亮期與第二次光暗期表現上升，rClock則無明顯改變，rBmal1、rCry1、rCK1ε皆有相近的節律，高峰在主觀性黑夜的光亮期，低點在主觀性白天的第二次光亮期，rBmal1在主觀性白天的光暗期的高峰受到抑制，rCry1在主觀性黑夜的光亮期上升，rCK1ε在主觀性白天第二次光亮的高峰受到抑制。在2L-2D的情形下，動物主觀性黑夜的光亮期，活動力明顯受到抑制，主觀性白天的光暗期，活動力先升後降，並且伴隨相位延遲的現象。在全光亮(24L)下則會使動物有大於24小時的節律，且降低大鼠每日二十四小時之總移動距離。
綜合以上研究，發現在不同亮暗間歇8L-8D，6L-6D，4L-4D，2L-2D，24L的情形下，大鼠活動性仍具日變節律，且部份日變節律相關基因的表現也受到影響。

Abstract
Circadian rhythm is the common phenomenon existed in most of eukaryotes on earth. This about 24-hour (circadian) rhythmic activity is easy to be found in mammalian behaviors, such as locomotor activity in normal light-dark conditions. Moreover, some genes also express circadian rhythmicity and participate in regulation of circadian rhythm. These genes include the Per1 (Period1), Per2, Per3, Clock, Bmal1, Cry1 (Cryptochrome1), Cry2, CK1ε (Casein kinase 1 ε), et al. In this thesis, we tried to know whether what different light-dark conditions affect the circadian rhythmic pattern of locomotor activity circadian and circadian rhythm related genes expression.
Adult male Sprague-Dawley rats, weighing 350-600 g, were used in this study. Animal was individually kept in its own cage, and six rats as one group were measured at the same time. We found that locomotor activity in animals exhibited the circadian pattern using the distance of movement as the index in both 12-hour lights-on and -off (12L-12D) and constant darkness conditions. Furthermore, one hour light impulse at the early subjective night induced phase delay in active pattern. Furthermore, we detected different circadian rhythmicity in locomotor activity in different light-dark conditions including 8L-8D, 6L-6D, 4L-4D, 2L-2D, 24L. We also sacrificed animals at different time points in different light-dark conditions to measure the expression of Per1, Per2, Per3, Clock, Bmal1, Cry1, Cry2, and CK1ε genes. The brain regions of hypothalamus and cerebellum were used to extract RNA and semi-quantified the genes expression by the reverse transcriptase-polymerase chain reaction (RT-PCR).
In 8L-8D condition, the initial phase of locomotor activity was shifted from the initial period of darkness into the later period of darkness in the first subjective night and the initial period of darkness in the second subjective night with four hours phase delay compared with 12L-12D condition. Gene expression of cerebellum in 8L-8D compared to 12L-12D was described below. Expression patterns of rPer1, rPer3, rClock, rBmal1, rCry1, and rCK1ε were higher in the first and second light-dark cycles than the third one in 8L-8D conditions. The rPer2 mRNA expression increased at the initial period of darkness in the second subjective day, but reduced at the light period in the second subjective night in 8L-8D conditions. The rCry2 mRNA expression increased at the later period of first darkness, but reduced at the second darkness and the third light period in 8L-8D conditions. In 6L-6D conditions, the normal 12 hours duration of higher locomotor activity was attenuated to six hours and showed at the later period of darkness in the subjective night. In hypothalamus, rPer2 mRNA expression pattern showed phase delay, and rPer3 one did phase advance. The rClock, and rCry1 and rCry2 mRNAs expression in hypothalamus was inhibited at the dark period of the subjective day, and at the subjective night, respectively. The circadian pattern of rBmal1 and rCry1 mRNAs expressed less robustly, and rPer1 and rCK1ε ones were not influenced. On the other hand, in the cerebellum, the peak expression of rPer1, rPer2 and rCry1 mRNAs were at each initial period of darkness, but rPer3 one was at initial period of first darkness and later period of second one. The peak expression of rClock, rBmal1, rCry2 and rCK1ε mRNAs were at initial period of first darkness. In 4L-4D conditions, locomotor activity in rats were suppressed by light period (four hours) even in the subjective night, but slightly increased during the dark period (four hours) even in the subjective day. In 4L-4D conditions, the peak pattern of rPer2 mRNA in the hypothalamus shifted to the first dark period in the subjective day. The higher expression of rClock mRNA in the hypothalamus was reduced at the later period of second darkness in the subjective night, but increased at the light period in the subjective night. Circadian expression pattern of rBmal1 mRNA in the hypothalamus showed the phase advance, rCry1 and rCK1ε ones expressed less robustly, and rCry2 one was no change. In 4L-4D conditions, the genes expression in cerebellum was also detected. The rPer2 mRNA expression increased at the first light and second dark period in the subjective day. Circadian pattern of rPer1 mRNA expressed less robustly, and rClock one showed no influence. The peak pattern of rBmal1, rCry1 and rCK1ε were at the light period in the subjective night. However, the peak of rBmal1 reduced at the dark period in the subjective day, the rCry1 one increased at the light period of the subjective night, and the rCK1ε one reduced at the second light period in the subjective day. In 2L-2D conditions, locomotor activity at the light period in the subjective night was inhibited and increasing initially at the dark period in the subjective day combining with phase delay. In constant light conditions, the pattern of locomotor activity was longer than 24 hours with suppression of total distance of movement.
In conclusion, we find that 8L-8D, 6L-6D, 4L-4D, 2L-2D and 24L conditions exhibit different patterns of circadian rhythm in locomotor activity, and the expression patterns of circadian rhythm related genes on hypothalamus and cerebellum were also influenced in 8L-8D, 6L-6D and 4L-4D conditions.

目 錄

致謝………………………………………………………… I
英文摘要…………………………………………………… III
中文摘要……………………………………………………. V
序論…………………………………………………………. 01
一、生物時鐘(Biological Clocks)………………………………… 02
二、日變節律與視叉上核(Circadian Rhythm and SCN)………03
三、視叉上核的傳入與傳出(Efferent and Afferent of SCN)… 04
四、日變節律相關基因(Circadian Rhythm Related Genes)… 06
五、生理機制與日變節律(Physiology and Circadian Rhythm) 08
六、亮暗間歇的影響(Effects of Light-Dark Durations)………… 09
七、日變節律基因與疾病(Circadian Related Genes and Diseases) 10
實驗研究目的(The Objective of Experiment)……………………11

材料與方法………………………………………………… 12
一、材料方法…………………………………………………… 13
二、執行步驟………………………………………………… 18

結果…………………………………………………………. 21
一、建立以移動軌跡為大鼠動物行為觀察模式之方法………………22
(Developing a Tracking System to Inspect the Locomotor Activities)
二、正常亮暗間歇(12L-12D)下大鼠日變節律相關基因的表現狀況…24
(The Expression of Circadian Related Genes in 12L-12D Conditions)
三、不同亮暗間歇(8L-8D)對大鼠活動性的影響與基因表現的變化…25
(Locomotor Activity and Circadian Related Genes in 8L-8D Conditions)
四、大鼠活動性與日變節律基因的表現在亮暗間歇(6L-6D)的情形… 27
(Locomotor Activity and Circadian Related Genes in 6L-6D Conditions)
五、非正常亮暗間歇(4L-4D)對大鼠活動性的影響與基因表現的變化29
(Locomotor Activity and Circadian Related Genes in 4L-4D Conditions)
六、大鼠活動性的變化在快速亮暗轉換(2L-2D)時的情形…………… 31
(Locomotor Activity in 2L-2D Rapid Light-Dark Change)
七、大鼠活動性的變化在全光亮(24L)時的情形………………………31
(Locomotor Activity in Constant Light Environment)
討論………………………………………………………… 32
圖表及說明………………………………………………… 49
參考文獻…………………………………………………… 94

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