探討魚油及褪黑激素對於慢性睡眠剝奪大鼠類憂鬱與認知行為、腸道菌相及其代謝物之影響

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Title:	探討魚油及褪黑激素對於慢性睡眠剝奪大鼠類憂鬱與認知行為、腸道菌相及其代謝物之影響 Effects of Fish Oil and Melatonin on Depressive-like and Cognitive Behavior, Gut Microbiota and Its Metabolites in Rats under Chronic Sleep Deprivation
Authors:	賴文德 LAI, WEN-DE
Contributors:	保健營養學系碩士班黃士懿
Keywords:	慢性睡眠剝奪;魚油;褪黑激素;腸道菌相;類憂鬱行為 chronic sleep deprivation;fish oil;melatonin;microbiota;depressive-like behavior
Date:	2021-06-24
Issue Date:	2022-01-13 13:57:37 (UTC+8)
Abstract:	根據美國國家睡眠基金會（National Sleep Foundation, NSF）建議，每日七至八小時的睡眠對維持健康至關重要。然而，NSF的統計資料指出，多數成年人有睡眠不足的問題。睡眠剝奪會損害持續的注意力和工作記憶等認知功能，並使情緒狀態異常。此外，腸道菌相失調（dysbiosis）與認知功能及情緒調節障礙之間可能存在因果關係。腸道菌因飲食所產生的短鏈脂肪酸及次級膽酸等代謝物，可能透過賀爾蒙分泌或特定腸通透蛋白活化，直接或間接影響腸道細胞的生理反應，造成個體生理變化。研究指出，微生物-腸-腦軸（microbiota-gut-brain axis）為大腦與腸道間的雙向訊息傳遞管道，腸道菌相改變會使其代謝產物的變化，而影響大腦訊息傳遞。Omega-3脂肪酸必須從飲食中獲取，其在大腦功能、學習、神經元可塑性和睡眠控制方面扮演著至關重要的角色。褪黑激素作用於上視神經交叉核（suprachiasmatic nuclei, SCN），透過影響節律的相位和幅度來幫助整合晝夜節律，故有鑒於其調節晝夜節律之特性，用於臨床上治療睡眠障礙已行之有年。但目前omega-3脂肪酸對睡眠剝奪引起的認知和精神表現的影響，以及omega-3脂肪酸是否能作為益生質，調整腸道菌相，透過微生物－腸－腦軸影響大腦結構、功能和訊息傳遞，仍有待研究釐清。因此，本研究欲探討在慢性睡眠剝奪下，大鼠在認知與學習、類焦慮和類憂鬱行為、腸道菌相及其相關代謝物之影響，並觀察在慢性睡眠剝奪模式合併介入魚油或褪黑激素下，其是否能改善慢性睡眠剝奪造成之影響。將32隻大鼠分為C、SD、SDF及SDM組，經過十週的介入及四週的慢性睡眠剝奪後，於犧牲前進行莫氏水迷宮試驗（MWM）、曠野試驗（OFT）、高架十字迷宮試驗（EPM）和強迫游水試驗（FST）。研究結果顯示，SD組大鼠於FST中表現出類憂鬱行為、於OFT和EPM中表現出類焦慮行為，以及於MWM中表現出認知功能障礙；反之，SDF組改善了類憂鬱行為、類焦慮行為和認知功能障礙；相較之下，SDM組雖改善認知功能障礙，但類憂鬱行為和類焦慮行為的表現與SD組無顯著差異。此外，在C、SD、SDF和SDM組之間觀察到β多樣性指數存在顯著差異，表示各組間有顯著不同之腸道菌相。而脂質類代謝物分析中，SDF和SDM組大鼠糞便中短鏈脂肪酸含量增加、次級膽酸含量減少，與上述精神表現呈正相關。綜合以上結果，魚油可改善慢性睡眠剝奪大鼠的精神表現、腸道菌相組成和其次級代謝產物；褪黑激素則可改善慢性睡眠剝奪大鼠的認知表現、腸道菌相組成和其次級代謝產物。 According to US National Sleep Foundation, 7-8 hours of sleep is essential for maintenance of good health, while statistics indicate that a vast majority of adults do not get adequate sleep. Studies suggest that a good night's sleep helps foster both mental and emotional resilience, while chronic sleep deprivation sets the stage for negative thinking and emotional vulnerability. Sleep problems may raise risk for, and even directly contribute to, the development of some psychiatric disorders. In addition, Sleep deprivation has detrimental effects on a wide array of cognitive functioning, with an especially high impact on sustained attention and working memory tasks. Melatonin is a natural hormone, produced by the pineal gland, plays roles in regulating the sleep-wake cycle, pubertal development and seasonal adaptation. Agonists of the melatonin receptor have a lot of therapeutic applications including treatment of sleep disorders and depression. The discovery and development of melatonin receptor agonists was motivated by the need for more potent analogues than melatonin, with better pharmacokinetics and longer half-life. Fish oil contains omega-3 polyunsaturated fatty acids (PUFA), and there are several mechanisms by which PUFAs are thought to induce an antidepressant effect, including anti-inflammatory action and direct effects on membrane properties. Studies indicate that omega-3 deficiencies are related to the behavioral problems (e.g., conduct disorder, hyperactivity-impulsivity, anxiety, depression, temper tantrums, and sleep difficulties) and learning difficulties. By working on the suprachiasmatic nuclei (SCN), melatonin helps to synchronize the circadian rhythm by affecting both the phase and amplitude of the rhythm. Therefore, in view of its ability to regulate the circadian rhythm, it has been used clinically for the treatment of sleep disorders for many years. However, whether the fish oil can enhance the binding affinity between the melatonin and its receptor under sleep deprivation has not yet been established clearly. Therefore, this study explored the effects of fish oil and melatonin on depressive-like behavior and cognitive function in rats under sleep deprivation. Thirty-two rats were divided into control (C), sleep deprivation (SD), sleep deprivation + fish oil (SDF) and sleep deprivation + melatonin (SDM) groups. After a 10-week intervention and 4-week chronic sleep deprivation, the open field test (OFT), the forced swim test (FST), the elevated plus maze (EPM) and Morris water maze (MWM) were conducted before sacrifice. These results showed that the rats in the SD group exhibited depressive-like behavior in the FST, anxiety-like behavior in the OFT and EPM and decline of cognitive function in the MWM. Nevertheless, SDF group improved depressive-like behavior, anxiety-like behavior and decline of cognitive function. In contrast, although SDM group improved the decline of cognitive function, but the depressive-like behavior and anxiety-like behavior data have reported no significant differences with SD group. In addition, a significant difference was observed in β-diversity indices among C, SD, SDF and SDM groups. The content of short-chain fatty acids increased and the content of secondary bile acids decreased in SDF and SDM groups, which was positively correlated with mental performance. In conclusion, fish oil affects mental performance, gut microbiota composition, and the secondary metabolites produced by microbiota in rats under chronic sleep deprivation.
Description:	碩士指導教授：黃士懿委員：黃啟彰委員：邱慶豐
Data Type:	thesis
Appears in Collections:	[保健營養學系暨研究所] 博碩士論文

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