Skip navigation

DSpace

機構典藏 DSpace 系統致力於保存各式數位資料(如:文字、圖片、PDF)並使其易於取用。

點此認識 DSpace
DSpace logo
English
中文
  • 瀏覽論文
    • 校院系所
    • 出版年
    • 作者
    • 標題
    • 關鍵字
  • 搜尋 TDR
  • 授權 Q&A
  • 幫助
    • 我的頁面
    • 接受 E-mail 通知
    • 編輯個人資料
  1. NTU Theses and Dissertations Repository
  2. 醫學院
  3. 解剖學暨細胞生物學科所
請用此 Handle URI 來引用此文件: http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/74682
標題: 探討睡眠剝奪對微膠細胞功能之影響並發展預防策略
Sleep Deprivation Alters Microglial Homeostasis and the Strategy to Prevent Its Negative Effects
作者: Li-Heng Tuan
段立珩
指導教授: 李立仁
關鍵字: 睡眠剝奪,微膠細胞,青少年,突觸修剪,神經發炎,自主運動,
Sleep deprivation,adolescent,microglia,synaptic pruning,neuroinflammation,voluntary exercise,
出版年 : 2020
學位: 博士
摘要: 睡眠不足對於神經系統的不良影響一直是科學社群所關切的重要議題,但只有少數的研究特別探討其對於青少年大腦所造成的傷害。青少年合適的睡眠時間是八到十小時,但大部分的青少年都睡不滿八小時,睡眠不足的結果,除了會讓課業表現不佳之外,也會增加產生心理與生理問題的風險。在青少年時期,大腦中正進行著讓神經迴路邁向成熟的各種發育工程;同時,這段時期也是許多精神疾病的好發期,許多研究指出,青少年期間不良的生活經驗會造成神經發育的異常,進而導致這些精神疾患的產生。睡眠不足可能也是擾亂青少年時期神經發育的因素之一。
在中樞神經系統中,由常駐其中的巨噬細胞,微膠細胞,擔任免疫工作的第一道防線。當遇到病原體或中樞神經系統的平衡被破壞時,微膠細胞會被活化而改變形狀,它們會吞噬病原體與細胞殘骸,也負責釋放促發炎反應的細胞激素。除此之外,微膠細胞對神經系統的發育也非常重要。在神經發育的早期,微膠細胞會吞噬突觸來執行突觸修剪以及促進突觸成熟。若在神經迴路發育的關鍵期,微膠細胞的功能失常,將影響突觸功能與神經網絡的建立。有鑑於微膠細胞在維持中樞神經系統的平衡與神經發育過程的重要性,我們在本研究中致力於探討在青少年這個神經發育的重要階段,睡眠剝奪對於微膠細胞功能的不良影響。
在第一部份的研究中,我們分別對青少年(五週大)與成年(十到十二週大)小鼠,作72小時的快速動眼期睡眠剝奪,並比較其反應變化。我們的結果顯示,在青少年小鼠,睡眠剝奪造成齒狀回顆粒細胞中樹突棘以及突觸數目的增加,以及微膠細胞吞噬功能的下降;這些結果意味著,微膠細胞所調控的突觸修剪功能受到睡眠剝奪影響而降低。在成年動物,睡眠剝奪會使得微膠細胞改變形狀,以及促發炎細胞激素的增加;這些變化顯示神經發炎的狀況。在兩個年紀的小鼠,72小時的睡眠剝奪皆會造成在學習測驗中神經活動的增加,以及短期記憶能力表現下降。
由於青少年普遍面臨著睡眠不足的情形,我們就想研發如何抵抗睡眠不足所帶來的傷害。有鑑於運動已被證實會藉由調節微膠細胞的功能,改善神經退化性疾病的症狀,在第二部份的研究中,我們探討自主運動對被睡眠剝奪的青少年大腦是否有保護的效果。我們提供滾輪給小鼠,讓它們自主運動,11天之後再作72小時睡眠剝奪。我們發現,自主運動可以提高與突觸修剪相關之微膠細胞接受器基因的表現、微膠細胞分支的複雜程度,這可能會為對大腦帶來保護作用。在受到睡眠剝奪時,這些小鼠齒狀回顆粒細胞中,樹突棘與突觸的數目並沒有上升,而微膠細胞的吞噬能力亦沒有下降。自主運動也有效地預防了睡眠剝奪所導致的學習行為中過多的神經活化,以及短期記憶表現的下降。
總體來說,本研究證實了睡眠剝奪影響青少年與成年大腦中微膠細胞的功能,進而導致神經活動的異常與記憶能力的缺失,然而,預防性自主運動可以顯著的改善睡眠剝奪後青少年微膠細胞的功能與記憶能力,顯示運動對於睡眠缺乏的青少年大腦具有保護性的效果。
The neurological impacts of sleep insufficiency have been extensively explored. However, only a few studies have addressed this issue in adolescents. Adequate sleep is essential for adolescents’ physical function and mental health. Most importantly, since adolescence is a critical period for brain development, emerging evidence revealed that insufficient sleep has detrimental effects on the developmental trajectories in the adolescent brains. Yet, the detailed mechanisms underpinning the interplays between sleep loss and brain development are still expecting disclosure.
Microglia, the resident immune cells and professional phagocytes in the central nervous system (CNS), respond to the pathologic conditions and disrupted homeostasis by increased cytokines secretion, phagocytose pathogens or cellular debris, and rapid morphological changes. Previous studies suggested that sleep loss induces microglial activation and subsequent neuroinflammatory responses. However, microglia also contribute to the maturating process of the nervous system. One of the prominent functions of microglia is to modulate synaptic refinement and maturation during postnatal development. A growing number of studies have highlighted the dysfunctions of microglia during the critical period of neural circuits development lead to aberrant synaptic functions and neural wiring. Therefore, due to the importance of microglia in the maintenance of CNS homeostasis as well as the neurodevelopmental trajectories, the current study aimed to uncover the adverse consequence of sleep loss in respect of microglial functions.
In the first part of our study, we examined and compared the effects of 72 h paradoxical sleep deprivation (SD) on adolescent (five-week-old) and adult (~twelve-week-old) mice. Following 72 h of SD, induced by a modified multiple-platform method, mice were subjected to behavioral, histological and neurochemical examinations. In both adolescent and adult mice, SD adversely affected short-term memory in a novel object recognition test. Compared with normal-sleep controls, sleep-deprived adolescent mice had an increased density of excitatory synapses in the granule cells (GCs) of the dentate gyrus (DG), but no such pattern was observed in the adult group. The engulfment of postsynaptic components within the microglia after SD was reduced in adolescents but not in adults, suggesting an impaired microglia-mediated synaptic pruning in adolescent SD mice. Possible contributing factors included the decreases in CX3CR1, CD11b, and P2Y12, closely associated with the synaptic pruning via microglial phagocytosis. In adult SD mice, microglia-associated inflammatory reactions were noted. In summary, sleep deprivation induces age-dependent microglial reactions in adolescent and adult mice, respectively, yet results in similar defects in short-term recognition memory. Sufficient sleep is indispensable for both adolescents and adults.
While adolescents at large are facing the problem of sleep insufficiency, there is an urgent need to prevent the detrimental effects of sleep loss. Physical exercise has been demonstrated to counteract the harmful consequences of various stress or neurodegenerative models by modulating microglial function. For that reason, in the second part of our study, we investigated the hypothesis that physical exercise might serve as a preventive intervention to rescue the failure of synaptic pruning and microglial function after SD in adolescent mice.
Three-week-old C57/BL6 male mice were randomly assigned into the voluntary exercise (VE) group in which a running wheel was provided or the sedentary control group. In each group, mice were further divided into 72 h SD or home cage (HC) normal sleep groups. After 72 h SD or normal sleep, four groups (HC, VE+HC, SD, VE+SD) of mice were subjected to a short-term memory test or sacrificed for further examination. Our result indicated that SD-induced impairments in short-term memory and an increase in the neural activity index were prevented by the preceding VE. Furthermore, the increased dendritic spine density in the SD group was not observed in the VE+SD group, implying that VE prevented SD-induced synaptic pruning deficits. We also observed greater microglial phagocytic capacity, characterized by increased internalized postsynaptic materials and lysosomal structure within individual microglia, in the VE+SD group than in the SD group. mRNA expression levels of microglia-specific receptors critical to developmental synaptic refinement were found to be upregulated in both the VE+HC and VE+SD groups.
Here, we provided evidence featuring a substantial effect of VE that significantly alleviated the SD-induced deficits in short-term memory and microglia-mediated synaptic pruning. Physical exercise could be a beneficial health practice for adolescents to cope with the adverse influence of inevitable sleep insufficiency.
URI: http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/74682
DOI: 10.6342/NTU202000089
全文授權: 有償授權
顯示於系所單位:解剖學暨細胞生物學科所

文件中的檔案:
檔案 大小格式 
ntu-109-1.pdf
  目前未授權公開取用
6.43 MBAdobe PDF
顯示文件完整紀錄


系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。

社群連結
聯絡資訊
10617臺北市大安區羅斯福路四段1號
No.1 Sec.4, Roosevelt Rd., Taipei, Taiwan, R.O.C. 106
Tel: (02)33662353
Email: ntuetds@ntu.edu.tw
意見箱
相關連結
館藏目錄
國內圖書館整合查詢 MetaCat
臺大學術典藏 NTU Scholars
臺大圖書館數位典藏館
本站聲明
© NTU Library All Rights Reserved