海馬迴內齒狀迴 (hippocampal dentate gyrus) 的顆粒下層 (subgranular zone) 具有終生持續神經細胞新生的現象，此一現象被認為與海馬迴所參與的學習與記憶的功能有關。成年動物海馬迴內神經新生會受到許多因子所調控，其中運動已知可增加海馬迴之神經新生與其功能；而發炎與老化則會降低海馬迴之神經新生及功能。本論文的主要研究目的是探討強制性跑步運動是否會影響中樞神經發炎及老化所抑制海馬迴的神經新生。首先以年輕成年小鼠腹腔重複注射脂多醣作為周邊誘發中樞發炎的模式，來探討跑步運動對發炎抑制海馬迴神經新生的影響。實驗結果發現，腹腔重複注射脂多醣會減少海馬迴內腦神經滋養因子，及未成熟新生神經細胞的數目，但並不會改變分裂細胞的總數。五週跑步運動則會增加海馬迴腦神經滋養因子及其接受體－酪氨酸激受體蛋白質的表現、促進神經幹細胞分裂、以及增加未成熟神經細胞的數目。有趣的是，跑步運動可以補償腹腔重複注射脂多醣所抑制的神經新生的數目，與海馬迴腦神經滋養因子表現量減少的現象及增加酪氨酸激受體的表現。然而，跑步運動卻無法改善腹腔注射脂多醣所降低小鼠在水迷宮記憶的表現。實驗結果亦發現跑步運動並未改變脂多醣所引發的中樞發炎[如：膠細胞的活化、腫瘤壞死因子 (tumor necrosis factor-alpha) 及介白素-1（Interleukin-1 beta）的濃度]。接著，以探討跑步運動是否會改善老化所抑制海馬迴的神經新生。首先分析不同年齡(3、7、9、13及24個月)小鼠海馬迴神經新生的情形。結果顯示在中年之前神經前趨細胞分裂的數目、未成熟神經細胞及新生神經細胞的數目隨年紀增加而減少，而中年之後到老年之間新生的神經數目少且無顯著性改變。在中年前期及中年期給予五週的跑步運動會增加神經前趨細胞分裂的數目及增加未成熟神細胞的數目。此外，五週的跑步運動會促進中年小鼠海馬迴內未成熟神經細胞樹突的成熟，與增加新生神經細胞的存活。跑步運動所造成的神經新生與滋養效果並非來自降低隨年齡而增加的血清中皮質酮的基礎濃度。然而，海馬迴內隨著年紀增加而逐漸減少的腦神經滋養因子及其接受器的表現量，會因五週跑步運動而顯著增加。總合以上實驗，不論在年輕或中年的小鼠，五週的跑步運動可增加神經神生及新生神經細胞存活。此外，五週的跑步運動改善脂多醣所干擾的神經新生。跑步運動的益處不是降低發炎反應或血清中皮質酮的基礎濃度，但可能藉由增加腦神經滋養因子及其受體表現。本研究推測跑步運動改變腦中化學物質使得腦部環境適合神經幹細胞增生及神經前趨細胞成熟及存活。

New neurons are continuously generated in the subgranular zone of adult dentate gyrus (DG) throughout life. The amount of neurogenesis has been correlated with the hippocampus-dependent functions. Several stimuli are known to modulate the process of adult neurogenesis. Among them, physical exercise has advantageous effects on neurogenesis and brain function, while inflammation and aging show the opposite. The aim of this study is to investigate the effect of mandatory treadmill running (TR) on adult hippocampal neurogenesis under the challenges of exogenous immunogen-induced neuroinflammation and endogenous aging. In order to study the effects of TR on chronic neuroinflammation-affected adult hippocampal neurogenesis, mice that received repetitive intraperitoneal lipopolysaccharride (LPS) injections were forced to TR. The results showed that peripheral LPS treatments obstructed neuronal differentiation, but not proliferation. Five weeks of TR facilitated both the proliferation of the neural stem cells and their differentiation into neurons. Importantly, five weeks of TR successfully counteracted the peripheral LPS-impaired neurogenesis in the dentate area. However, five weeks of TR did not offset the LPS-disturbed performance in water maze test. The advantageous effects of TR were not due to the alteration of inflammatory responses, as glial activation and levels of up-regulated tumor necrosis factor-alpha and interleukin-1 beta were unaltered. Interestingly, TR replenished the LPS-reduced levels of brain-derived neurotrophic factor (BDNF) and its receptor, tropmyosin-related kinase B (TrkB),which is known to promote neuronal differentiation and survival. These findings suggested that TR effectively ameliorates the LPS-disturbed hippocampal neurogenesis. To investigate the effects of TR on aging-reduced hippocampal neurogenesis and the survival of newborn neurons, mice of different ages (3, 7, 9, 13, 24 months old) were studied. Compared to 3-month-old mice, the numbers of newborn neurons decreased dramatically by middle age and remained at low levels after middle age. Five weeks of TR not only increased the numbers of neural stem cell and immature neurons, but also promoted the maturation and survival of immature neurons in middle-aged mice. The neurogenic and neurotrophic effects of TR were not due to the reduction of the age-related elevation of serum corticosterone, as the basal levels of serum corticosterone were not affected by five weeks of TR. Significantly, TR elevated the age-dependent declines of BDNF and TrkB in middle-aged mice. Taken together, five weeks of TR enhanced neurogenesis and survival of newborn neurons in dentate area of young and middle-aged animals. Furthermore, five weeks of TR ameliorated the LPS-disturbed hippocampal neurogenesis. The advantageous effects of TR were not due to the alternation of inflammatory response or basal serum corticosterone, but possibly by enhancing the BDNF/TrkB signal pathway. These results suggest that TR alters the brain chemistries toward an environment that is favorable to neural stem cells proliferation and maturation and survival of neuronal progenitor cells.

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