在成年哺乳動物腦中，神經新生的現象發生在兩個腦區：側腦室旁區(subventricular zone)與海馬迴的齒迴內側區(subgranular zone)。運動已知會增加齒迴區神經新生的數目，但其中的機制卻尚未被解開。腎上腺皮質所分泌的糖皮質酮(在囓齒類為皮質酮)可直接作用在中樞神經系統，並且會影響神經新生。又因為運動已知會影響皮質酮的分泌，所以我假設皮質酮參與運動所導致的齒迴區神經增生現象。由於跑步機運動能有效的控制運動的強度與時間長短，因此，我採取跑步機運動的模式來探討皮質酮是否參與運動所導致C57BL/6公鼠齒迴區神經增生的現象。結果發現小鼠在5週跑步機運動後，血清皮質酮的濃度有短暫上升的現象。而運動對皮質酮兩個接受器【糖皮質酮接受器(glucocorticoid receptor, GR)與礦物皮質酮(mineralcorticoid receptor, MR)】的表現量，則有不同的影響：其中GR的表現量沒有太大改變，但MR卻被向下調控。據此，我將運動導致神經增生的成因分成兩方面檢測：（1）短暫的皮質酮上升，與（2）MR的向下調控。首先，利用單一皮質酮針劑注射，並求得最佳模擬運動後皮質酮上升的劑量為4mg/kg。接著，以每天腹腔注射皮質酮(4mg/kg)的方式，持續三週模擬運動後皮質酮上升的現象。結果顯示三週皮質酮的注射，並不會改變齒迴區的神經前驅細胞數目。至於海馬迴中會受到運動而改變的brain-derived neurotrophic factor (BDNF)和MR的蛋白質濃度，也無變化產生。這些結果表示血液中短暫皮質酮上升現象並不是運動導致神經新生的主因之一。在檢驗成因的第二方面，我選擇以抑制MR的方式來仿效在運動過程中MR向下調控的現象。持續三週在動物運動前90分鐘施打專一性MR的抑制劑(Spironolactone, 100mg/kg)，明顯的促進運動所導致的齒迴區神經前驅細胞數目，但不影響BDNF的表現。進一步的檢驗發現，施打MR抑制劑並不改變運動所導致的新生細胞數，但卻增加了未成熟的神經細胞。因此本研究的結論指出運動所導致的海馬迴神經新生現象，部分原因是來自於抑制皮質酮/MR的訊息傳遞路徑使得分化趨向未成熟神經細胞，而此路徑與BDNF的表現量無關。

Adult mammalian neurogenesis has been well accepted in two brain areas: subventricular zone (SVZ) and subgranular zone (SGZ) of hippocampal dentate area. Physical exercise is known to enhance neurogenesis, although the underlying mechanism remains unclear. Glucocorticoids (corticosterone in rodent), secreted by adrenal cortex, is known to influence neurogenesis. As serum corticosterone is affected by physical exercise, an involvement of corticosterone in exercise-induced neurogenesis is hypothesized. The treadmill running (TR) paradigm was adopted to accurately define the intensity and duration of exercise. The result showed that 5 weeks TR increased transiently serum corticosterone levels; whereas the level of hippocampal mineralcorticoid receptor (MR), one of two corticosterone receptors, was down-regulated. The concentration of the other corticosterone receptor, glucocorticoid receptor (GR), remained unaltered. Accordingly, the TR-induced neurogenesis in dentate area were evaluated at two different settings: (1) transient elevation of corticosterone and (2) down-regulation of MR. The result indicated that single intraperitoneal (i.p.) corticosterone injection of 4mg/kg gave a serum corticosterone concentration resembling the TR-induced corticosterone elevation. Therefore, the effect of transient elevation of corticosterone on the neuronal progenitor proliferation in dentate area was investigated in mice that received daily corticosterone (4mg/kg, i.p.) injection for three weeks. The results indicated that such treatment did not change the number of neuronal progenitor in dentate area. Nor did the expression levels of hippocampal BDNF and MR, both were affected by TR, changed. These findings suggested that transient corticosterone elevation did not contribute to the TR-induced proliferation of neuronal progenitors in dentate area. To examine whether the down-regulation of MR is involved in the TR-induced neurogenesis, animals were treated with a selective MR antagonist, spironolactone (100mg/kg/day) for three weeks. The results showed that spironolactone significantly enhanced TR-induced progenitor cell number in the dentate area, while it did not change the level of hippocampal BDNF. Further studies showed that the MR antagonist did not change the number of cell proliferation but increased that of immature neuron. In conclusion, these results suggest that the phenomenon of TR-induced neurogenesis in the dentate area is partially due to the inhibition of corticosterone/MR signaling which subsequently enhances the neuronal differentiation and shows no correlation with the BDNF expression.

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