成年動物海馬迴內終其一生具有神經新生的功能，此現象會隨著年紀增加而有下降趨勢。海馬迴內神經新生的效率會受到四個因素所調控：1)神經前驅幹細胞之數目；2) 神經前驅幹細胞增生速率；3) 新生細胞分化為神經細胞或神經膠細胞之比例；4)新生神經細胞之存活率。我們先前的研究發現，跑步運動可增加成年動物海馬迴神經新生的數目。然而，老化與跑步運動是透過哪個因素來調控小鼠神經新生的效率，則尚不清楚。因此，此研究的主要目的是探討強制性跑步運動對老化小鼠神經新生的影響。我們給予不同年紀小鼠1個月跑步機運動訓練後，以免疫組織染色法，用Nestin抗體辨認神經前驅幹細胞、BrdU抗體辨認新生細胞、DCX抗體辨認新生神經細胞、以及BrdU/DCX比例計算分化速率。實驗結果顯示，神經前驅幹細胞數目不會隨著年紀增加而變化，跑步運動則會增加其數量。1個月的跑步運動，不會改變神經前驅幹細胞增生的速率，或新生神經細胞分化的速率。新生的細胞在一個月後，有大量死亡的現象，跑步運動無增加其存活率。綜合以上結果，隨著年紀增加而下降的海馬迴神經新生的數目，主要是因為神經前驅幹細胞增生的速率、新生神經細胞分化的速率、及新生神經細胞的存活率下降有關。跑步運動則是透過增加神經前驅幹細胞之數量，來增加成年動物海馬迴神經新生的數目。

Adult hippocampal neurogenesis continues throughout life, but declines as age increased. The rate of hippocampal neurogenesis is determined by 1) the number of neural stem/progenitor cells (NSCs) in the hippocampus, 2) the proliferation rate of the NSCs, 3) cell lineage specification (neuron or glia pathway), and 4) the survival of the newborn neurons. The previous study has been shown that mandatory treadmill running (TR) is known to increase adult hippocampal neurogenesis. However, it remains unclear at which stages of adult hippocampal neurogenesis are affected by aging and TR. The purpose of this study is to investigate the effects of TR on the aging-reduced neurogenesis. The mice were forced to run on treadmill for 1 m before the brains were processed for immunohistochemistry. The numbers of NSCs, labeled by Nestin, in the hippocampus were unchanged as age increased; whereas, TR increased the number of NSCs. The proliferation rates, determined by dividing the numbers of bromodeoxyuridine (BrdU) to the numbers of Nestin+ cells, were decreased by middle age and were not changed by TR. The rates of neuron specification, calculated by dividing the numbers of BrdU+/Dublecortin (DCX+, a specific marker for immature neuron) cells to the numbers of BrdU+ cells, were decreased with age and did not enhance by TR. The majority of newborn cells died one month after BrdU injection. TR did not improve the survival rate of BrdU+ cells. In conclusion, aging-induced decreases of hippocampal neurogenesis are mainly caused by reduced proliferation rate of the NSCs, neuronal specification rate and survival rate of the newborn cells. TR-induced increases of number of NSCs may explain the TR-induced adult hippocampal neurogenesis.

Cotman CW, Berchtold NC (2002) Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 25:295-301.
Creer DJ, Romberg C, Saksida LM, van Praag H, Bussey TJ (2010) Running enhances spatial pattern separation in mice. Proc Natl Acad Sci U S A 107:2367-2372.
Galvan V, Jin K (2007) Neurogenesis in the aging brain. Clin Interv Aging 2:605-610.
Hattiangady B, Shetty AK (2008) Aging does not alter the number or phenotype of putative stem/progenitor cells in the neurogenic region of the hippocampus. Neurobiol Aging 29:129-147.
Kempermann G, Kuhn HG, Gage FH (1998) Experience-induced neurogenesis in the senescent dentate gyrus. J Neurosci 18:3206-3212.
Kempermann G, Wiskott L, Gage FH (2004) Functional significance of adult neurogenesis. Curr Opin Neurobiol 14:186-191.
Klempin F, Kempermann G (2007) Adult hippocampal neurogenesis and aging. Eur Arch Psychiatry Clin Neurosci 257:271-280.
Kuhn HG, Dickinson-Anson H, Gage FH (1996) Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16:2027-2033.
Leuner B, Kozorovitskiy Y, Gross CG, Gould E (2007) Diminished adult neurogenesis in the marmoset brain precedes old age. Proc Natl Acad Sci U S A 104:17169-17173.
Llorens-Martin M, Torres-Aleman I, Trejo JL (2006) Pronounced individual variation in the response to the stimulatory action of exercise on immature hippocampal neurons. Hippocampus 16:480-490.
Ming GL, Song H (2005) Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28:223-250.
Rao MS, Hattiangady B, Abdel-Rahman A, Stanley DP, Shetty AK (2005) Newly born cells in the ageing dentate gyrus display normal migration, survival and neuronal fate choice but endure retarded early maturation. Eur J Neurosci 21:464-476.
Rao MS, Hattiangady B, Shetty AK (2006) The window and mechanisms of major age-related decline in the production of new neurons within the dentate gyrus of the hippocampus. Aging Cell 5:545-558.
Riddle DR, Lichtenwalner RJ (2007) Brain Aging. Boca Raton
Sutoo D, Akiyama K (2003) Regulation of brain function by exercise. Neurobiol Dis 13:1-14.
Toni N, Laplagne DA, Zhao C, Lombardi G, Ribak CE, Gage FH, Schinder AF (2008) Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat Neurosci 11:901-907.
van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH (2002) Functional neurogenesis in the adult hippocampus. Nature 415:1030-1034.
van Praag H, Shubert T, Zhao C, Gage FH (2005) Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 25:8680-8685.
Varela-Nallar L, Aranguiz FC, Abbott AC, Slater PG, Inestrosa NC (2010) Adult hippocampal neurogenesis in aging and Alzheimer's disease. Birth Defects Res C Embryo Today 90:284-296.
Walter J, Keiner S, Witte OW, Redecker C (2010) Differential stroke-induced proliferative response of distinct precursor cell subpopulations in the young and aged dentate gyrus. Neuroscience 169:1279-1286.
Wu CW, Chang YT, Yu L, Chen HI, Jen CJ, Wu SY, Lo CP, Kuo YM (2008) Exercise enhances the proliferation of neural stem cells and neurite growth and survival of neuronal progenitor cells in dentate gyrus of middle-aged mice. J Appl Physiol 105:1585-1594.