人和動物的記憶會隨著老化而下降，這可能是因為負責記憶的相關腦區(如:海馬迴)退化的結果。先前的研究指出，跑步運動可增加海馬迴的神經新生與記憶的能力。但是，跑步運動是否可改善老化所引起的記憶能力缺損，目前仍不清楚。本研究假設，跑步運動可增加老年小鼠海馬迴之神經可塑性，進而提升老年小鼠的記憶能力。我們取三組不同年齡之小鼠(年輕組: 2-3月；中年組: 9-12月；老年組: >18月)，給予6周中度的跑步機訓練後，分別檢驗其對記憶能力與神經可塑性之影響。神經可塑性會從海馬迴CA1腦區錐狀神經細胞的形態、長期增益效益、和突觸相關蛋白表現量三方面來分析。實驗結果顯示，中年及老年小鼠的海馬迴相關之非空間性記憶表現，明顯比年輕小鼠差。在神經形態方面，中年及老年小鼠CA1腦區錐狀神經細胞的樹突總長度、分枝程度、複雜度、頂樹突(apical dendrite)直徑和突觸小刺密度均比年輕小鼠低。由強烈高頻電刺激所引發的神經長期增益效益，老年小鼠略低於年輕小鼠(p = 0.058)。而與突觸相關的蛋白(snap25、syt1、NR1、PSD95、BDNF/TrkB)表現量，此三個年紀則並沒有明顯的差異。六週運動訓練有效的改善因老化所引起的非空間性記憶缺失。運動訓練顯著的增加中年與老年小鼠的樹突神經總長度、分枝程度、複雜度、樹突小刺密度和頂樹突直徑。此外，運動訓練能增加年輕和老年小鼠之長期增益效益和腦神經滋養因子(brain-derived neurotrophic factor)的表現量；但並沒有顯著改變snap25、syt1、NR1、PSD95的表現量。總結本實驗的數據顯示，長期中度的跑步機運動，能有效地改善小鼠因老化而下降之記憶能力。這可能是因為跑步運動提升老年小鼠海馬迴CA1腦區之腦神經滋養因子的表現量，進而增進其神經可塑性。

Memory declines with age. This phenomenon is associated with hippocampal degeneration, such as shrinkage in neuron size, regressions of dendrites and dendritic spines, and alteration in synaptic proteins. Running exercise is known to promote neurogenesis and enhance the performance of learning and memory. However, whether running exercise is capable of improving learning and memory in aged animals remains unclear. In this study, we compared the memory performance and neuronal plasticity of young (2~3 months), middle-aged (9~12 months) and aged (>18 months) mice with or without six weeks of moderate intensity treadmill running training. Neuronal plasticity was determined by the morphology, long-term potentiation (LTP) and synaptic proteins of the pyramidal neurons of the hippocampal CA1 region. The results revealed that middle-aged and aged mice had worse hippocampus-dependent non-spatial memory than that of young mice. The lengths and branch numbers of total dendrites, and diameter and spine density of apical dendrite were reduced in the middle-aged and aged mice. A marginal decline (p = 0.058) of the LTP in old mice was evident. The levels of synaptic proteins (i.e. snap25, syt1, NR1, PSD95, BDNF/TrkB) were similar among three groups. Six weeks of running exercise significantly enhanced the age-reduced memory performance. Running exercise increased the length and branch numbers of total dendrites and diameter and spine density of apical dendrite in middle-aged and aged mice. Furthermore, the levels of LTP and BDNF were increased by running exercise in both young and aged mice. However, the levels of snap25, syt1, NR1, PSD95 and TrkB were unaltered by running exercise. In conclusion, moderate intensity running exercise effectively improves the aging-associated memory impairment. The beneficial effects of running exercise are probably caused by enhancing BDNF signaling, which then increases hippocampal neuroplasticity.

Aggleton JP, Hunt PR, Rawlins JNP (1986) The Effects of Hippocampal-Lesions Upon Spatial and Nonspatial Tests of Working Memory. Behav Brain Res 19:133-146.
Andersen P (1990) Synaptic integration in hippocampal CA1 pyramids. Prog Brain Res 83:215-222.
Auffret A, Gautheron V, Repici M, Kraftsik R, Mount HTJ, Mariani J, Rovira C (2009) Age-Dependent Impairment of Spine Morphology and Synaptic Plasticity in Hippocampal CA1 Neurons of a Presenilin 1 Transgenic Mouse Model of Alzheimer's Disease. J. Neurosci. 29:10144-10152.
Barnabe-Heider F, Miller FD (2003) Endogenously produced neurotrophins regulate survival and differentiation of cortical progenitors via distinct signaling pathways. Journal of Neuroscience 23:5149-5160.
Barnes CA (1995) Involvement of Ltp in Memory - Are We Searching under the Street Light. Neuron 15:751-754.
Barnes CA (2003) Long-term potentiation and the ageing brain. Philos T Roy Soc B 358:765-772.
Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464:529-535.
Blalock EM, Chen KC, Sharrow K, Herman JP, Porter NM, Foster TC, Landfield PW (2003) Gene microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment. J. Neurosci. 23:3807-3819.
Borniquel S, Valle I, Cadenas S, Lamas S, Monsalve M (2006) Nitric oxide regulates mitochondrial oxidative stress protection via the transcriptional coactivator PGC-1 alpha. Faseb J 20:1889-+.
Bourne JN, Harris KM (2008) Balancing structure and function at hippocampal dendritic spines. Annu Rev Neurosci 31:47-67.
Choi DW, Rothman SM (1990) The Role of Glutamate Neurotoxicity in Hypoxic-Ischemic Neuronal Death. Annu Rev Neurosci 13:171-182.
Cohen SJ, Munchow AH, Rios LM, Zhang G, Asgeirsdottir HN, Stackman RW (2013) The Rodent Hippocampus Is Essential for Nonspatial Object Memory. Curr Biol 23:1685-1690.
Danzer SC, Kotloski RJ, Walter C, Hughes M, McNamara JO (2008) Altered morphology of hippocampal dentate granule cell presynaptic and postsynaptic terminals following conditional deletion of TrkB. Hippocampus 18:668-678.
De Roo M, Klauser P, Garcia PM, Poglia L, Muller D (2008) Spine dynamics and synapse remodeling during LTP and memory processes. Prog Brain Res 169:199-207.
Dickstein DL, Kabaso D, Rocher AB, Luebke JI, Wearne SL, Hof PR (2007) Changes in the structural complexity of the aged brain. Aging Cell 6:275-284.
Fukui K, Onodera K, Shinkai T, Suzuki S, Urano S (2001) Impairment of learning and memory in rats caused by oxidative stress and aging, and changes in antioxidative defense systems. Ann N Y Acad Sci 928:168-175.
Ge SY, Yang CH, Hsu KS, Ming GL, Song HJ (2007) A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron 54:559-566.
Geinisman Y (2000) Structural synaptic modifications associated with hippocampal LTP and behavioral learning. Cereb Cortex 10:952-962.
Grealy MA, Johnson DA, Rushton SK (1999) Improving cognitive function after brain injury: the use of exercise and virtual reality. Arch Phys Med Rehabil 80:661-667.
Griesbach GS, Gomez-Pinilla F, Hovda DA (2007) Time window for voluntary exercise-induced increases in hippocampal neuroplasticity molecules after traumatic brain injury is severity dependent. J Neurotraum 24:1161-1171.
Hampson RE, Simeral JD, Deadwyler SA (1999) Distribution of spatial and nonspatial information in dorsal hippocampus. Nature 402:610-614.
Harris KM (1999) Structure, development, and plasticity of dendritic spines. Curr Opin Neurobiol 9:343-348.
Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA (2003) Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 60:1119-1122.
Hill JJ, Hashimoto T, Lewis DA (2006) Molecular mechanisms contributing to dendritic spine alterations in the prefrontal cortex of subjects with schizophrenia. Mol Psychiatr 11:557-566.
Holtmaat A, Svoboda K (2009) Experience-dependent structural synaptic plasticity in the mammalian brain. Nat Rev Neurosci 10:647-658.
Ji YY, Lu Y, Yang F, Shen WH, Tang TTT, Feng LY, Duan SM, Lu B (2010) Acute and gradual increases in BDNF concentration elicit distinct signaling and functions in neurons. Nat Neurosci. 13:302-U307.
Klyubin I, Walsh DM, Cullen WK, Fadeeva JV, Anwyl R, Selkoe DJ, Rowan MJ (2004) Soluble Arctic amyloid beta protein inhibits hippocampal long-term potentiation in vivo. Eur J Neurosci 19:2839-2846.
Kolb B, Forgie M, Gibb R, Gorny G, Rowntree S (1998) Age, experience and the changing brain. Neurosci Biobehav Rev 22:143-159.
Kumar A, Thinschmidt JS, Foster TC, King MA (2007) Aging effects on the limits and stability of long-term synaptic potentiation and depression in rat hippocampal area CA1. J Neurophysiol 98:594-601.
Lin TW, Chen SJ, Huang TY, Chang CY, Chuang JI, Wu FS, Kuo YM, Jen CJ (2012) Different types of exercise induce differential effects on neuronal adaptations and memory performance. Neurobiol Learn Mem 97:140-147.
Machado S, Portella CE, Silva JG, Velasques B, Bastos VH, Cunha M, Basile L, Cagy M, Piedade RA, Ribeiro P (2008) Learning and implicit memory: Mechanisms and neuroplasticity. Rev Neurologia 46:543-549.
Markowska AL, Mooney M, Sonntag WE (1998) Insulin-like growth factor-1 ameliorates age-related behavioral deficits. Neuroscience 87:559-569.
Norman KA (2010) How hippocampus and cortex contribute to recognition memory: revisiting the complementary learning systems model. Hippocampus 20:1217-1227.
Pieraccini F, Lombardelli A, Calossi S, Polizzotto N, Annese PM, Tavanti M, Bossini L, Castrogiovanni P (2005) Hippocampal atrophy and neuroplasticity in posttraumatic stress disorder. Eur Neuropsychopharm 15:S385-S385.
Pittenger C, Duman RS (2008) Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33:88-109.
Radak Z, Kaneko T, Tahara S, Nakamoto H, Pucsok J, Sasvari M, Nyakas C, Goto S (2001) Regular exercise improves cognitive function and decreases oxidative damage in rat brain. Neurochem Int 38:17-23.
Rech RL, de Lima MNM, Dornelles A, Garcia VA, Alcalde LA, Vedana G, Schroder N (2010) Reversal of age-associated memory impairment by rosuvastatin in rats. Exp Gerontol 45:351-356.
Schefer V, Talan MI (1996) Oxygen consumption in adult and AGED C57BL/6J mice during acute treadmill exercise of different intensity. Exp Gerontol 31:387-392.
Schmid AW, Freir DB, Herron CE (2008) Inhibition of LTP in vivo by beta-amyloid peptide in different conformational states. Brain Res 1197:135-142.
Shankar S, Teyler TJ, Robbins N (1998) Aging differentially alters forms of long-term potentiation in rat hippocampal area CA1. J Neurophysiol 79:334-341.
Sik A, van Nieuwehuyzen P, Prickaerts J, Blokland A (2003a) Performance of different mouse strains in an object recognition task. Behav Brain Res 147:49-54.
Sik A, van Nieuwehuyzen P, Prickaerts J, Blokland A (2003b) Performance of different mouse strains in an object recognition task. Behav Brain Res 147:49-54.
Soya H, Nakamura T, Deocaris CC, Kimpara A, Iimura M, Fujikawa T, Chang H, McEwen BS, Nishijima T (2007) BDNF induction with mild exercise in the rat hippocampus. Biochem Biophys Res Commun 358:961-967.
Tada T, Sheng M (2006) Molecular mechanisms of dendritic spine morphogenesis. Curr Opin Neurobiol 16:95-101.
Tafoya LCR, Mameli M, Miyashita T, Guzowski JF, Valenzuela CF, Wilson MC (2006) Expression and function of SNAP-25 as a universal SNARE component in GABAergic neurons (vol 26, pg 7826, 2006). J. Neurosci. 26:8875-8875.
van Praag H (2008) Neurogenesis and exercise: Past and future directions. Neuromol Med 10:128-140.
Vessey JP, Schoderboeck L, Gingl E, Luzi E, Riefler J, Di Leva F, Karra D, Thomas S, Kiebler MA, Macchi P (2010) Mammalian Pumilio 2 regulates dendrite morphogenesis and synaptic function. P Natl Acad Sci USA 107:3222-3227.
Voglis G, Tavernarakis N (2006) The role of synaptic ion channels in synaptic plasticity. EMBO Rep 7:1104-1110.
von Bohlen und Halbach O, Zacher C, Gass P, Unsicker K (2006) Age-related alterations in hippocampal spines and deficiencies in spatial memory in mice. J Neurosci Res 83:525-531.
Washbourne P, Thompson PM, Carta M, Costa ET, Mathews JR, Lopez-Bendito G, Molnar Z, Becher MW, Valenzuela CF, Partridge LD, Wilson MC (2002) Genetic ablation of the t-SNARE SNAP-25 distinguishes mechanisms of neuroexocytosis. Nat Neurosci. 5:19-26.
Wong ROL, Ghosh A (2002) Activity-dependent regulation of dendritic growth and patterning. Nat Rev Neurosci 3:803-812.
Yamada M, Okabe S (2011) Transgenic mice for visualizing memory encoding spines using a candidate LTP-marker protein, EGFP-CapZ. Neurosci Res 71:E410-E410.
Yuste R, Bonhoeffer T (2001) Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu Rev Neurosci 24:1071-1089.