Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Biological Mechanisms of Physical Activity in Preventing Cognitive Decline


In order to guarantee better conditions for competition, the nervous system has developed not only mechanisms controlling muscle effectors, but also retrograde systems that, starting from peripheral structures, may influence brain functions. Under such perspective, physical activity could play an important role in influencing cognitive brain functions including learning and memory. The results of epidemiological studies (cross-sectional, prospective and retrospective) support a positive relationship between cognition and physical activities. Recent meta-analysis confirmed a significant effect of exercise on cognitive functions. However, the biological mechanisms that underlie such beneficial effects are still to be completely elucidated. They include supramolecular mechanisms (e.g. neurogenesis, synaptogenesis, and angiogenesis) which, in turn, are controlled by molecular mechanisms, such as BDNF, IGF-1, hormone and second messengers.

This is a preview of subscription content, log in to check access.

Fig. 1


  1. Abraham WC, Logan B, Greenwood JM, Dragunow M (2002) Induction and experience-dependent consolidation of stable long-term potentiation lasting months in the hippocampus. J Neurosci 22:9626–9634

  2. Adams JP, Roberson ED, English JD, Selcher JC, Sweatt JD (2000) MAP-K regulation of gene expression in the central nervous system. Acta Neurobiol Exp (Warsz) 60:377–394

  3. Adlard PA, Perreau VM, Cotman CW (2005) The exercise-induced expression of BDNF within the hippocampus varies across life-span. Neurobiol Aging 26:511–520

  4. Ajmani RS, Metter EJ, Jaykumar R, Ingram DK, Spangler EL, Abugo OO et al (2000) Hemodynamic changes during aging associated with cerebral blood flow and impaired cognitive function. Neurobiol Aging 21:257–269

  5. Akagi S, Mizoguchi A, Sobue K, Nakamura H, Ide C (1996) Localization of synapsin I in normal fibers and regenerating axonal sprouts of the rat sciatic nerve. Histochem Cell Biol 105:365–373

  6. Ang ET, Wong PTH, Mochhala S, Ng YK (2003) Neuroprotection associated with running: Is it a result of increased endogenous neurotrophic factors? Neuroscience 118:335–345

  7. Angevaren M, Aufdemkampe G, Verhaar HJ, Aleman A, Vanhees L (2008) Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment. Cochrane Database Syst. Rev. 3:CD005381

  8. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963–970

  9. Berchtold NC, Kesslak JP, Pike CJ, Adlard PA, Cotman CW (2001) Estrogen and exercise interact to regulate brain-derived neurotrophic factor mRNA and protein expression in the hippocampus. Eur J Neurosci 14:1992–2002

  10. Berchtold NC, Kesslak JP, Cotman CW (2002) Hippocampal brain-derived neurotrophic gene regulation by exercise and the medial septum. J Neurosci Res 68:511–521

  11. Black JE, Isaacs KR, Anderson BJ, Alcantara AA, Greenough WT (1990) Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats. Proc Natl Acad Sci USA 87:5568–5572

  12. Black JE, Zelazny AM, Greenough WT (1991) Capillary and mitochondrial support of neural plasticity in adult rat visual cortex. Exp Neurol 111:204–209

  13. Bliss TVP, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39

  14. Blomstrand E, Perrett D, Parry-Billings M, Newsholme EA (1989) Effect of sustained exercise on plasma amino acid concentrations and on 5-hydroxytryptamine metabolism in six different brain regions in the rat. Acta Physiol Scand 136:473–481

  15. Blum S, Moore AN, Adams F, Dash PK (1999) A mitogen-activated protein kinase cascade in the CA1/CA2 subfield of the dorsal hippocampus is essential for long-term spatial memory. J Neurosci 19:3535–3544

  16. Blumenthal JA, Maden DJ (1988) Effects of aerobic exercise training, age, and physical fitness on memory-search performance. Psychol Aging 3:280–285

  17. Bolton MM, Pittman AJ, Lo DC (2000) Brain-derived neurotrophic factor differentially regulates excitatory and inhibitory synaptic transmission in hippocampal cultures. J Neurosci 20:3221–3232

  18. Brezun JM, Daszuta A (1999) Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats. Neuroscience 89:999–1002

  19. Brezun JM, Daszuta A (2000) Serotonin may stimulate granule cell proliferation in the adult hippocampus, as observed in rats grafted with foetal raphe neurons. Eur J Neurosci 12:391–396

  20. Brown J, Cooper-Kuhn CM, Kempermann G, Van Praag H, Winkler J, Gage FH et al (2003) Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur J Neurosci 17:2042–2046

  21. Cammarota M, de Stein ML, Paratcha G, Bevilaqua LR, Izquierdo I, Medina JH (2000) Rapid and transient learning-associated increase in NMDA NR1 subunit in the rat hippocampus. Neurochem Res 25:567–572

  22. Carro E, Nunez A, Busiguina S, Torres-Aleman I (2000) Circulating insulin-like growth factor I mediates effects of exercise on the brain. J Neurosci 20:2926–2933

  23. Carro E, Trejo LJ, Busiguina S, Torres-Aleman I (2001) Circulating insulin-like growth factor 1 mediates the protective effects of physical exercise against brain insults of different etiology and anatomy. J Neurosci 21:5678–5684

  24. Chennaoui M, Drogou C, Gomez-Merino D (2008) Effects of physical training on IL-1beta, IL-6 and IL-1ra concentrations in various brain areas of the rat. Eur Cytokine Netw 19:8–14

  25. Churchill JD, Galvez R, Colcombe S, Rodney AS, Kramer AF, William TG (2002) Exercise, experience and the aging brain. Neurobiol Aging 23:941–955

  26. Colcombe S, Kramer AF (2003) Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol Sci 14:125–130

  27. Connor B, Young D, Yan Q, Faull RL, Synek B, Dragunow M (1997) Brain-derived neurotrophic factor is reduced in Alzheimer’s disease. Mol Brain Res 49:71–81

  28. Cracchiolo JR, Mori T, Nazian SJ, Tan J, Potter H, Arendash GW (2007) Enhanced cognitive activity—over and above social or physical activity—is required to protect Alzheimer’s mice against cognitive impairment, reduce Aβ deposition, and increase synaptic immunoreactivity. Neurobiol Learn Mem 88:277–294

  29. Czurko A, Hirase H, Csicsvari J, Buzsaki G (1999) Sustained activation of hippocampal pyramidal cells by ‘space clamping’ in a running wheel. Eur J Neurosci 11:344–352

  30. Dalsgaard MK, Quistorff B, Danielsen ER, Selmer C, Vogelsang T, Secher NH (2004) A reduced cerebral metabolic ratio in exercise reflects metabolism and not accumulation of lactate within the human brain. J Physiol Lond 554:571–578

  31. Dietrich MO, Andrews ZB, Horvath TL (2008) Exercise-induced synaptogenesis in the hippocampus is dependent on UCP2-regulated mitochondrial adaptation. J Neurosci 28:10766–10771

  32. Ding Y, Li J, Luan X, Ding YH, Lai Q, Rafols JA et al (2004) Exercise pre-conditioning reduces brain damage in ischemic rats that may be associated with regional angiogenesis and cellular overexpression of neurotrophin. Neuroscience 124:583–591

  33. Dishman RK, Renner KJ, Youngstedt SD, Reigle TG, Bunnel BN, Burke KA et al (1997) Activity wheel running reduces escape latency and alters brain monoamine levels after footshock. Brain Res Bull 42:399–406

  34. Dishman RK, Renner KJ, White-Welkley JE, Bunnell BN (2000) Treadmill exercise training augments brain norepinephrine response to familiar and novel stress. Brain Res Bull 52:337–342

  35. Eadie BD, Redila VA, Christie BR (2005) Voluntary exercise alters the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dentritic complexity, and spine density. J Comp Neurol 486:39–47

  36. English JD, Sweatt JD (1996) Activation of p42 mitogen-activated protein kinase in hippocampal long-term potentiation. J Biol Chem 271:24329–24332

  37. English JD, Sweatt JD (1997) A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation. J Biol Chem 272:19103–19106

  38. Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn AM, Nordborg C, Peterson DA et al (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317

  39. Farmer J, Zhao X, van Praag H, Wodtke K, Gage FH, Christie BR (2004) Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo. Neuroscience 124:71–79

  40. Figurov A, Pozzo-Miller LD, Olafsson P, Wang T, Lu B (1996) Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381:706–709

  41. Finkbeiner S, Tavazoie SF, Maloratsky A, Jacobs KM, Harris KM, Greenberg ME (1997) CREB: a major mediator of neuronal neurotrophin responses. Neuron 19:1031–1047

  42. Fordyce DE, Starnes JW, Farrar RP (1991) Compensation of the age-related decline in hippocampal muscarinic receptor density through daily exercise or underfeeding. J Gerontol 46:245–248

  43. Fox PT, Raichle ME (1986) Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proc Natl Acad Sci USA 83:1140–1144

  44. Friedland RP, Fritsch T, Smyth KA, Koss E, Lerner AJ, Chen CH et al (2001) Patients with Alzheimer’s disease have reduced activities in midlife compared with healthy control-group members. Proc Natl Acad Sci USA 98:3440–3445

  45. Gomez-Pinilla F, Dao L, So V (1997) Physical exercise induces FGF-2 and its mRNA in the hippocampus. Brain Res 764:1–8

  46. Gould E, Tanapat P (1997) Lesion-induced proliferation of neuronal progenitors in the dentate gyrus of the adult rat. Neuroscience 80:427–436

  47. Greengard P, Valtorta F, Czernik AJ, Benfenati F (1993) Synaptic vesicle phosphoproteins and regulation of synaptic function. Science 259:780–785

  48. Greenwood BN, Foley TE, Day HE, Campisi J, Hammack SH, Campeau S et al (2003) Freewheel running prevents learned helplessness/behavioural depression: role of dorsal raphe serotoninergic neurons. J Neurosci 23:2889–2898

  49. Greenwood BN, Foley TE, Burhans DJ, Maiser SF, Fleshner M (2005) The consequences of uncontrollable stress are sensitive to the duration of prior wheel running. Brain Res 1033:164–178

  50. Hamer M, Chida Y (2009) Physical activity and risk of neurodegenerative disease: a systematic review of prospective evidence. Psychol Med 39:3–11

  51. Hardingham G, Arnold FJ, Bading H (2001) Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity. Nat Neurosci 4:261–267

  52. Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF et al (2003) Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 23:6690–6694

  53. Helge JW, Stallknecht B, Pedersen BK, Galbo H, Kiens B, Richter EA (2003) The effect of graded exercise on IL-6 release and glucose uptake in skeletal muscle. J Physiol 546:299–305

  54. Heyn P, Abreu BC, Ottenbacher KJ (2004) The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch Phys Med Rehabil 85:1679–1704

  55. Hillman CH, Erickson KI, Kramer AF (2008) Be smart, exercise your heart: exercise effects on brain and cognition. Nat Rev Neurosci 9:58–65

  56. Hu S, Ying Z, Gomez-Pinilla F, Frautschy SA (2009) Exercise can increase small heat shock proteins (sHSP) and pre- and post-synaptic proteins in the hippocampus. Brain Res 1249:191–201

  57. Ide K, Secher NH (2000) Cerebral blood flow and metabolism during exercise. Prog Neurobiol 61:397–414

  58. Isaacs KR, Anderson BJ, Alcantara AA, Black JE, Greenough WT (1992) Exercise and the brain: angiogenesis in the adult rat cerebellum after vigorous physical activity and motor skill learning. J Cereb Blood Flow Metab 12:110–119

  59. Jankowsky JL, Melnikova T, Fadale DJ, Xu GM, Slunt HH, Gonzales V et al (2005) Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer’s disease. J Neurosci 25:5217–5224

  60. Jonsdottir I, Schjerling P, Ostrowski K, Asp S, Richter EA, Pedersen BK (2000) Muscle contractions induces interleukin-6 mRNA production in rat skeletal muscles. J Physiol Lond 528:157–163

  61. Kempermann G (2008) The neurogenic reserve hypothesis: What is adult hippocampal neurogenesis good for? Trends Neurosci 31:163–169

  62. Kim H, Lee SH, Kim SS, Yoo JH, Kim CJ (2007) The influence of maternal treadmill running during pregnancy on short-term memory and hippocampal cell survival in rat pups. Int J Dev Neurosci 25:243–249

  63. Knipper M, Berzaghi M, Blöchl A, Breer H, Thoenen H, Lindholm D (1994) Positive feedback between acetylcholine and the neurotrophins nerve growth factor and brain-derived neurotrophic factor in the rat hippocampus. Eur J Neurosci 6:668–671

  64. Knusel B, Winslow JW, Rosenthal A, Burton LE, Seid DP, Nikolics K et al (1991) Promotion of central cholinergic and dopaminergic neuron differentiation by brain-derived neurotrophic factor but not neurotrophin 3. Proc Natl Acad Sci USA 88:961–965

  65. Kramer AF, Hahn S, Cohen NJ, Banich MT, McAuley E, Harrison CR et al (1999) Ageing, fitness and neurocognitive function. Nature 400:418–419

  66. Ladoux A, Frelin C (1993) Hypoxia is a strong inducer of vascular endothelial growth factor mRNA expression in the heart. Biochem Biophys Res Commun 195:1005–1010

  67. Lambert TJ, Fernandez SM, Frick KM (2005) Different types of environmental enrichment have discrepant effects on spatial memory and synaptophysin levels in female mice. Neurobiol Learn Mem 83:206–216

  68. Lautenschlager NT, Cox KL, Flicker L, Foster JK, van Bockxmeer FM, Xiao J et al (2008) Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA 300:1027–1037

  69. Lazarov O, Robinson J, Tang YP, Hairston IS, Korade-Mirnics Z, Lee VM et al (2005) Environmental enrichment reduces Aβ levels and amyloid deposition in transgenic mice. Cell 120:701–713

  70. Lindvall O, Kokaia Z, Bengzon J, Elmér E, Kokaia M (1994) Neurotrophins and brain insults. Trends Neurosci 17:490–496

  71. Liu J, Solway K, Messing RO, Sharp FR (1998) Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci 18:7768–7778

  72. Lledo PM, Alonso M, Grubb MS (2006) Adults neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 7:179–193

  73. Lo DC (1995) Neurotrophic factors and synaptic plasticity. Neuron 15:979–981

  74. Lopez-Lopez C, LeRoith D, Torres-Aleman I (2004) Insulin-like growth factor I is required for vessel remodeling in the adult brain. Proc Natl Acad Sci USA 101:9833–9838

  75. Lou SJ, Liu JY, Chang H, Chen PJ (2008) Hippocampal neurogenesis and gene expression depend on exercise intensity in juvenile rats. Brain Res 1210:48–55

  76. Ma YL, Wang HL, Wu HC, Wei CL, Lee EH (1998) Brain-derived neurotrophic factor antisense oligonucleotide impairs memory retention and inhibits long-term potentiation in rats. Neuroscience 82:957–967

  77. MacRae PG, Spirduso WW, Walters TJ, Farrar RP, Wilcox RE (1987) Endurance training effects on striatal D2 dopamine receptor binding and striatal dopamine metabolites in presenescent older rats. Psychopharmacology 92:236–240

  78. McCloskey DP, Adamo DS, Anderson BJ (2001) Exercise increases metabolic capacity in the motor cortex and striatum, but not in the hippocampus. Brain Res 891:168–175

  79. Melloni RH Jr, Apostolides PJ, Hamos JE, De Gennaro LJ (1994) Dynamics of synapsin I gene expression during the establishment and restoration of functional synapses in the rat hippocampus. Neuroscience 58:683–703

  80. Middleton L, Kirkland S, Rockwood K (2008) Prevention of CIND by physical activity: different impact on VCI-ND compared with MCI. J Neurol Sci 269:80–84

  81. Ming GL, Song H (2005) Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28:223–250

  82. Molteni R, Ying Z, Gomez-Pinilla F (2002) Differential effects of acute and chronic exercise on plasticity-related genes in the rat hippocampus revealed by microarray. Eur J Neurosci 16:1107–1116

  83. Naylor AS, Persson AI, Eriksson PS, Jonsdottir IH, Thorlin T (2005) Extended voluntary running inhibits exercise-induced adult hippocampal progenitor proliferation in the spontaneously hypertensive rat. J Neurophysiol 93:2406–2414

  84. Neeper SA, Gomez-Pinilla F, Choi J, Cotman CW (1995) Exercise and brain neurotrophins. Nature 373:109

  85. Nithianantharajah J, Levis H, Murphy M (2004) Environmental enrichment results in cortical and subcortical changes in levels of synaptophysin and PSD-95 proteins. Neurobiol Learn Mem 81:200–210

  86. O’Neal HA, Van Hoomissen JD, Holmes PV, Dishman RK (2001) Prepro-galanin mRNA levels are increased in rat locus coeruleus after treadmill exercise training. Neurosci Lett 299:69–72

  87. Olson AK, Eadie BD, Ernst C, Christie BR (2006) Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways. Hippocampus 16:250–260

  88. Ostrowski K, Rohde T, Asp S, Schjerling P, Pedersen BK (2001) Chemokines are elevated in plasma after strenuous exercise in humans. Eur J Appl Physiol 84:244–245

  89. Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, Lowenstein DH (1997) Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci 17:3727–3738

  90. Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC, Kandel ER (1996) Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16:1137–1145

  91. Pilegaard H, Ordway GA, Saltin B, Neufer PD (2000) Transcriptional regulation of gene expression in human skeletal muscle during recovery from exercise. Am J Physiol Endocrinol Metab 279:806–814

  92. Poutlton NP, Muir GD (2005) Treadmill training ameliorates dopamine loss but not behavioral deficits in hemi-parkinsonian rats. Exp Neurol 193:181–197

  93. Pozzo-Miller LD, Gottschalk W, Zhang L, McDermott K, Du J, Gopalakrishnan R et al (1999) Impairments in high frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci 19:4972–4983

  94. Sadamoto Y, Igase K, Sakanaka M, Sato K, Otsuka H, Sakaki S et al (1998) Erythropoietin prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery. Biochem Biophys Res Commun 253:26–32

  95. Satake S, Kuzuya M, Miura H, Asai T, Ramos MA, Muraguchi M et al (1998) Up-regulation of vascular endothelial growth factor in response to glucose deprivation. Biol Cell 90:161–168

  96. Silva AJ, Paylor R, Wehner JM, Tonegawa S (1992) Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science 257:206–211

  97. Soares J, Holmes PV, Renner KJ, Edwards GL, Bunnel BN, Dishman RK (1999) Brain noradrenergic responses to foot-shock after chronic activity-wheel running. Behav Neurosci 113:558–566

  98. Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD et al (1997) The [14C] deoxyglucose method for the measurement of local glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28:897–916

  99. Song DK, Choe B, Bae JH, Park WK, Han IS, Ho WK et al (1998) Brain-derived neurotrophic factor rapidly potentiates synaptic transmission through NMDA, but suppresses it through non-NMDA receptors in rat hippocampal neuron. Brain Res 799:176–179

  100. Starkie RL, Rolland J, Angus DJ, Anderson MJ, Febbraio MA (2001) Circulating monocytes are not the source of elevations in plasma IL-6 and TNF-alpha levels after prolonged running. Am J Physiol Cell Physiol 280:769–774

  101. Steensberg A, Febbraio MA, Osada T, Schjerling P, van Hall G, Saltin B et al (2001) Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content. J Physiol 537:633–639

  102. Steiner B, Zurborg S, Hörster H, Fabel K, Kepermann G (2008) Differential 24 h responsiveness of prox1-expressing precursor cells in adult hippocampal neurogenesis to physical activity, environmental enrichment, and kainic acid-induced seizures. Neuroscience 154:521–529

  103. Sturman MT, Morris MC, Mendes de Leon CF, Bienias JL, Wilson RS, Evans DA (2005) Physical activity, cognitive activity, and cognitive decline in a biracial community population. Arch Neurol 62:1750–1754

  104. Sweatt JD (2001) The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem 76:1–10

  105. Taaffe DR, Irie F, Masaki KH, Abbott RD, Petrovitch H, Ross GW et al (2008) Physical activity, physical function, and incident dementia in elderly men: the Honolulu–Asia Aging Study. J Gerontol A Biol Sci Med Sci 63:529–535

  106. Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME (1998) Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20:709–726

  107. Thiele C, Hannah M, Fahrenholz F, Huttner WB (2000) Cholesterol binds to synaptophysin and is required for biogenesis of synaptic vesicles. Nat Cell Biol 2:42–49

  108. Tokuyama W, Okuno H, Hashimoto T, Xin Li Y, Miyashita Y (2000) BDNF upregulation during declarative memory formation in monkey inferior temporal cortex. Nat Neurosci 3:1134–1142

  109. Tong L, Shen H, Perreau VM, Balazs R, Cotman CW (2001) Effects of exercise on gene-expression profile in the rat hippocampus. Neurobiol Dis 8:1046–1056

  110. Trejo JL, Carro E, Torres-Aleman EI (2001) Circulating insulin-like growth factor mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J Neurosci 21:1628–1634

  111. Tsutsumi T, Don BM, Zaichkowsky LD, Delizonna LL (1997) Physical fitness and psychological benefits of strength training in community dwelling older adults. Appl Human Sci 16:257–266

  112. Tully T (1997) Regulation of gene expression and its role in long-term memory and synaptic-plasticity. Proc Natl Acad Sci USA 94:4239–4241

  113. Uda M, Ishido M, Kami K, Masuhara M (2006) Effects of chronic treadmill running on neurogenesis in the dentate gyrus of the hippocampus of adult rat. Brain Res 1104:64–72

  114. van Praag H, Christie BR, Sejnoswski TS, Gage FH (1999a) Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA 96:13427–13431

  115. van Praag H, Kempermann G, Gage FH (1999b) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2:266–270

  116. van Praag H, Shubert T, Zhao C, Gage FH (2005) Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 25:8680–8685

  117. van Uffelen JG, Chin A, Paw MJ, Hopman-Rock M, van Mechelen W (2008) The effects of exercise on cognition in older adults with and without cognitive decline: a systematic review. Clin J Sport Med 18:486–500

  118. Vaynman S, Gomez-Pinilla F (2006) Revenge of the “sit”: how lifestyle impacts neuronal and cognitive health through molecular systems that interface energy metabolism with neuronal plasticity. J Neurosci Res 84:699–715

  119. Vaynman S, Ying Z, Gomez-Pinilla F (2003) Interplay between BDNF and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity. Neuroscience 122:647–657

  120. Vaynman S, Ying Z, Gomez-Pinilla F (2004) Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 20:2580–2590

  121. Vaynman S, Ying Z, Wu A, Gomez-Pinilla F (2006) Coupling energy metabolism with a mechanism to support BDNF mediated synaptic plasticity. Neuroscience 139:1221–1234

  122. Verghese J, Lipton RB, Katz M, Hall CB, Derby CA, Kuslansky G et al (2003) Leisure activities and the risk of dementia in the elderly. N Engl J Med 348:2508–2516

  123. Verghese J, Wang C, Katz MJ, Sanders A, Lipton RB (2009) Leisure activities and risk of vascular cognitive impairment in older adults. J Geriatr Psychiatry Neurol 22:110–118

  124. Weuve J, Kang JH, Manson JE, Breteler MMB, Ware JH, Grodstein F (2004) Physical activity, including walking, and cognitive function in older women. JAMA 292:1454–1461

  125. Williamson JD, Espeland M, Kritchevsky SB, Newman AB, King AC, Pahor M et al (2009) Changes in cognitive function in a randomized trial of physical activity: results of the lifestyle interventions and independence for elders pilot study. J Gerontol A Biol Sci Med Sci 64:688–694

  126. Wolf SA, Kronenberg G, Lehmann K, Blankenship A, Overall R, Staufenbiel M et al (2006) Cognitive and physical activity differently modulate disease progression in the amyloid precursor protein (APP)-23 model of Alzheimer’s disease. Biol Psychiatry 60:1314–1323

  127. Xuan AG, Long DH, Gu HG, Yang DD, Hong LP, Leng SL (2008) BDNF improves the effects of neural stem cells on the rat model of Alzheimer’s disease with unilateral lesion of fimbria-fornix. Neurosci Lett 440:331–335

  128. Yin JC, Tully T (1996) CREB and the formation of long-term memory. Curr Opin Neurobiol 6:264–268

  129. Yin JC, Del Vecchio M, Zhou H, Tully T (1995) CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila. Cell 81:107–115

  130. Ying SW, Futter M, Rosenblum K, Webber MJ, Hunt SP, Bliss TV et al (2002) Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci 22:1532–1540

Download references


This study was sponsored by grants from MIUR (PRIN); Regione Campania (L.R. 5/02), Italy; Progetto Strategico Alzheimer (Ministero della Salute-Regione Lazio) Italy; and Provincia di Salerno (Assessorato allo Sport, Salute e Qualità della Vita) Italy.

Author information

Correspondence to G. Sorrentino.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lista, I., Sorrentino, G. Biological Mechanisms of Physical Activity in Preventing Cognitive Decline. Cell Mol Neurobiol 30, 493–503 (2010). https://doi.org/10.1007/s10571-009-9488-x

Download citation


  • Physical activity
  • Exercise
  • Cognitive decline
  • Prevention
  • Neurogenesis
  • Synaptogenesis
  • Angiogenesis
  • BDNF
  • Alzheimer’s disease