Brain Structure and Function

, Volume 222, Issue 4, pp 1797–1808 | Cite as

Physical exercise induces structural alterations in the hippocampal astrocytes: exploring the role of BDNF-TrkB signaling

  • Atoossa Fahimi
  • Mehmet Akif Baktir
  • Sarah Moghadam
  • Fatemeh S. Mojabi
  • Krithika Sumanth
  • M. Windy McNerney
  • Ravikumar Ponnusamy
  • Ahmad SalehiEmail author
Original Article


While it has been known that physical activity can improve cognitive function and protect against neurodegeneration, the underlying mechanisms for these protective effects are yet to be fully elucidated. There is a large body of evidence indicating that physical exercise improves neurogenesis and maintenance of neurons. Yet, its possible effects on glial cells remain poorly understood. Here, we tested whether physical exercise in mice alters the expression of trophic factor-related genes and the status of astrocytes in the dentate gyrus of the hippocampus. In addition to a significant increase in Bdnf mRNA and protein levels, we found that 4 weeks of treadmill and running wheel exercise in mice, led to (1) a significant increase in synaptic load in the dentate gyrus, (2) alterations in astrocytic morphology, and (3) orientation of astrocytic projections towards dentate granule cells. Importantly, these changes were possibly linked to increased TrkB receptor levels in astrocytes. Our study suggests that astrocytes actively respond and could indeed mediate the positive effects of physical exercise on the central nervous system and potentially counter degenerative processes during aging and neurodegenerative disorders.


Physical activity Hippocampus Dentate gyrus Bdnf GFAP Astrocytes 



This study was supported by Grants from the Lumind/RDS and Jerome Lejeune foundations and the Alzheimer’s Association. The support provided by the MIRECC and WRIISC programs at the VA Palo Alto Health Care System is highly appreciated.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

429_2016_1308_MOESM1_ESM.eps (1.6 mb)
Fig. S1A-B a) Schematic representation of the treadmill used in this study. The device had six separate lanes separated by opaque walls for simultaneous physical exercise with minimal stress. b) The timeline of physical exercise in this experiment: following a week of habituation, each exercise mouse received 5 days of treadmill exercise (5 days per week for 4 weeks). TM = treadmill, RW = Running wheel. Treadmill exercise was consisted of two 20-minute running time followed by a 10-minute rest on the belts (EPS 1627 kb)
429_2016_1308_MOESM2_ESM.docx (118 kb)
Supplementary material 2 (Table S1) (DOCX 118 kb)


  1. Agudelo LZ et al (2014) Skeletal muscle PGC-1alpha1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 159(1):33–45PubMedCrossRefGoogle Scholar
  2. Armanini MP et al (1995) Truncated and catalytic isoforms of trkB are co-expressed in neurons of rat and mouse CNS. Eur J Neurosci 7(6):1403–1409PubMedCrossRefGoogle Scholar
  3. Aroeira RI, Sebastiao AM, Valente CA (2015) BDNF, via truncated TrkB receptor, modulates GlyT1 and GlyT2 in astrocytes. Glia 63(12):2181–2197PubMedCrossRefGoogle Scholar
  4. Barnes DE, Yaffe K (2011) The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol 10(9):819–828PubMedPubMedCentralCrossRefGoogle Scholar
  5. Bezzi P et al (2004) Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat Neurosci 7(6):613–620PubMedCrossRefGoogle Scholar
  6. Brockett AT, LaMarca EA, Gould E (2015) Physical exercise enhances cognitive flexibility as well as astrocytic and synaptic markers in the medial prefrontal cortex. PLoS One 10(5):e0124859PubMedPubMedCentralCrossRefGoogle Scholar
  7. Chen YC et al (1998) Physical training modifies the age-related decrease of GAP-43 and synaptophysin in the hippocampal formation in C57BL/6J mouse. Brain Res 806(2):238–245PubMedCrossRefGoogle Scholar
  8. Chowdhury TG et al (2014) Activity-based anorexia during adolescence disrupts normal development of the CA1 pyramidal cells in the ventral hippocampus of female rats. Hippocampus 24(12):1421–1429PubMedPubMedCentralCrossRefGoogle Scholar
  9. Coelho FG et al (2014) Acute aerobic exercise increases brain-derived neurotrophic factor levels in elderly with Alzheimer’s disease. J Alzheimers Dis 39(2):401–408PubMedGoogle Scholar
  10. Cotman CW, Berchtold NC, Christie LA (2007) Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 30(9):464–472PubMedCrossRefGoogle Scholar
  11. Cui W et al (2001) Inducible ablation of astrocytes shows that these cells are required for neuronal survival in the adult brain. Glia 34(4):272–282PubMedCrossRefGoogle Scholar
  12. Dang V et al (2014) Formoterol, a long-acting beta2 adrenergic agonist, improves cognitive function and promotes dendritic complexity in a mouse model of Down syndrome. Biol Psychiatry 75(3):179–188PubMedCrossRefGoogle Scholar
  13. Das D et al (2015) Assessment of dendritic arborization in the dentate gyrus of the hippocampal region in mice. J Vis Exp. doi: 10.3791/52371
  14. de Andrade LP et al (2013) Benefits of multimodal exercise intervention for postural control and frontal cognitive functions in individuals with Alzheimer’s disease: a controlled trial. J Am Geriatr Soc 61(11):1919–1926PubMedCrossRefGoogle Scholar
  15. Diniz DG et al (2010) Environmental impoverishment and aging alter object recognition, spatial learning, and dentate gyrus astrocytes. Eur J Neurosci 32(3):509–519PubMedCrossRefGoogle Scholar
  16. Erickson KI, Kramer AF (2009) Aerobic exercise effects on cognitive and neural plasticity in older adults. Br J Sports Med 43(1):22–24PubMedCrossRefGoogle Scholar
  17. Filous AR, Silver J (2016) Targeting astrocytes in CNS injury and disease: a translational research approach. Prog Neurobiol 144:173–187PubMedCrossRefGoogle Scholar
  18. Gosselet F et al (2013) Amyloid-beta peptides, Alzheimer’s disease and the blood-brain barrier. Curr Alzheimer Res 10(10):1015–1033PubMedCrossRefGoogle Scholar
  19. Helgager J, Huang YZ, McNamara JO (2014) Brain-derived neurotrophic factor but not vesicular zinc promotes TrkB activation within mossy fibers of mouse hippocampus in vivo. J Comp Neurol 522(17):3885–3899PubMedPubMedCentralCrossRefGoogle Scholar
  20. Hofer M et al (1990) Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO J 9(8):2459–2464PubMedPubMedCentralGoogle Scholar
  21. Jeong YJ et al (2015) 1950 MHz electromagnetic fields ameliorate Abeta pathology in Alzheimer’s disease mice. Curr Alzheimer Res 12(5):481–492PubMedCrossRefGoogle Scholar
  22. Kim SY et al (2004) Differential expression of phospholipase D isozymes in the hippocampus following kainic acid-induced seizures. J Neuropathol Exp Neurol 63(8):812–820PubMedCrossRefGoogle Scholar
  23. Kim K et al (2015) Effects of treadmill exercise-intensity on short-term memory in the rats born of the lipopolysaccharide-exposed maternal rats. J Exerc Rehabil 11(6):296–302PubMedPubMedCentralCrossRefGoogle Scholar
  24. Kokaia Z et al (1995) Regulation of brain-derived neurotrophic factor gene expression after transient middle cerebral artery occlusion with and without brain damage. Exp Neurol 136(1):73–88PubMedCrossRefGoogle Scholar
  25. Latimer CS et al (2011) Reversal of glial and neurovascular markers of unhealthy brain aging by exercise in middle-aged female mice. PLoS One 6(10):e26812PubMedPubMedCentralCrossRefGoogle Scholar
  26. Leem YH et al (2011) Chronic exercise ameliorates the neuroinflammation in mice carrying NSE/htau23. Biochem Biophys Res Commun 406(3):359–365PubMedCrossRefGoogle Scholar
  27. LeMaster AM et al (1999) Overexpression of brain-derived neurotrophic factor enhances sensory innervation and selectively increases neuron number. J Neurosci 19(14):5919–5931PubMedGoogle Scholar
  28. Lewerenz J, Maher P (2015) Chronic glutamate toxicity in neurodegenerative diseases-what is the evidence? Front Neurosci 9:469PubMedPubMedCentralCrossRefGoogle Scholar
  29. Liu N et al (2012) Intracerebral transplantation of bone marrow stromal cells ameliorates tissue plasminogen activator-induced brain damage after cerebral ischemia in mice detected by in vivo and ex vivo optical imaging. J Neurosci Res 90(11):2086–2093PubMedCrossRefGoogle Scholar
  30. Marlatt MW et al (2012) Running throughout middle-age improves memory function, hippocampal neurogenesis, and BDNF levels in female C57BL/6J mice. Dev Neurobiol 72(6):943–952PubMedPubMedCentralCrossRefGoogle Scholar
  31. Matsuura Y et al (2013) The effect of Anti-NGF receptor (p75 Neurotrophin Receptor) antibodies on nociceptive behavior and activation of spinal microglia in the rat brachial plexus avulsion model. Spine (Phila Pa 1976) 38(6):E332–E338CrossRefGoogle Scholar
  32. Mestriner RG et al (2011) Skilled reaching training promotes astroglial changes and facilitated sensorimotor recovery after collagenase-induced intracerebral hemorrhage. Exp Neurol 227(1):53–61PubMedCrossRefGoogle Scholar
  33. Miklic S, Juric DM, Carman-Krzan M (2004) Differences in the regulation of BDNF and NGF synthesis in cultured neonatal rat astrocytes. Int J Dev Neurosci 22(3):119–130PubMedCrossRefGoogle Scholar
  34. Moretti L et al (2009) Radiosensitization of solid tumors by Z-VAD, a pan-caspase inhibitor. Mol Cancer Ther 8(5):1270–1279PubMedPubMedCentralCrossRefGoogle Scholar
  35. Nascimento CM et al (2014) Physical exercise in MCI elderly promotes reduction of pro-inflammatory cytokines and improvements on cognition and BDNF peripheral levels. Curr Alzheimer Res 11(8):799–805PubMedCrossRefGoogle Scholar
  36. Nascimento CM et al (2015) Physical exercise improves peripheral BDNF levels and cognitive functions in mild cognitive impairment elderly with different bdnf Val66Met genotypes. J Alzheimers Dis 43(1):81–91PubMedGoogle Scholar
  37. Neeper SA et al (1996) Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Res 726(1–2):49–56PubMedCrossRefGoogle Scholar
  38. Nijs J et al (2015) Brain-derived neurotrophic factor as a driving force behind neuroplasticity in neuropathic and central sensitization pain: a new therapeutic target? Expert Opin Ther Targets 19(4):565–576PubMedCrossRefGoogle Scholar
  39. Ohira K et al (2005) Differential expression of the truncated TrkB receptor, T1, in the primary motor and prefrontal cortices of the adult macaque monkey. Neurosci Lett 385(2):105–109PubMedCrossRefGoogle Scholar
  40. Pereira BC et al (2015) Eccentric exercise leads to glial activation but not apoptosis in mice spinal cords. Int J Sports Med 36(5):378–385PubMedCrossRefGoogle Scholar
  41. Phillips C et al (2014) Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling. Front Cell Neurosci 8:170PubMedPubMedCentralCrossRefGoogle Scholar
  42. Phillips C et al (2015a) The link between physical activity and cognitive dysfunction in Alzheimer disease. Phys Ther 95(7):1046–1060PubMedCrossRefGoogle Scholar
  43. Phillips C et al (2015b) Evolution of monoaminergic system degeneration in down syndrome and Alzheimer’s disease. In: Salehi A, Rafii M, Phillips C (eds) Recent advances in alzheimer research, (Volume 1), common pathogenic mechanisms between down syndrome and Alzheimer’s disease. Steps toward Therapy. Bentham Science Publisher, SharjahGoogle Scholar
  44. Pollock GS et al (2001) Effects of early visual experience and diurnal rhythms on BDNF mRNA and protein levels in the visual system, hippocampus, and cerebellum. J Neurosci 21(11):3923–3931PubMedGoogle Scholar
  45. Quirie A et al (2012) Comparative effect of treadmill exercise on mature BDNF production in control versus stroke rats. PLoS One 7(9):e44218PubMedPubMedCentralCrossRefGoogle Scholar
  46. Rodriguez JJ et al (2013) Enriched environment and physical activity reverse astrogliodegeneration in the hippocampus of AD transgenic mice. Cell Death Dis 4:e678PubMedPubMedCentralCrossRefGoogle Scholar
  47. Rose CR et al (2003) Truncated TrkB-T1 mediates neurotrophin-evoked calcium signalling in glia cells. Nature 426(6962):74–78PubMedCrossRefGoogle Scholar
  48. Rossi S et al (2005) Rabbit monoclonal antibodies: a comparative study between a novel category of immunoreagents and the corresponding mouse monoclonal antibodies. Am J Clin Pathol 124(2):295–302PubMedCrossRefGoogle Scholar
  49. Salehi A et al (2006) Increased App expression in a mouse model of Down’s syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron 51(1):29–42PubMedCrossRefGoogle Scholar
  50. Salehi A et al (2009) Restoration of norepinephrine-modulated contextual memory in a mouse model of Down syndrome. Sci Transl Med 1(7):7ra17PubMedCrossRefGoogle Scholar
  51. Salis AS (2013) Proactive and reactive effects of vigorous exercise on learning and vocabulary comprehension. Percept Mot Skills 116(3):918–928PubMedCrossRefGoogle Scholar
  52. Saur L et al (2014) Physical exercise increases GFAP expression and induces morphological changes in hippocampal astrocytes. Brain Struct Funct 219(1):293–302PubMedCrossRefGoogle Scholar
  53. Scarmeas N et al (2009) Physical activity, diet, and risk of Alzheimer disease. JAMA 302(6):627–637PubMedPubMedCentralCrossRefGoogle Scholar
  54. Scarmeas N et al (2011) Physical activity and Alzheimer disease course. Am J Geriatr Psychiatry 19(5):471–481PubMedPubMedCentralCrossRefGoogle Scholar
  55. Schwartz JP, Nishiyama N (1994) Neurotrophic factor gene expression in astrocytes during development and following injury. Brain Res Bull 35(5–6):403–407PubMedCrossRefGoogle Scholar
  56. Sepulveda-Falla D et al (2011) Deposition of hyperphosphorylated tau in cerebellum of PS1 E280A Alzheimer’s disease. Brain Pathol 21(4):452–463PubMedCrossRefGoogle Scholar
  57. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119(1):7–35PubMedCrossRefGoogle Scholar
  58. Song S et al (2016) Granulocyte-colony stimulating factor promotes brain repair following traumatic brain injury by recruitment of microglia and increasing neurotrophic factor expression. Restor Neurol Neurosci 34(3):415–431PubMedCrossRefGoogle Scholar
  59. Steinberg M et al (2009) Evaluation of a home-based exercise program in the treatment of Alzheimer’s disease: the maximizing independence in dementia (MIND) study. Int J Geriatr Psychiatry 24(7):680–685PubMedPubMedCentralCrossRefGoogle Scholar
  60. Stranahan AM, Khalil D, Gould E (2007) Running induces widespread structural alterations in the hippocampus and entorhinal cortex. Hippocampus 17(11):1017–1022PubMedPubMedCentralCrossRefGoogle Scholar
  61. Tynan RJ et al (2013) Chronic stress-induced disruption of the astrocyte network is driven by structural atrophy and not loss of astrocytes. Acta Neuropathol 126(1):75–91PubMedCrossRefGoogle Scholar
  62. van Praag H (2008) Neurogenesis and exercise: past and future directions. Neuromol Med 10(2):128–140CrossRefGoogle Scholar
  63. Vaynman S, Ying Z, Gomez-Pinilla F (2004) Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 20(10):2580–2590PubMedCrossRefGoogle Scholar
  64. Viola GG, Loss CM (2014) Letter to Editor about: “Physical exercise increases GFAP expression and induces morphological changes in hippocampal astrocytes”. Brain Struct Funct 219(4):1509–1510PubMedCrossRefGoogle Scholar
  65. Voss MW et al (2013) Neurobiological markers of exercise-related brain plasticity in older adults. Brain Behav Immun 28:90–99PubMedCrossRefGoogle Scholar
  66. Waterhouse EG, Xu B (2009) New insights into the role of brain-derived neurotrophic factor in synaptic plasticity. Mol Cell Neurosci 42(2):81–89PubMedPubMedCentralCrossRefGoogle Scholar
  67. Yang TT et al (2015) Aging and exercise affect hippocampal neurogenesis via different mechanisms. PLoS One 10(7):e0132152PubMedPubMedCentralCrossRefGoogle Scholar
  68. Zafra F et al (1992) Regulation of brain-derived neurotrophic factor and nerve growth factor mRNA in primary cultures of hippocampal neurons and astrocytes. J Neurosci 12(12):4793–4799PubMedGoogle Scholar
  69. Zhao C et al (2006) Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci 26(1):3–11PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2016

Authors and Affiliations

  1. 1.VA Palo Alto Health Care SystemPalo AltoUSA
  2. 2.Department of Psychiatry and Behavioral SciencesStanford University School of MedicinePalo AltoUSA

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