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Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus

Abstract

Exposure to an enriched environment increases neurogenesis in the dentate gyrus of adult rodents. Environmental enrichment, however, typically consists of many components, such as expanded learning opportunities, increased social interaction, more physical activity and larger housing. We attempted to separate components by assigning adult mice to various conditions: water-maze learning (learner), swim-time-yoked control (swimmer), voluntary wheel running (runner), and enriched (enriched) and standard housing (control) groups. Neither maze training nor yoked swimming had any effect on bromodeoxyuridine (BrdU)-positive cell number. However, running doubled the number of surviving newborn cells, in amounts similar to enrichment conditions. Our findings demonstrate that voluntary exercise is sufficient for enhanced neurogenesis in the adult mouse dentate gyrus.

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Figure 1: BrdU-positive cell number.
Figure 2: Proliferation and neurogenesis in the dentate gyrus.
Figure 3: Water-maze training in the learners group.
Figure 4: Living conditions in the different experimental groups.

References

  1. 1

    Rasool, C. G., Svendsen, C. & Selkoe, D. J. Neurofibrillary degeneration of cholinergic and non-cholinergic neurons of the basal forebrain in Alzheimer's disease. Ann. Neurol. 20, 482–488 ( 1986).

    CAS  Article  Google Scholar 

  2. 2

    Uhl, G. R., Hedreen, J. C. & Price, D. L. Parkinson's disease: Loss of neurons from the ventral tegmental area contralateral to therapeutic surgical lesions. Neurology 35, 1215–1218 (1985).

    CAS  Article  Google Scholar 

  3. 3

    Adams, R. D. & Victor, M. Principles of Neurology (McGraw-Hill, New York, 1991).

    Google Scholar 

  4. 4

    Altman, J. & Das, G. D. Autoradiographic and histological evidence of postnatal neurogenesis in rats. J. Comp. Neurol. 124, 319–335 (1965).

    CAS  Article  Google Scholar 

  5. 5

    Kuhn, H. G., Dickinson-Anson, H. & Gage, F. H. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J. Neurosci. 16, 2027–2033 ( 1996).

    CAS  Article  Google Scholar 

  6. 6

    Kempermann, G., Kuhn, H. G. & Gage, F. H. More hippocampal neurons in adult mice living in an enriched environment. Nature 386, 493– 495 (1997).

    CAS  Article  Google Scholar 

  7. 7

    Kempermann, G., Kuhn, H. G. & Gage, F. H. Genetic influence in the dentate gyrus of mice. Proc. Natl. Acad. Sci. USA 94, 10409– 10414 (1997).

    CAS  Article  Google Scholar 

  8. 8

    Lois, C. & Alvarez-Buylla, A. Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc. Natl. Acad. Sci. USA 90, 2074–2077 (1993).

    CAS  Article  Google Scholar 

  9. 9

    Gould, E., Tanapat, P., McEwen, B. S., Flugge, G. & Fuchs, E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc. Natl. Acad. Sci. USA 95, 3168– 3171 (1998).

    CAS  Article  Google Scholar 

  10. 10

    Eriksson, P. S. et al. Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313–1317 ( 1998).

    CAS  Article  Google Scholar 

  11. 11

    Rosenzweig, M. R., Krech, D., Bennett, E. L. & Diamond, M. C. Effects of environmental complexity and training on brain chemistry and anatomy. J. Comp. Physiol. Psychol. 55, 429– 437 (1962).

    CAS  Article  Google Scholar 

  12. 12

    Greenough, W. T. Experiential modification of the developing brain. Am. Sci. 63, 37–46 (1975).

    CAS  PubMed  Google Scholar 

  13. 13

    Juraska, J. M., Fitch, J., Henderson, C. & Rivers, N. Sex differences in the dendritic branching of dentate granule cells following differential experience. Brain Res. 333, 73– 80 (1985).

    CAS  Article  Google Scholar 

  14. 14

    Juraska, J. M., Fitch, J. & Washburne, D. L. The dendritic morphology of pyramidal neurons in the rat hippocampal CA3 area II. Effects of gender and experience. Brain Res. 479, 115–119 (1989).

    CAS  Article  Google Scholar 

  15. 15

    Rosenzweig, M. R., Bennett, E. L., Herbert, M. & Morimoto, H. Social grouping cannot account for cerebral effects of enriched environments. Brain Res. 153, 563–576 (1978).

    CAS  Article  Google Scholar 

  16. 16

    Kempermann, G., Kuhn, H. G. & Gage, F. H. Experience-induced neurogenesis in the senescent dentate gyrus. J. Neurosci. 18, 3206– 3212 (1998).

    CAS  Article  Google Scholar 

  17. 17

    Kempermann, G., Brandon, E. P. & Gage, F. H. Environmental stimulation of 129/SvJ mice causes increased cell proliferation and neurogenesis in the adult dentate gyrus. Curr. Biol. 8, 939–942 (1998).

    CAS  Article  Google Scholar 

  18. 18

    Bennett, E. L., Rosenzweig, M. R., Morimoto, H. & Herbert, M. Maze training alters brain weights and cortical RNA/DNA ratios. Behav. Neural. Biol. 26, 1–22 (1979).

    CAS  Article  Google Scholar 

  19. 19

    Barnea, A. & Nottebohm, F. Seasonal recruitment of hippocampal neurons in adult free-ranging black-capped chickadees. Proc. Natl. Acad. Sci. USA 91, 11217–11221 (1994).

    CAS  Article  Google Scholar 

  20. 20

    Barnea, A. & Nottebohm, F. Recruitment and replacement of hippocampal neurons in young and adult chickadees: An addition to the theory of hippocampal learning. Proc. Natl. Acad. Sci. USA 93, 714–718 (1996).

    CAS  Article  Google Scholar 

  21. 21

    Patel S. H., Clayton, N. S. & Krebs, J. R. Spatial learning induces neurogenesis in the avian brain. Behav. Brain Res. 89, 115– 128 (1998).

    Article  Google Scholar 

  22. 22

    Johansson, B. B. & Ohlsson, A. Environment, social interaction and physical activity as determinants of functional outcome after cerebral activity in the rat. Exp. Neurol. 139, 322–327 (1997).

    Article  Google Scholar 

  23. 23

    Fordyce, D. E. & Wehner, J. M. Physical activity enhances spatial learning performance with an associated alteration in hippocampal protein kinase C activity in C57BL/6 and DBA/2 mice. Brain Res. 619, 111–119 ( 1993).

    CAS  Article  Google Scholar 

  24. 24

    Blomquist, K. B. & Danner F. Effect of physical conditioning on information-processing efficiency. Percept. Motor Skills 65, 175–186 ( 1987).

    CAS  Article  Google Scholar 

  25. 25

    Neeper, S. A., Gomez-Pinilla F., Choi, J. & Cotman, C. Exercise and brain neurotrophins. Nature 373, 109 (1995).

    CAS  Article  Google Scholar 

  26. 26

    Gensburger, C., Labourdette, G. & Sensenbrenner, M. Brain basic fibroblast growth fator stimulates the proliferation of rat neuronal precursor cells in vitro. FEBS Lett. 217, 1–5 (1987).

    CAS  Article  Google Scholar 

  27. 27

    Ray, J., Peterson, D. A., Schinstine, M. & Gage, F. H. Proliferation, differentiation, and long-term culture of primary hippocampal neurons. Proc. Natl. Acad. Sci. USA 90, 3602–3606 (1993).

    CAS  Article  Google Scholar 

  28. 28

    Tao, Y., Black, I. B. & DiCicco-Bloom, E. Neurogenesis in neonatal rat brain is regulated by peripheral injection of basic fibroblast growth factor (bFGF). J. Comp. Neurol. 376, 653–663 ( 1996).

    CAS  Article  Google Scholar 

  29. 29

    Kuhn, H. G, Winkler, J., Kempermann, G., Thal, L. J. & Gage, F. H. Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J. Neurosci. 17, 5820– 5829 (1997).

    CAS  Article  Google Scholar 

  30. 30

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

    CAS  Article  Google Scholar 

  31. 31

    Gomez-Pinilla, F., So, V. & Kesslak, J. P. Spatial learning and physical activity contribute to the induction of fibroblast growth factor: neural substrates for increased cognition associated with exercise. Neuroscience 85, 53–61 (1998).

    CAS  Article  Google Scholar 

  32. 32

    Mullen, R. J., Buck, C. R. & Smith, A. M. NeuN, a neuronal specific nuclear protein in vertebrates. Development 116, 201–211 (1992).

    CAS  PubMed  Google Scholar 

  33. 33

    Boyes, B. E., Kim, S. U., Lee, V. & Sung, S. C. Immunohistochemical colocalization of S100b and the glial fibrillary acidic protein in rat brain. Neuroscience 17, 857–865 (1986).

    CAS  Article  Google Scholar 

  34. 34

    Morris, R. G. M. Development of a water maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 11, 47– 60 (1984).

    CAS  Article  Google Scholar 

  35. 35

    Palmer, T., Takahashi, J. & Gage, F. H. The adult rat hippocampus contains primordial neural stem cells. Mol. Cell. Neurosci. 8, 389– 404 (1997).

    CAS  Article  Google Scholar 

  36. 36

    Park, G. A., Pappas, B. A., Murtha, S. M. & Ally, A. Enriched environment primes forebrain choline acetyltransfrease activity to respond to learning experience. Neurosci. Lett. 143 , 259–262 (1992).

    CAS  Article  Google Scholar 

  37. 37

    Dudar, J. D., Wishaw, I. Q. & Szerb, J. C. Release of acetylcholine from the hippocampus of freely moving rats during sensory stimulation and running. Neuropharmacology 18, 673–678 ( 1979).

    CAS  Article  Google Scholar 

  38. 38

    Falkenberg, T. et al. Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment. Neurosci. Lett. 138, 153– 156 (1992).

    CAS  Article  Google Scholar 

  39. 39

    Nowakowski, R. S., Lewin, S. B. & Miller, M. W. Bromodeoxyuridine immunohistochemical determination of the lengths of cell cycle and the DNA-synthetic phase for an anatomically defined population. J. Neurocytol. 18, 311 –318 (1989).

    CAS  Article  Google Scholar 

  40. 40

    Czurko, A., Hirase, H., Csicsvari, J. & Buzsáki, G. Sustained activation of hippocampal pyramidal cells by 'space clamping' in a running wheel. Eur. J. Neurosci. 11, 344 –352 (1999).

    CAS  Article  Google Scholar 

  41. 41

    Valentinuzzi, V. S., Scarbrough, K., Takahashi, J. S. & Turek, F. W. Effects of aging on the circadian rhythm of wheel-running activity in C57BL/6 mice. Am. J. Physiol. 273, R1957– 1964 (1997).

    CAS  Article  Google Scholar 

  42. 42

    Staubli, U. & Xu, F. B. Effects of 5-HT3 receptor antagonism on hippocampal theta rhythm, memory and LTP induction in the freely moving rat. J. Neurosci. 15, 2445– 2452 (1995).

    CAS  Article  Google Scholar 

  43. 43

    van Praag, H., Black, I. B. & Staubli, U. V. Neonatal vs. adult unilateral hippocampal lesions: differential alterations in contralateral hippocampal theta rhythm. Brain Res. 768, 233–241 (1997).

    CAS  Article  Google Scholar 

  44. 44

    Gould, E. & Cameron, H. A. Regulation of neuronal birth, migration and death in the rat dentate gyrus. Dev. Neurosci. 18, 22–35 (1996).

    CAS  Article  Google Scholar 

  45. 45

    Gould, E., Beylin A., Tanapat, P., Reeves, A. J. & Shors, T. J. Learning enhances adult neurogenesis in the hippocampal formation. Nat. Neurosci. 2, 260–265 (1999).

    CAS  Article  Google Scholar 

  46. 46

    Morris, R. G. M., Andersen, E., Lynch, G. S. & Baudry, M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate antagonist, APV. Nature 319 , 774–776 (1986).

    CAS  Article  Google Scholar 

  47. 47

    Cameron, H. A., McEwen, B. S. & Gould, E. Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J. Neurosci. 15, 4687–4692 ( 1995).

    CAS  Article  Google Scholar 

  48. 48

    Conrad, C. D. & Roy, E. J. Selective loss of hippocampal granule cells following adrenalectomy: implications for spatial memory. J. Neurosci. 13, 2582–2590 (1993).

    CAS  Article  Google Scholar 

  49. 49

    Gould, E., Cameron, H. A., Daniels, D. C., Wooley, C. S. & McEwen, B. S. Adrenal hormones suppress cell division in the adult rat dentate gyrus. J. Neurosci. 12, 3642–3650 (1992).

    CAS  Article  Google Scholar 

  50. 50

    Parent, J. M. et al. Dentate granule neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult hippocampus. J. Neurosci. 17, 3727–3738 (1997).

    CAS  Article  Google Scholar 

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Acknowledgements

We thank Eugene Brandon, Mary Lynn Gage, Uwe Konietzko, Marie-Claude Senut and Xinyu Zhao for comments on the manuscript, and Linda Kitabayashi for assisitance with photography and confocal imaging. We also thank Alice Smith, Tony Slimp and coworkers in the Salk Institute Animal Research Facility for their support of this study. This work was funded by NIA, NINDS, Pasarow Foundation, Hollfelder Foundation and APA.

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Correspondence to Fred H. Gage.

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van Praag, H., Kempermann, G. & Gage, F. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2, 266–270 (1999). https://doi.org/10.1038/6368

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