Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Social isolation delays the positive effects of running on adult neurogenesis

Nature Neuroscience volume 9, pages 526–533 (2006)Cite this article

Abstract

Social isolation can exacerbate the negative consequences of stress and increase the risk of developing psychopathology. However, the influence of living alone on experiences generally considered to be beneficial to the brain, such as physical exercise, remains unknown. We report here that individual housing precludes the positive influence of short-term running on adult neurogenesis in the hippocampus of rats and, in the presence of additional stress, suppresses the generation of new neurons. Individual housing also influenced corticosterone levels—runners in both housing conditions had elevated corticosterone during the active phase, but individually housed runners had higher levels of this hormone in response to stress. Moreover, lowering corticosterone levels converted the influence of short-term running on neurogenesis in individually housed rats from negative to positive. These results suggest that, in the absence of social interaction, a normally beneficial experience can exert a potentially deleterious influence on the brain.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Social isolation reverses the positive influence of short-term running on adult neurogenesis.
Figure 2: Social context mediates the running effect on cell proliferation; newly generated cells express neuronal, glial and endothelial markers.
Figure 3: Glucocorticoid levels are altered by running and social housing.
Figure 4: Lowering glucocorticoid levels reverses the suppression of neurogenesis in isolated runners.
Figure 5: A long duration of physical activity enhances cell proliferation in the dentate gyrus of socially isolated rats.
Figure 6: Daily stress interacts with running and social housing to alter cell proliferation.
Figure 7: The duration of previous isolation affects the response of cell proliferation to running alone.

References

  1. Selye, H. The Stress of Life. (McGraw-Hill, New York, 1976).

    Google Scholar 

  2. Roy, M.P., Steptoe, A. & Kirschbaum, C. Life events and social support as moderators of individual differences in cardiovascular and cortisol reactivity. J. Pers. Soc. Psychol. 75, 1273–1281 (1998).

    Article  CAS  Google Scholar 

  3. Weiss, J.M. Effects of coping behavior with and without a feedback signal on stress pathology in rats. J. Comp. Physiol. Psychol. 77, 22–30 (1971).

    Article  CAS  Google Scholar 

  4. Amat, J. et al. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat. Neurosci. 8, 365–371 (2005).

    Article  CAS  Google Scholar 

  5. Weiss, I.C., Pryce, C.R., Jongen-Relo, A.L., Nanz-Bah, N.I. & Feldon, J. Effect of social isolation on stress-related behavioral and neuroendocrine state in the rat. Behav. Brain. Res 152, 279–295 (2004).

    Article  CAS  Google Scholar 

  6. Bartolomucci, A. et al. Individual housing induces altered immuno-endocrine responses to psychological stress in male mice. Psychoneuroendocrinology 28, 540–558 (2003).

    Article  CAS  Google Scholar 

  7. Ruis, M.A. et al. Housing familiar male wildtype rats together reduces the long-term adverse behavioral and physiological effects of social defeat. Psychoneuroendocrinology 24, 285–300 (1999).

    Article  CAS  Google Scholar 

  8. Seeman, T.E. & McEwen, B.S. Impact of social environment characteristics on neuroendocrine regulation. Psychosom. Med. 58, 459–471 (1996).

    Article  CAS  Google Scholar 

  9. McEwen, B.S. Allostasis and allostatic load: implications for neuropsychopharmacology. Neuropsychopharmacology 22, 108–124 (2000).

    Article  CAS  Google Scholar 

  10. Droste, S.K. et al. Effects of long-term voluntary exercise on the mouse hypothalamic-pituitary-adrenocortical axis. Endocrinology 144, 3012–3023 (2003).

    Article  CAS  Google Scholar 

  11. Neeper, S.A., Gomez-Pinilla, F., Choi, J. & Cotman, C.W. Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Res. 726, 49–56 (1996).

    Article  CAS  Google Scholar 

  12. Farmer, J., Zhao, X., Gage, F.H. & Chistie, B.R. 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 (2004).

    Article  CAS  Google Scholar 

  13. van Praag, H., Chistie, B.R., Sejnowski, T.J. & Gage, F.H. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl. Acad. Sci. USA 96, 13427–13431 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Fabel, K., Fabel, K. & Palmer, T.D. VEGF is necessary for exercise-induced neurogenesis. Eur. J. Neurosci. 18, 2803–2812 (2003).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Cameron, H.A. & Gould, E. Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience 61, 203–209 (1994).

    Article  CAS  Google Scholar 

  18. Tanapat, P., Hastings, N.B., Rydel, T.A., Galea, L.A. & Gould, E. Exposure to fox odor inhibits cell proliferation in the hippocampus of adult rats via an adrenal hormone-dependent mechanism. J. Comp. Neurol. 437, 496–504 (2001).

    Article  CAS  Google Scholar 

  19. Montaron, M.F. et al. Lifelong corticosterone level determines age-related decline in neurogenesis and memory. Neurobiol. Aging published online June 13 2005 (doi: 10.1016/j.neurobiolaging.2005.02.014).

  20. Cameron, H.A. & McKay, R.D. Restoring production of hippocampal neurons in old age. Nat. Neurosci. 2, 894–897 (1999).

    Article  CAS  Google Scholar 

  21. Ambrogini, P. et al. Persistently high corticosterone levels but not normal circadian fluctuations of the hormone affect cell proliferation in the adult rat dentate gyrus. Neuroendocrinology 76, 366–372 (2002).

    Article  CAS  Google Scholar 

  22. Allen, D.L. et al. Cardiac and skeletal muscle adaptations to voluntary wheel running in the mouse. J. Appl. Physiol. 90, 1900–1908 (2001).

    Article  CAS  Google Scholar 

  23. Cassano, W.J. Jr . & D'mello, A.P. Acute stress-induced facilitation of the hypothalamic-pituitary-adrenal axis: evidence for the roles of stressor duration and serotonin. Neuroendocrinology 74, 167–177 (2001).

    Article  CAS  Google Scholar 

  24. Banasr, M., Hery, M., Printemps, R. & Daszuta, A. Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated though different and common 5HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology 29, 450–460 (2004).

    Article  CAS  Google Scholar 

  25. Gomez-Merino, D., Bequet, F., Berthelot, M., Chennaoui, M. & Guezennec, C.Y. Site-dependent effects of an acute intensive exercise on extracellular 5-HT and 5-HIAA levels in rat brain. Neurosci. Lett. 301, 143–146 (2001).

    Article  CAS  Google Scholar 

  26. Schiller, L., Jahkel, M., Kretzschmar, M., Brust, P. & Oehler, J. Autoradiographic analyses of 5HT1A and 5HT2A receptors after social isolation in mice. Brain Res. 980, 169–178 (2003).

    Article  CAS  Google Scholar 

  27. Chalmers, D.T., Kwak, S.P., Mansour, A., Akil, H. & Watson, S.J. Corticosteroids regulate brain hippocampal 5HT1A receptor mRNA expression. J. Neurosci. 13, 914–923 (1993).

    Article  CAS  Google Scholar 

  28. Palmer, T.D., Willhoite, A.R. & Gage, F.H. Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479–494 (2000).

    Article  CAS  Google Scholar 

  29. Leventhal, C., Rafii, S., Rafii, D., Shahar, A. & Goldman, S.A. Endothelial trophic support of neuronal production and recruitment from the adult mammalian subependyma. Mol. Cell. Neurosci. 13, 450–464 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  31. Westenbroek, C., Den Boer, J.A., Veenhuis, M. & Ter Horst, G. Chronic stress and social housing differentially affect neurogenesis in male and female rats. Brain Res. Bull. 64, 303–308 (2004).

    Article  Google Scholar 

  32. Brown, J. et al. Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur. J. Neurosci. 17, 2042–2046 (2003).

    Article  Google Scholar 

  33. Trejo, J.L., Carro, E. & Torres-Aleman, I. Circulating IGF-1 mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J. Neurosci. 21, 1628–1634 (2001).

    Article  CAS  Google Scholar 

  34. Kim, Y.-P. et al. Age-dependence of the effect of treadmill exercise on cell proliferation in the dentate gyrus of rats. Neurosci. Lett. 355, 152–154 (2004).

    Article  CAS  Google Scholar 

  35. Rhodes, J.S., van Praag, H., Garland, T. & Gage, F.H. Exercise increases hippocampal neurogenesis to high levels but does not improve spatial learning in mice bred for increased voluntary wheel-running. Behav. Neurosci. 117, 1006–1016 (2003).

    Article  Google Scholar 

  36. Holmes, M.M., Galea, L.A., Mistlberger, R.E. & Kempermann, G. Adult hippocampal neurogenesis and voluntary running activity: circadian and dose-dependent effects. J. Neurosci. Res. 76, 216–222 (2004).

    Article  CAS  Google Scholar 

  37. Bjornebekk, A., Mathe, A.A. & Brene, S. The antidepressant effect of running is associated with increased hippocampal cell proliferation. Int. J. Neuropsychopharmacol. 8, 357–368 (2005).

    Article  CAS  Google Scholar 

  38. Persson, A.I. et al. Differential regulation of hippocampal cell proliferation by opioid receptor antagonists in running and non-running spontaneously hypertensive rats. Eur. J. Neurosci. 19, 1847–1855 (2004).

    Article  Google Scholar 

  39. Naylor, A.S., Persson, A.I., Erikkson, P.S., Jonsdottir, I.H. & Thorlin, T. Extended voluntary running inhibits exercise induced adult hippocampal progenitor proliferation in the spontaneously hypertensive rat. J. Neurophysiol. 93, 2406–2414 (2004).

    Article  Google Scholar 

  40. Tanapat, P., Hastings, N.B., Reeves, A.J. & Gould, E. Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. J. Neurosci. 19, 5792–5801 (1999).

    Article  CAS  Google Scholar 

  41. Perfilieva, E., Risedal, A., Nyberg, J., Johansson, B.B. & Eriksson, P.S. Gender and strain influence on neurogenesis in dentate gyrus of young rats. J. Cereb. Blood Flow Metab. 21, 211–217 (2001).

    Article  CAS  Google Scholar 

  42. Eadie, B.D., Redila, V.A. & Chistie, B.R. Voluntary exercise alters the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dendritic complexity, and spine density. J. Comp. Neurol. 486, 39–47 (2005).

    Article  Google Scholar 

  43. Iversen, I.H. Techniques for establishing schedules with wheel running as reinforcement in rats. J. Exp. Anal. Behav. 60, 219–238 (1993).

    Article  CAS  Google Scholar 

  44. Hoffmann, P., Thorén, P. & Ely, D. Effect of voluntary exercise on open-field behavior and on aggression in the spontaneously hypertensive rat (SHR). Behav. Neural Biol. 47, 346–355 (1987).

    Article  CAS  Google Scholar 

  45. Widenfalk, J., Olson, L. & Thoren, P. Deprived of habitual running, rats downregulate BDNF and TrkB messages in the brain. Neurosci. Res. 34, 125–132 (1999).

    Article  CAS  Google Scholar 

  46. Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).

    Article  CAS  Google Scholar 

  47. Malberg, J.E., Eisch, A.J., Nestler, E.J. & Duman, R.S. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20, 9104–9110 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the assistance of C. Gross, Y. Kozorovitskiy, B. Leuner and C. Mirescu in the preparation of this manuscript. This work was supported by a National Research Service Award predoctoral fellowship to A.S. and a National Institutes of Mental Health grant to E.G.

Author information

Authors and Affiliations

  1. Department of Psychology, Princeton University, Princeton, 08544, NJ

    Alexis M Stranahan, David Khalil & Elizabeth Gould

Authors
  1. Alexis M Stranahan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Khalil
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elizabeth Gould
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elizabeth Gould.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Differences in the amount of running do not explain differences in neurogenesis across housing conditions or glucocorticoid status. (PDF 18 kb)

Supplementary Fig. 2

The volume of the dentate gyrus increases with prolonged physical activity. (PDF 64 kb)

Supplementary Fig. 3

The increase in neurogenesis with short-term running in group-housed animals is sustained over longer periods of activity. (PDF 106 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Stranahan, A., Khalil, D. & Gould, E. Social isolation delays the positive effects of running on adult neurogenesis. Nat Neurosci 9, 526–533 (2006). https://doi.org/10.1038/nn1668

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1668

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing