Article | Published:

Social isolation delays the positive effects of running on adult neurogenesis

Nature Neurosciencevolume 9pages526533 (2006) | Download Citation



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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

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

  2. 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).

  3. 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).

  4. 4

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

  5. 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).

  6. 6

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

  7. 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).

  8. 8

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

  9. 9

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

  10. 10

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

  11. 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).

  12. 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).

  13. 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).

  14. 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).

  15. 15

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

  16. 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).

  17. 17

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

  18. 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).

  19. 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. 20

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

  21. 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).

  22. 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).

  23. 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).

  24. 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).

  25. 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).

  26. 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).

  27. 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).

  28. 28

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

  29. 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).

  30. 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).

  31. 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).

  32. 32

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

  33. 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).

  34. 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).

  35. 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).

  36. 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).

  37. 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).

  38. 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).

  39. 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).

  40. 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).

  41. 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).

  42. 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).

  43. 43

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

  44. 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).

  45. 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).

  46. 46

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

  47. 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).

Download references


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


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

    • Alexis M Stranahan
    • , David Khalil
    •  & Elizabeth Gould


  1. Search for Alexis M Stranahan in:

  2. Search for David Khalil in:

  3. Search for Elizabeth Gould in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Elizabeth Gould.

Supplementary information

  1. Supplementary Fig. 1

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

  2. Supplementary Fig. 2

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

  3. 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)

About this article

Publication history




Issue Date


Further reading