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Early life experience alters response of adult neurogenesis to stress

Nature Neuroscience volume 7, pages 841–846 (2004)Cite this article

Abstract

Maternal deprivation produces persistent abnormalities in behavioral and neuroendocrine functions associated with the hippocampus, a brain region that shows considerable structural change in response to experience throughout life. Here we show that adverse experience early in life affects the regulation of adult neurogenesis in the hippocampus. More specifically, a decrease in cell proliferation and immature neuron production are observed in the dentate gyrus of adult rats that are maternally separated as pups. Although maternally separated rats show normal basal levels of corticosterone, the suppression of cell proliferation in these rats can be reversed by lowering corticosterone below the control value. In addition, normal stress-induced suppression of cell proliferation and neurogenesis, despite normal activation of the hypothalamic pituitary adrenal (HPA) axis, is not observed in maternally separated rats. Our results suggest that early adverse experience inhibits structural plasticity via hypersensitivity to glucocorticoids and diminishes the ability of the hippocampus to respond to stress in adulthood.

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Figure 1: Suppression of baseline cell proliferation and immature neuron production by prolonged perinatal maternal deprivation.
Figure 2: Prolonged maternal separation results in a reduction in immature neurons in the dentate gyrus.
Figure 3: Reversal of suppressed baseline cell proliferation in maternally deprived rats by lowering corticosterone (Cort) in adulthood.
Figure 4: There is no significant stress-induced suppression of cell proliferation and neurogenesis in maternally deprived adult rats, despite normal activation of the HPA axis to fox odor.

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References

  1. Heim, C. & Nemeroff, C.B. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol. Psychiatry 49, 1023–1039 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Sanchez, M.M., Ladd, C.O. & Plotsky, P.M. Early adverse experience as a developmental risk factor for later psychopathology: evidence from rodent and primate models. Dev. Psychopathol. 13, 419–449 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Newport, D.J., Stowe, Z.N. & Nemeroff, C.B. Parental depression: animal models of an adverse life event. Am. J. Psychiatry 159, 1265–1283 (2002).

    Article  PubMed  Google Scholar 

  4. Levine, S. Influence of psychological variables on the activity of the hypothalamic-pituitary-adrenal axis. Eur. J. Pharmacol. 405, 149–160 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Huot, R.L., Plotsky, P.M., Lenox, R.H. & McNamara, R.K. Neonatal maternal separation reduces hippocampal mossy fiber density in adult Long Evans rats. Brain Res. 950, 52–63 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Sapolsky, R.M. & Meaney, M.J. Maturation of the adrenocortical stress response: neuroendocrine control mechanisms and the stress hyporesponsive period. Brain Res. 396, 64–76 (1986).

    Article  CAS  PubMed  Google Scholar 

  7. Plotsky, P.M. & Meaney, M.J. Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Brain Res. Mol. Brain Res. 18, 195–200 (1993).

    Article  CAS  PubMed  Google Scholar 

  8. Liu, D., Caldji, C., Sharma, S., Plotsky, P.M. & Meaney, M.J. Influence of neonatal rearing conditions on stress-induced adrenocorticotropin responses and norepinephrine release in the hypothalamic paraventricular nucleus. J. Neuroendocrinol. 12, 5–12 (2000).

    Article  PubMed  Google Scholar 

  9. Meaney, M.J., Aitken, D.H., Viau, V., Sharma, S. & Sarrieau, A. Neonatal handling alters adrenocortical negative feedback sensitivity and hippocampal type II glucocorticoid receptor binding in the rat. Neuroendocrinology 50, 597–604 (1989).

    Article  CAS  PubMed  Google Scholar 

  10. Viau, V., Sharma, S., Plotsky, P.M. & Meaney, M.J. Increased plasma ACTH responses to stress in nonhandled compared with handled rats require basal levels of corticosterone and are associated with increased levels of ACTH secretagogues in the median eminence. J. Neurosci. 13, 1097–1105 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Huot, R.L., Thrivikraman, K.V., Meaney, M.J. & Plotsky, P.M. Development of adult ethanol preference and anxiety as a consequence of neonatal maternal separation in Long Evans rats and reversal with antidepressant treatment. Psychopharmacology 158, 366–373 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Lovic, V., Gonzalez, A. & Fleming, A.S. Maternally separated rats show deficits in maternal care in adulthood. Dev. Psychobiol. 39, 19–33 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Magarinos, A.M., Somoza, G. & De Nicola, A.F. Glucocorticoid negative feedback and glucocorticoid receptors after hippocampectomy in rats. Horm. Metab. Res. 19, 105–109 (1987).

    Article  CAS  PubMed  Google Scholar 

  14. Sapolsky, R.M., Armanini, M.P., Sutton, S.W. & Plotsky, P.M. Elevation of hypophysial portal concentrations of adrenocorticotropin secretagogues after fornix transection. Endocrinology 125, 2881–2887 (1989).

    Article  CAS  PubMed  Google Scholar 

  15. Herman, J.P., Cullinan, W.E., Morano, M.I., Akil, H. & Watson, S.J. Contribution of the ventral subiculum to inhibitory regulation of the hypothalamo-pituitary-adrenocortical axis. J. Neuroendocrinol. 7, 475–482 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Deacon, R.M., Bannerman, D.M. & Rawlins, J.N. Anxiolytic effects of cytotoxic hippocampal lesions in rats. Behav. Neurosci. 116, 494–497 (2002).

    Article  PubMed  Google Scholar 

  17. Bannerman, D.M. et al. Double dissociation of function within the hippocampus: spatial memory and hyponeophagia. Behav. Neurosci. 116, 884–901 (2003).

    Article  Google Scholar 

  18. Riedel, G. et al. Reversible neural inactivation reveals hippocampal participation in several memory processes. Nat. Neurosci. 2, 898–905 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Gould, E. & Gross, C.G. Neurogenesis in adult mammals: some progress and problems. J. Neurosci. 22, 619–623 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cameron, H.A. & McKay, R.D. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J. Comp. Neurol. 435, 406–417 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. 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, 3642–2650 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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  PubMed  Google Scholar 

  24. Gould, E., McEwen, B.S., Tanapat, P., Galea, L.A. & Fuchs, E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J. Neurosci. 17, 2492–2498 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Malberg, J.E. & Duman, R.S. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 28, 1562–1571 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Viau, V., Sharma, S. & Meaney, M.J. Changes in plasma adrenocorticotropin, corticosterone, corticosteroid-binding globulin, and hippocampal glucocorticoid receptor occupancy/translocation in rat pups in response to stress. J. Neuroendocrinol. 8, 1–8 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Hastings, N.B. & Gould, E. Rapid extension of axons into the CA3 region by adult-generated granule cells. J. Comp. Neurol. 413, 146–154 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Snyder, J.S., Kee, N. & Wojtowicz, J.M. Effects of adult neurogenesis on synaptic plasticity in the rat dentate gyrus. J. Neurophysiol. 85, 2423–2431 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Wang, S., Scott, B.W. & Wojtowicz, J.M. Heterogenous properties of dentate granule neurons in the adult rat. J. Neurobiol. 42, 248–257 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Schmidt-Hieber, C., Jonas, P. & Bischofberger, J. Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 429, 184–187 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  34. Dobrossy, M.D. et al. Differential effects of learning on neurogenesis: learning increases or decreases the number of newly born cells depending on their birth date. Mol. Psychiatry 8, 974–982 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Shors, T.J., Townsend, D.A., Zhao, M., Kozorovitskiy, Y. & Gould, E. Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus 12, 578–584 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Madsen, T.M., Kristjansen, P.E., Bolwig, T.G. & Wortwein, G. Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat. Neuroscience 119, 635–642 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Sheline, Y.I. Hippocampal atrophy in major depression: a result of depression-induced neurotoxicity? Mol. Psychiatry 1, 298–299 (1996).

    CAS  PubMed  Google Scholar 

  38. Sheline, Y.I., Sanghavi, M., Mintun, M.A. & Gado, M.H. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J. Neurosci. 19, 5034–5043 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bremner, J.D. et al. Hippocampal volume reduction in major depression. Am. J. Psychiatry 158, 652–653 (2000).

    Google Scholar 

  40. Stein, M.B., Koverola, C., Hanna, C., Torchia, M.G. & McClarty, B. Hippocampal volume in women victimized by childhood sexual abuse. Psychol. Med. 27, 951–959 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Vythilingam, M. et al. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am. J. Psychiatry 159, 2072–2080 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Jans, J.E. & Woodside, B.C. Nest temperature: effects on maternal behavior, pup development, and interactions with handling. Dev. Psychobiol. 23, 519–534 (1990).

    Article  CAS  PubMed  Google Scholar 

  43. Gould, E., Woolley, C.S. & McEwen, B.S. Short-term glucocorticoid manipulations affect neuronal morphology and survival in the adult dentate gyrus. Neuroscience 37, 367–375 (1990).

    Article  CAS  PubMed  Google Scholar 

  44. Vernet-Maury, E., Polak, E.H. & Demael, A. Structure-activity relationship of stress-inducing odorants in the rat. J. Chem. Ecol. 10, 1007–1019 (1984).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank to D.L. Samburg, N.B. Hastings, P. Tanapat and Y. Kozorovitskiy for help with this manuscript. This work was supported by funding from the NIH (grant MH59740) and the Conte Center for the Neuroscience of Mental Disorders (MH58922).

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  1. Department of Psychology, Princeton University, Princeton, 08544, New Jersey, USA

    Christian Mirescu, Jennifer D Peters & Elizabeth Gould

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Correspondence to Elizabeth Gould.

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Mirescu, C., Peters, J. & Gould, E. Early life experience alters response of adult neurogenesis to stress. Nat Neurosci 7, 841–846 (2004). https://doi.org/10.1038/nn1290

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