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Adult hippocampal neurogenesis buffers stress responses and depressive behaviour

Nature volume 476, pages 458–461 (2011)Cite this article

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Abstract

Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness1,2. In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis3. Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking4,5. Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioural components of the stress response. Using either transgenic or radiation methods to inhibit adult neurogenesis specifically, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice than intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic–pituitary–adrenal (HPA) axis6,7. Relative to controls, neurogenesis-deficient mice also showed increased food avoidance in a novel environment after acute stress, increased behavioural despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness.

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Figure 1: GFAP-TK mice show specific inhibition of adult neurogenesis.
Figure 2: The glucocorticoid response to stress is increased in neurogenesis-deficient mice.
Figure 3: Increased stress response is not due to reduced neurogenesis in the subventricular zone.
Figure 4: Mice lacking neurogenesis show increased anxiety/depression-like behaviours.

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References

  1. Holsboer, F. & Ising, M. Stress hormone regulation: biological role and translation into therapy. Annu Rev. Psychol. 61, 81–109 (2010)

    Article  Google Scholar 

  2. McEwen, B. S. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol. Rev. 87, 873–904 (2007)

    Article  Google Scholar 

  3. Mirescu, C. & Gould, E. Stress and adult neurogenesis. Hippocampus 16, 233–238 (2006)

    Article  CAS  Google Scholar 

  4. Sapolsky, R. M. Is impaired neurogenesis relevant to the affective symptoms of depression? Biol. Psychiatry 56, 137–139 (2004)

    Article  Google Scholar 

  5. Drew, M. R. & Hen, R. Adult hippocampal neurogenesis as target for the treatment of depression. CNS Neurol. Disord. Drug Targets 6, 205–218 (2007)

    Article  CAS  Google Scholar 

  6. Roozendaal, B. et al. Memory retrieval impairment induced by hippocampal CA3 lesions is blocked by adrenocortical suppression. Nature Neurosci. 4, 1169–1171 (2001)

    Article  CAS  Google Scholar 

  7. Jankord, R. & Herman, J. P. Limbic regulation of hypothalamo-pituitary-adrenocortical function during acute and chronic stress. Ann. NY Acad. Sci. 1148, 64–73 (2008)

    Article  ADS  Google Scholar 

  8. Garcia, A. D., Doan, N. B., Imura, T., Bush, T. G. & Sofroniew, M. V. GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nature Neurosci. 7, 1233–1241 (2004)

    Article  CAS  Google Scholar 

  9. Seri, B., Garcia-Verdugo, J. M., McEwen, B. S. & Alvarez-Buylla, A. Astrocytes give rise to new neurons in the adult mammalian hippocampus. J. Neurosci. 21, 7153–7160 (2001)

    Article  CAS  Google Scholar 

  10. Borrelli, E., Heyman, R. A., Arias, C., Sawchenko, P. E. & Evans, R. M. Transgenic mice with inducible dwarfism. Nature 339, 538–541 (1989)

    Article  ADS  CAS  Google Scholar 

  11. Burns, K. A., Murphy, B., Danzer, S. C. & Kuan, C.-Y. Developmental and post-injury cortical gliogenesis: a genetic fate-mapping study with Nestin-CreER mice. Glia 57, 1115–1129 (2009)

    Article  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  13. Furay, A. R., Bruestle, A. E. & Herman, J. P. The role of the forebrain glucocorticoid receptor in acute and chronic stress. Endocrinology 149, 5482–5490 (2008)

    Article  CAS  Google Scholar 

  14. Wojtowicz, J. M. Irradiation as an experimental tool in studies of adult neurogenesis. Hippocampus 16, 261–266 (2006)

    Article  CAS  Google Scholar 

  15. Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716 (1999)

    Article  CAS  Google Scholar 

  16. Airan, R. D. et al. High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science 317, 819–823 (2007)

    Article  ADS  CAS  Google Scholar 

  17. Surget, A. et al. Antidepressants recruit new neurons to improve stress response regulation. Mol. Psychiatry 10.1038/mp.2011.48 (2011)

  18. David, D. J. et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62, 479–493 (2009)

    Article  CAS  Google Scholar 

  19. Anacker, C., Zunszain, P. A., Carvalho, L. A. & Pariante, C. M. The glucocorticoid receptor: pivot of depression and of antidepressant treatment? Psychoneuroendocrinology 36, 415–425 (2011)

    Article  CAS  Google Scholar 

  20. Ridder, S. et al. Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions. J. Neurosci. 25, 6243–6250 (2005)

    Article  CAS  Google Scholar 

  21. Castagné, V., Moser, P. & Porsolt, R. D. in Methods of Behavior Analysis in Neuroscience 2nd edn (ed. Buccafusco, J. J. ) Ch. 6 (CRC Press, 2009)

    Google Scholar 

  22. Revest, J.-M. et al. Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Mol. Psychiatry 14, 959–967 (2009)

    Article  Google Scholar 

  23. Treadway, M. T. & Zald, D. H. Reconsidering anhedonia in depression: lessons from translational neuroscience. Neurosci. Biobehav. Rev. 35, 537–555 (2011)

    Article  Google Scholar 

  24. Barkus, C. et al. Hippocampal NMDA receptors and anxiety: at the interface between cognition and emotion. Eur. J. Pharmacol. 626, 49–56 (2010)

    Article  CAS  Google Scholar 

  25. Duman, C. H. Models of depression. Vitam. Horm. 82, 1–21 (2010)

    Article  Google Scholar 

  26. Sandi, C. & Pinelo-Nava, M. T. Stress and memory: behavioral effects and neurobiological mechanisms. Neural Plast. 2007, 78970 (2007)

    Article  Google Scholar 

  27. Oomen, C. A. et al. Severe early life stress hampers spatial learning and neurogenesis, but improves hippocampal synaptic plasticity and emotional learning under high-stress conditions in adulthood. J. Neurosci. 30, 6635–6645 (2010)

    Article  CAS  Google Scholar 

  28. Delaney, C. L., Brenner, M. & Messing, A. Conditional ablation of cerebellar astrocytes in postnatal transgenic mice. J. Neurosci. 16, 6908–6918 (1996)

    Article  CAS  Google Scholar 

  29. Snyder, J. et al. Adult-born hippocampal neurons are more numerous, faster maturing, and more involved in behavior in rats than in mice. J. Neurosci. 29, 14484–14495 (2009)

    Article  CAS  Google Scholar 

  30. Brown, T. S. & Murphy, H. M. Factors affecting sucrose preference behavior in rats with hippocampal lesions. Physiol. Behav. 11, 833–844 (1973)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank A. Sowers and J. Mitchell for help with irradiation, M. Brenner for providing the plasmid construct, GlaxoSmithKline for providing the antibody against HSV-TK, and K. Sanzone, F. Kamhi, L. Glover, S. Ferrante and L. Grigereit for assisting with mouse breeding and treatment. This research was supported by the Intramural Program of the National Institute of Mental Health, National Institutes of Health, USA, ZIA MH002784 (to H.A.C.).

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  1. National Institute of Mental Health, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Jason S. Snyder, Amélie Soumier, Michelle Brewer, James Pickel & Heather A. Cameron

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  1. Jason S. Snyder
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  2. Amélie Soumier
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  3. Michelle Brewer
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  5. Heather A. Cameron
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Contributions

J.S.S. performed histological, endocrine and behavioural experiments, analysed data and wrote the paper; A.S. performed behavioural experiments and analysed behavioural data; H.A.C. performed endocrine experiments, analysed data and wrote the paper; J.P. and M.B. generated the transgenic mice.

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Correspondence to Heather A. Cameron.

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The authors declare no competing financial interests.

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Snyder, J., Soumier, A., Brewer, M. et al. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476, 458–461 (2011). https://doi.org/10.1038/nature10287

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