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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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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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  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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