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Articles, Behavioral/Cognitive

Glucocorticoids Orchestrate Divergent Effects on Mood through Adult Neurogenesis

Michael L. Lehmann, Rebecca A. Brachman, Keri Martinowich, Robert J. Schloesser and Miles Herkenham
Journal of Neuroscience 13 February 2013, 33 (7) 2961-2972; DOI: https://doi.org/10.1523/JNEUROSCI.3878-12.2013
Michael L. Lehmann
1Section on Functional Neuroanatomy, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-3724, and
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Rebecca A. Brachman
1Section on Functional Neuroanatomy, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-3724, and
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Keri Martinowich
2Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892
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Robert J. Schloesser
2Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892
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Miles Herkenham
1Section on Functional Neuroanatomy, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-3724, and
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Abstract

Both social defeat stress and environmental enrichment stimulate adrenal glucocorticoid secretion, but they have opposing effects on hippocampal neurogenesis and mood. Hypothalamic-pituitary-adrenal axis dysregulation and decreased neurogenesis are consequences of social defeat. These outcomes are correlated with depressive states, but a causal role in the etiology of depression remains elusive. The antidepressant actions of environmental enrichment are neurogenesis-dependent, but the contribution of enrichment-elevated glucocorticoids is unexplored. Importantly, for both social defeat and environmental enrichment, how glucocorticoids interact with neurogenesis to alter mood is unknown. Here, we investigate causal roles of glucocorticoids and neurogenesis in induction of depressive-like behavior and its amelioration by environmental enrichment in mice. By blocking neurogenesis and surgically clamping adrenal hormone secretions, we showed that neurogenesis, via hypothalamic-pituitary-adrenal axis interactions, is directly involved in precipitating the depressive phenotype after social defeat. Mice adrenalectomized before social defeat showed enhanced behavioral resiliency and increased survival of adult-born hippocampal neurons compared with sham-operated defeated mice. However, mice lacking hippocampal neurogenesis did not show protective effects of adrenalectomy. Moreover, glucocorticoids secreted during environmental enrichment promoted neurogenesis and were required for restoration of normal behavior after social defeat. The data demonstrate that glucocorticoid-dependent declines in neurogenesis drive changes in mood after social defeat and that glucocorticoids secreted during enrichment promote neurogenesis and restore normal behavior after defeat. These data provide new evidence for direct involvement of neurogenesis in the etiology of depression, suggesting that treatments promoting neurogenesis can enhance stress resilience.

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The Journal of Neuroscience: 33 (7)
Journal of Neuroscience
Vol. 33, Issue 7
13 Feb 2013
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Glucocorticoids Orchestrate Divergent Effects on Mood through Adult Neurogenesis
Michael L. Lehmann, Rebecca A. Brachman, Keri Martinowich, Robert J. Schloesser, Miles Herkenham
Journal of Neuroscience 13 February 2013, 33 (7) 2961-2972; DOI: 10.1523/JNEUROSCI.3878-12.2013

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Glucocorticoids Orchestrate Divergent Effects on Mood through Adult Neurogenesis
Michael L. Lehmann, Rebecca A. Brachman, Keri Martinowich, Robert J. Schloesser, Miles Herkenham
Journal of Neuroscience 13 February 2013, 33 (7) 2961-2972; DOI: 10.1523/JNEUROSCI.3878-12.2013
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