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Mechanisms of stress in the brain

Abstract

The brain is the central organ involved in perceiving and adapting to social and physical stressors via multiple interacting mediators, from the cell surface to the cytoskeleton to epigenetic regulation and nongenomic mechanisms. A key result of stress is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicates failed resilience. Excitatory amino acids and glucocorticoids have key roles in these processes, along with a growing list of extra- and intracellular mediators that includes endocannabinoids and brain-derived neurotrophic factor (BDNF). The result is a continually changing pattern of gene expression mediated by epigenetic mechanisms involving histone modifications and CpG methylation and hydroxymethylation as well as by the activity of retrotransposons that may alter genomic stability. Elucidation of the underlying mechanisms of plasticity and vulnerability of the brain provides a basis for understanding the efficacy of interventions for anxiety and depressive disorders as well as age-related cognitive decline.

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Figure 1: Effects of acute and chronic stress, mediated in part by glutamate and glucocorticoids as well as other molecules described in the text and in Box 1.
Figure 2: Gene expression changes in hippocampus in response to stress and glucocorticoid challenge depend on the prior stress history of the subject.
Figure 3: Molecular epigenetic modifications.
Figure 4: Glucocorticoids are released from the adrenal glands.

Marina Corral Spence/Nature Publishing Group

Figure 5: Biphasic effect of glucocorticoids (Cort) in regulating mitochondrial function.
Figure 6: Individual differences in naive C57Bl6 mice in anxiety-related behavior reveal animals more sensitive to stress-induced downregulation of hippocampal mGlu2 expression, a biomarker of depressive-like behavior and antidepressant response.
Figure 7: Mice cannot adjust to a 10 h light/10 h dark cycle, as indicated by body temperature and locomotor activity rhythms.

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Acknowledgements

The McEwen laboratory acknowledges research support from US National Institutes of Health (R01 MH41256), and the Hope for Depression Research Network and the American Foundation for Suicide Prevention to C.N. and National Research Service Award F32 MH102065 to J.D.G.

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Correspondence to Bruce S McEwen.

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McEwen, B., Bowles, N., Gray, J. et al. Mechanisms of stress in the brain. Nat Neurosci 18, 1353–1363 (2015). https://doi.org/10.1038/nn.4086

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