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The cortisol switch between vulnerability and resilience

Molecular Psychiatry (2023)Cite this article

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Abstract

In concert with neuropeptides and transmitters, the end products of the hypothalamus-pituitary-adrenal (HPA) axis, the glucocorticoid hormones cortisol and corticosterone (CORT), promote resilience: i.e., the ability to cope with threats, adversity, and trauma. To exert this protective action, CORT activates mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) that operate in a complementary manner -as an on/off switch- to coordinate circadian events, stress-coping, and adaptation. The evolutionary older limbic MR facilitates contextual memory retrieval and supports an on-switch in the selection of stress-coping styles at a low cost. The rise in circulating CORT concentration after stress subsequently activates a GR-mediated off-switch underlying recovery of homeostasis by providing the energy for restraining the primary stress reactions and promoting cognitive control over emotional reactivity. GR activation facilitates contextual memory storage of the experience to enable future stress-coping. Such complementary MR-GR-mediated actions involve rapid non-genomic and slower gene-mediated mechanisms; they are time-dependent, conditional, and sexually dimorphic, and depend on genetic background and prior experience. If coping fails, GR activation impairs cognitive control and promotes emotional arousal which eventually may compromise resilience. Such breakdown of resilience involves a transition to a chronic stress construct, where information processing is crashed; it leads to an imbalanced MR-GR switch and hence increased vulnerability. Novel MR-GR modulators are becoming available that may reset a dysregulated stress response system to reinstate the cognitive flexibility required for resilience.

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Fig. 1: CORT action.
Fig. 2: Stress: from perception to adaptation.
Fig. 3: CORT and the stress response.

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Acknowledgements

MJ is supported by the Consortium on Individual Development (CID), which is funded through the Gravitation program of the Dutch Ministry of Education, Culture, and Science and Netherlands Organization for Scientific Research (project #024.001.003).

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Authors and Affiliations

  1. Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden University, Leiden, The Netherlands

    E. Ronald de Kloet

  2. Leiden/Amsterdam Center of Drug Research, Leiden University, Leiden, The Netherlands

    E. Ronald de Kloet

  3. Dept. Translational Neuroscience, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

    Marian Joëls

  4. University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Marian Joëls

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  1. E. Ronald de Kloet
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ERdK and MJ contributed equally to conceptualizing and writing the manuscript.

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Correspondence to E. Ronald de Kloet.

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ERdK owns stock of Corcept Therapeutics. MJ declares no conflict of interest.

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de Kloet, E.R., Joëls, M. The cortisol switch between vulnerability and resilience. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-022-01934-8

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