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Cited by 2,614Stress Responses and CortisolNeuroscience and Neuropharmacology ResearchEstrogen and related hormone effects

Brain corticosteroid receptor balance in health and disease

de Kloet, E. Ronald, Vreugdenhil, Erno, Oitzl, Melly S., Joëls, Marian·1998·Endocrine Reviews
DOI 10.1210/edrv.19.3.0331
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Abstract

In this review, we have described the function of MR and GR in hippocampal neurons. The balance in actions mediated by the two corticosteroid receptor types in these neurons appears critical for neuronal excitability, stress responsiveness, and behavioral adaptation. Dysregulation of this MR/GR balance brings neurons in a vulnerable state with consequences for regulation of the stress response and enhanced vulnerability to disease in genetically predisposed individuals. The following specific inferences can be made on the basis of the currently available facts. 1. Corticosterone binds with high affinity to MRs predominantly localized in limbic brain (hippocampus) and with a 10-fold lower affinity to GRs that are widely distributed in brain. MRs are close to saturated with low basal concentrations of corticosterone, while high corticosterone concentrations during stress occupy both MRs and GRs. 2. The neuronal effects of corticosterone, mediated by MRs and GRs, are long-lasting, site-specific, and conditional. The action depends on cellular context, which is in part determined by other signals that can activate their own transcription factors interacting with MR and GR. These interactions provide an impressive diversity and complexity to corticosteroid modulation of gene expression. 3. Conditions of predominant MR activation, i.e., at the circadian trough at rest, are associated with the maintenance of excitability so that steady excitatory inputs to the hippocampal CA1 area result in considerable excitatory hippocampal output. By contrast, additional GR activation, e.g., after acute stress, generally depresses the CA1 hippocampal output. A similar effect is seen after adrenalectomy, indicating a U-shaped dose-response dependency of these cellular responses after the exposure to corticosterone. 4. Corticosterone through GR blocks the stress-induced HPA activation in hypothalamic CRH neurons and modulates the activity of the excitatory and inhibitory neural inputs to these neurons. Limbic (e.g., hippocampal) MRs mediate the effect of corticosterone on the maintenance of basal HPA activity and are of relevance for the sensitivity or threshold of the central stress response system. How this control occurs is not known, but it probably involves a steady excitatory hippocampal output, which regulates a GABA-ergic inhibitory tone on PVN neurons. Colocalized hippocampal GRs mediate a counteracting (i.e., disinhibitory) influence. Through GRs in ascending aminergic pathways, corticosterone potentiates the effect of stressors and arousal on HPA activation. The functional interaction between these corticosteroid-responsive inputs at the level of the PVN is probably the key to understanding HPA dysregulation associated with stress-related brain disorders. 5. Fine-tuning of HPA regulation occurs through MR- and GR-mediated effects on the processing of information in higher brain structures. Under healthy conditions, hippocampal MRs are involved in processes underlying integration of sensory information, interpretation of environmental information, and execution of appropriate behavioral reactions. Activation of hippocampal GRs facilitates storage of information and promotes elimination of inadequate behavioral responses. These behavioral effects mediated by MR and GR are linked, but how they influence endocrine regulation is not well understood. 6. Dexamethasone preferentially targets the pituitary in the blockade of stress-induced HPA activation. The brain penetration of this synthetic glucocorticoid is hampered by the mdr1a P-glycoprotein in the blood-brain barrier. Administration of moderate amounts of dexamethasone partially depletes the brain of corticosterone, and this has destabilizing consequences for excitability and information processing. 7. The set points of HPA regulation and MR/GR balance are genetically programmed, but can be reset by early life experiences involving mother-infant interaction. 8. (ABSTRACT TRUNCATED)

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Crossref · 10.1210/edrv.19.3.0331

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  • GRs are highly expressed in the hippocampus and in hypophysiotropic PVN neurons.

    “While GRs are ubiquitously expressed throughout the brain, they are highly expressed in the hippocampus (De Kloet, Vreugdenhil, Oitzl, & Joels, 1998) and hypophysiotropic neurons of the PVN (Kovacs, Foldes, & Sawchenko, 2000; Sawchenko, 1987), two brain regions key to negative feedback.”

    From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as De Kloet, Vreugdenhil, Oitzl, & Joels, 1998

    In “Corticosteroid receptor diversity in brain and pituitary” (page unavailable), the review says GRs are present in hippocampal dentate gyrus neurons and CA1 cells and are widely distributed in the brain. It does not establish that hippocampal GR expression is particularly high. The PVN-neuron clause is attributed to different citations in the citing sentence, not to this paper. (LLM, conf=0.82)

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  • Low cortisol concentrations during SWS-rich sleep benefit declarative memory consolidation by preventing activation of glucocorticoid receptors that inhibit hippocampal LTP and CA1 output.

    “Low cortisol concentrations during SWS-rich sleep benefit declarative memory consolidation by preventing activation of glucocorticoid receptors that mediate an inhibitory influence on hippocampal LTP and output from CA1 (648, 649, 666).”

    From About Sleep's Role in Memory (2013) · cites this paper as [649]

    The Summary and “Amino acid transmission” section report that additional glucocorticoid-receptor activation reduces CA1 hippocampal output and that synaptic potentiation is less effective at elevated corticosterone levels. The paper does not establish that low cortisol during SWS-rich sleep benefits declarative memory consolidation through this mechanism; its discussion of memory emphasizes that corticosteroid effects depend on dose and timing. Page numbers were not available in our copy. (LLM, conf=0.87)

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  • MRs have a much higher affinity for CORT (Kd = 0.5 nM) than GRs (Kd = 5.0 nM).

    “Mineralocorticoid receptors have a much higher affinity (Kd = 0.5 nM) for CORT than do GRs (Kd =5.0 nM) (De Kloet, Veldhuis, Wagenaars, & Bergink, 1984; De Kloet, Vreugdenhil, Oitzl, & Joels, 1998)”

    From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as De Kloet, Vreugdenhil, Oitzl, & Joels, 1998

  • 11β-HSD type 1 generates bioactive glucocorticoids from inactive 11-keto derivatives while type 2 catalyzes the opposite reaction; type 1 is widely expressed by neurons and glial cells, whereas type 2 expression is more restricted.

    “Briefly, 11β-HSD type 1 generates the bioactive form (cortisol or corticosterone) from inactive 11-keto derivatives while 11β-HSD type 2 catalyzes the opposite reaction. Interestingly, 11-keto derivatives do not bind to CBG in plasma nor are expelled by the efflux pumps of the BBB. As a result, 11-keto-GCs reach the CNS more readily than the bioactive form. 11β-HSD type 1 is widely expressed by”

    From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [66]

  • Cortisol has 10-fold greater binding affinity for the mineralocorticoid receptor than the glucocorticoid receptor, so mineralocorticoid receptors are heavily bound by basal/low glucocorticoid levels while substantial glucocorticoid receptor ligation occurs only upon stress or the highest ultradian peaks.

    “The binding affinity of cortisol is however 10-fold greater for the MR than the GR (66). MRs are thus heavily bound by basal/low levels of GCs while substantial ligation of GRs only occurs upon stress or when the highest ultraradian peaks are reached.”

    From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [66]

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Research works printed but not linked: 1

  1. Sutanto W, De Kloet ER 1993 The role of GABA in the regulation of the stress response. In: Stanford CS, Salmon P (eds) Stress: From Synapse to Syndrome. Academic Press, New York, pp 333-354 253.

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Authors
de Kloet, E. R., Vreugdenhil, E., Oitzl, M. S., & Joëls, M.
Affiliations
  • Division of Medical Pharmacology (E.R.D.K., E.V., M.S.O.), Leiden/Amsterdam Center for Drug Research, University of Leiden, 2300 RA Leiden, The Netherlands;
  • Leiden University (NL)
  • Institute for Neurobiology (M.J.), University of Amsterdam, 1098 SM Amsterdam, The Netherlands
ORCID
Venue
Endocrine Reviews
Publisher
The Endocrine Society
Published
1998-06-01
Volume
19
Issue
3
Pages
269-301
ISSN
  • 0163-769X (ISSN-L)
  • 1945-7189
DOI
10.1210/edrv.19.3.0331
OpenAlex
W2171238991
Cited by
2,614
References
434
Citations by year
2026: 11 · 2025: 38 · 2024: 53 · 2023: 60 · 2022: 69 · 2021: 74 · 2020: 78 · 2019: 70 · 2018: 60 · 2017: 90 · 2016: 86 · 2015: 99 · 2014: 139 · 2013: 128 · 2012: 132
FWCI
8.12
Type
journal article
Language
en
Open access
closed
Locations
  • Endocrine Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • UvA-DARE (University of Amsterdam) (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • European Commission (BRST960179)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek
  • Internationale Stichting Alzheimer Onderzoek
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
mineralocorticoid receptor, glucocorticoid receptor, corticosterone, hippocampal neurons, neuronal excitability, stress response, hypothalamic-pituitary-adrenal axis, paraventricular nucleus, GABAergic inhibition, adrenalectomy, circadian rhythm, gene expression regulation, neuroendocrine adaptation, limbic system
MeSH terms
Adrenal Cortex Hormones, Aging, Brain, Brain Diseases, Health, Humans, Receptors, Steroid, Stress, Physiological

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