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Cited by 425Stress Responses and CortisolMemory and Neural MechanismsNeuroscience and Neuropharmacology Research

Chronic Stress-induced Hippocampal Vulnerability: The Glucocorticoid Vulnerability Hypothesis

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Conrad, Cheryl D.·2008·Reviews in the Neurosciences
DOI 10.1515/revneuro.2008.19.6.395PMC PMC2746750
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Abstract

The hippocampus, a limbic structure important in learning and memory, is particularly sensitive to chronic stress and to glucocorticoids. While glucocorticoids are essential for an effective stress response, their oversecretion was originally hypothesized to contribute to age-related hippocampal degeneration. However, conflicting findings were reported on whether prolonged exposure to elevated glucocorticoids endangered the hippocampus and whether the primate hippocampus even responded to glucocorticoids as the rodent hippocampus did. This review discusses the seemingly inconsistent findings about the effects of elevated and prolonged glucocorticoids on hippocampal health and proposes that a chronic stress history, which includes repeated elevation of glucocorticoids, may make the hippocampus vulnerable to potential injury. Studies are described to show that chronic stress or prolonged exposure to glucocorticoids can compromise the hippocampus by producing dendritic retraction, a reversible form of plasticity that includes dendritic restructuring without irreversible cell death. Conditions that produce dendritic retraction are hypothesized to make the hippocampus vulnerable to neurotoxic or metabolic challenges. Of particular interest is the finding that the hippocampus can recover from dendritic retraction without any noticeable cell loss. When conditions surrounding dendritic retraction are present, the potential for harm is increased because dendritic retraction may persist for weeks, months or even years, thereby broadening the window of time during which the hippocampus is vulnerable to harm, called the 'glucocorticoid vulnerability hypothesis'. The relevance of these findings is discussed with regard to conditions exhibiting parallels in hippocampal plasticity, including Cushing's disease, major depressive disorder (MDD), and post-traumatic stress disorder (PTSD).

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  • Prolonged exposure to stressful conditions and increased levels of glucocorticoids (or increased sensitivity to glucocorticoids) result in hippocampal damage, including reduction in the number of dendrites, loss of dendritic spines, and damages in neurogenesis.

    “Prolonged exposure to stressful conditions and increased level of glucocorticoids (or increased sensitivity to glucocorticoids) result in hippocampal damage (reduction in the number of dendrites, loss of dendritic spines and damages in neurogenesis) (Conrad, 2008).”

    From Neuroimaging research in posttraumatic stress disorder – Focus on amygdala, hippocampus and prefrontal cortex (2019) · cites this paper as Conrad, 2008

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  • Chronic or severe stress can cause excessive glucocorticoid production, which may harm hippocampal neurons and make the organism more susceptible to neurodegeneration, potentially breaking the regulatory circuit between hippocampus and hypothalamus.

    “However, excessive glucocorticoid production associated with chronic or severe stress may impair hippocampal neuronal function and predispose the organism to neurodegeneration (96), potentially disrupting the regulatory circuit that connects the hippocampus and the hypothalamus.”

    From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [96]

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Research works printed but not linked: 3

  1. [4]Aus Der Mühlen K, Ockenfels H. Morphologische Veränderungen im Diencephalon und Telencephalon nach Störungen des Regelkreisis Adenohypophyse-Nebennierenrinde. Z Zellforsch. 1969;93:126–141. [PubMed] [Google Scholar]
  2. [34]Dallman MF, Bhatnagar S, Viau V. Hypothalamo-Pituitary-Adrenal Axis. In: Fink G, editor. Encyclopedia of Stress. New York NY: Academic Press; 2000. p. 468477. [Google Scholar]
  3. [106]Pearson Murphy BE. Glucocorticoids, Overview. In: Fink G, editor. Encyclopedia of Stress. London, UK: Academic Press; 2000. pp. 244–261. [Google Scholar]

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Authors
Conrad, C. D.
Affiliations
Arizona State University (US)
Corresponding author
Conrad, Cheryl D.
ORCID
Conrad, Cheryl D.
Venue
Reviews in the Neurosciences
Publisher
Walter de Gruyter GmbH
Published
2008-01
Volume
19
Issue
6
Pages
395-411
ISSN
  • 0334-1763 (ISSN-L)
  • 2191-0200
DOI
10.1515/revneuro.2008.19.6.395
PMC
PMC2746750
OpenAlex
W2077552311
Cited by
425
References
181
Citations by year
2026: 23 · 2025: 18 · 2024: 29 · 2023: 19 · 2022: 32 · 2021: 42 · 2020: 27 · 2019: 24 · 2018: 31 · 2017: 31 · 2016: 23 · 2015: 24 · 2014: 19 · 2013: 18 · 2012: 14
FWCI
1.24
Type
journal article
Language
en
Open access
Locations
  • Reviews in the Neurosciences (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Mental Health (MH64727, R01MH064727)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
chronic stress, hippocampus, glucocorticoids, dendritic retraction, hippocampal plasticity, neuroprotection, Cushing's disease, major depressive disorder, post-traumatic stress disorder, neurotoxicity
MeSH terms
Animals, Major Depressive Disorder, Glucocorticoids, Hippocampus, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Stress Disorders, Post-Traumatic, Stress, Psychological, Time Factors

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