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Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex
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The hippocampus provided the gateway into much of what we have learned about stress and brain structural and functional plasticity, and this initial focus has expanded to other interconnected brain regions, such as the amygdala and prefrontal cortex. Starting with the discovery of adrenal steroid, and later, estrogen receptors in the hippocampal formation, and subsequent discovery of dendritic and spine synapse remodeling and neurogenesis in the dentate gyrus, mechanistic studies have revealed both genomic and rapid non-genomic actions of circulating steroid hormones in the brain. Many of these actions occur epigenetically and result in ever-changing patterns of gene expression, in which there are important sex differences that need further exploration. Moreover, glucocorticoid and estrogen actions occur synergistically with an increasing number of cellular mediators that help determine the qualitative nature of the response. The hippocampus has also been a gateway to understanding lasting epigenetic effects of early-life experiences. These findings in animal models have resulted in translation to the human brain and have helped change thinking about the nature of brain malfunction in psychiatric disorders and during aging, as well as the mechanisms of the effects of early-life adversity on the brain and the body.
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“Chronically elevated glucocorticoid levels, in turn, are known to induce remodeling of the hippocampus, amygdala, and mPFC [71]”
From Trauma, PTSD, and the Developing Brain (2017) · cites this paper as [71]
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“It has been proved that the changes in the structure and function of neurons may occur under the chronic stress and lead to the occurrence of MDD. 37 , 38”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [37]
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“These findings reveal alterations at the levels of intracellular signaling, gene expression, neurotrophic factors, neurogenesis, neuroinflammation, excitatory and inhibitory neurotransmission, and synaptic number and function, and have been described in several brain regions implicated in depression 13-22 .”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [18]
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“Exaggerated fear is a core symptom of clinical anxiety and fear responding is closely linked to stress (Maren and Holmes, 2016;McEwen et al., 2016;Raio and Phelps, 2015), which (as described in Sections VI.G. and VII.H.) is tightly intertwined with gut-brain axis function.”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as McEwen et al., 2016
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“Accompanying these behavioral changes are marked physiological and structural alterations, not only in the amygdala and hippocampus but, importantly, the PFC [98,99], that are similar to those seen in MDD.”
From Prefrontal cortex and depression (2022) · cites this paper as [99]
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“In rodents, the most abundant and consistent changes are in the mPFC (anterior cingulate, prelimbic and infralimbic) with somewhat more variable, mixed direction effects in the OFC (Fig. 3, top left-hand panel).”
From Prefrontal cortex and depression (2022) · cites this paper as [99]
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“Studies of chronic stress or glucocorticoid exposure in adult animals show notable effects on frontolimbic circuitry including dendritic atrophy of the mPFC and hippocampus, and expansion of the basolateral amygdala [71].”
From Trauma, PTSD, and the Developing Brain (2017) · cites this paper as [71]
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“In recent years, it has become increasingly clear that the effect of stress on neuronal morphology and functions varies across brain regions (53–56).”
From Chronic Stress Remodels Synapses in an Amygdala Circuit-Specific Manner (2019) · cites this paper as [56]
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McEwen, B. S., & Plapinger, L. (1970) · Nature · doi:10.1038/226263a0 · Cited by 59
Self-citationNuclear and Extranuclear Estrogen Binding Sites in the Rat Forebrain and Autonomic Medullary Areas
Milner, T. A., Lubbers, L. S., Alves, S. E., & McEwen, B. S. (2008) · Endocrinology · doi:10.1210/en.2008-0307 · Cited by 57
Self-citation
Flagged first, then by citations
4 of the 218 references couldn’t be matched to a known paper.
Research works printed but not linked: 4
- Hill MN, McEwen BS (2010). Involvement of the endocannabinoid system in the neurobehavioural effects of stress and glucocorticoids. Prog Neuropsychopharmacol Biol Psychiatry 34: 791–797. · DOI · Paper page
- Jensen E, Jacobson H (1962). Basic guides to the mechanism of estrogen action. Rec Prog Horm Res 18: 387–408.
- McEwen BS, Lasley EN (2005) The End of Sex as We Know It In Cerebrum The Dana Forum on Brain Science. Dana Press http://www.dana.org/Cerebrum/2005/The_End_of_Sex_as_We_Know_It/ .
- Waddington CH (1942). The epigenotype. Endeavoour 1: 18–20.
Cited by
Sorted by citations
Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., et al. (2019) · Physiological Reviews · doi:10.1152/physrev.00018.2018 · Cited by 5,286
Major depressive disorder: hypothesis, mechanism, prevention and treatment
Cui, L., Li, S., Wang, S., Wu, X., Liu, Y., Yu, W., Wang, Y., Tang, Y., Xia, M., & Li, B. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01738-y · Cited by 1,244
“It has been proved that the changes in the structure and function of neurons may occur under the chronic stress and lead to the occurrence of MDD. 37,38 In some MDD patients, stress leads to long-term elevated glucocorticoids, resulting in synaptic structural changes and remodeling, and the…”
BackgroundDuman, R. S., Sanacora, G., & Krystal, J. H. (2019) · Neuron · doi:10.1016/j.neuron.2019.03.013 · Cited by 1,026
Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model
Price, R. B., & Duman, R. (2020) · Molecular Psychiatry · doi:10.1038/s41380-019-0615-x · Cited by 739
Biological embedding of childhood adversity: from physiological mechanisms to clinical implications
Berens, A. E., Jensen, S. K. G., & Nelson, C. A. (2017) · BMC Medicine · doi:10.1186/s12916-017-0895-4 · Cited by 657
“, hippocampus and amygdala) key to memory, learning, and emotion regulation, as well as the PFC, critical for higher cognition, executive functioning, and “top-down” control of lower regions [26].”
Background
Metadata
- Authors
- McEwen, B. S., Nasca, C., & Gray, J. D.
- Affiliations
- Rockefeller University (US)
- Venue
- Neuropsychopharmacology
- Published
- 2015-06-16
- Volume
- 41
- Issue
- 1
- Pages
- 3-23
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4677120
- OpenAlex
- W756325778
- Cited by
- 1,574
- References
- 218
- Citations by year
- 2026: 185 · 2025: 223 · 2024: 172 · 2023: 158 · 2022: 165 · 2021: 181 · 2020: 152 · 2019: 126 · 2018: 104 · 2017: 61 · 2016: 40 · 2015: 6
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Foundation for Suicide Prevention
- Hope for Depression Research Foundation
- National Institutes of Health (MH41256)
- National Institute of Mental Health (R01 MH41256, F32MH102065, R01MH041256)
- 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
- stress, hippocampus, amygdala, prefrontal cortex, neuroplasticity, dendritic remodeling, synaptic remodeling, dentate gyrus neurogenesis, glucocorticoids, estrogen receptor, non-genomic steroid action, epigenetics, sex differences, childhood adversity, early life experience, mental illness, brain aging
- MeSH terms
- Amygdala, Animals, Hippocampus, Humans, Nerve Net, Neuronal Plasticity, Neurons, Stress, Psychological, Prefrontal Cortex
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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