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Cited by 596Stress Responses and CortisolMemory and Neural MechanismsNeuroscience and Neuropharmacology Research

Stress and anxiety: Structural plasticity and epigenetic regulation as a consequence of stress

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McEwen, Bruce S., Eiland, Lisa, Hunter, Richard G., Miller, Melinda M.·2012·Neuropharmacology
DOI 10.1016/j.neuropharm.2011.07.014PMC PMC3196296
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Abstract

The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as the behavioral and physiological responses to the stressor. The adult, as well as developing brain, possess a remarkable ability to show reversible structural and functional plasticity in response to stressful and other experiences, including neuronal replacement, dendritic remodeling, and synapse turnover. This is particularly evident in the hippocampus, where all three types of structural plasticity have been recognized and investigated, using a combination of morphological, molecular, pharmacological, electrophysiological and behavioral approaches. The amygdala and the prefrontal cortex, brain regions involved in anxiety and fear, mood, cognitive function and behavioral control, also show structural plasticity. Acute and chronic stress cause an imbalance of neural circuitry subserving cognition, decision making, anxiety and mood that can increase or decrease expression of those behaviors and behavioral states. In the short term, such as for increased fearful vigilance and anxiety in a threatening environment, these changes may be adaptive; but, if the danger passes and the behavioral state persists along with the changes in neural circuitry, such maladaptation may need intervention with a combination of pharmacological and behavioral therapies, as is the case for chronic or mood anxiety disorders. We shall review cellular and molecular mechanisms, as well as recent work on individual differences in anxiety-like behavior and also developmental influences that bias how the brain responds to stressors. Finally, we suggest that such an approach needs to be extended to other brain areas that are also involved in anxiety and mood. This article is part of a Special Issue entitled 'Anxiety and Depression'.

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Crossref · 10.1016/j.neuropharm.2011.07.014

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  • Dendrite complexity and synaptic density can be increased or the effects of stress reversed by antidepressants, enriched environment, and exercise.

    “Dendrite complexity and synaptic density can also be increased or the effects of stress reversed by antidepressants, enriched environment, and exercise (6, 7, 21).”

    From Synaptic Dysfunction in Depression: Potential Therapeutic Targets (2012) · cites this paper as [21]

    The 'Key role of BDNF' section says antidepressants and regular physical activity can elevate BDNF, a facilitator of plasticity. The 'Functional consequences' section says stress-related CA3 dendritic shrinkage can reverse after the stressor ends. Neither passage establishes that those interventions increase dendritic complexity or synaptic density or reverse stress effects, and the retrieved passages do not establish that claim for an enriched environment. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The DG-CA3 circuitry is believed to be responsible for event sequence-related memory formation and fear learning, which underlies the anxiety phenotype.

    “This DG–CA3 circuitry is believed to be responsible for event sequence-related memory formation and fear learning, which underlies the anxiety phenotype (McEwen et al., 2012; Zhang et al., 2014).”

    From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as McEwen et al., 2012

    The Hippocampus subsection of section 2 says the dentate gyrus–CA3 system is believed to play a role in remembering sequences of events. It does not attribute fear learning or the anxiety phenotype specifically to that circuitry; section 8 discusses emotional memories and fear in terms of interactions among broader brain regions. Page numbers are not available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Antidepressants can block or reverse neuronal deficits.

    “Antidepressants can block or reverse these neuronal deficits, although typical antidepressants have limited efficacy and delayed response times of weeks to months.”

    From Synaptic Dysfunction in Depression: Potential Therapeutic Targets (2012) · cites this paper as [21]

    The 'Key role of BDNF' section (page unavailable) says antidepressants can elevate BDNF and that fluoxetine can enhance plasticity and ameliorate effects of monocular deprivation. It also says BDNF can prevent stress-induced loss of dendritic branching, but does not establish that antidepressant drugs themselves block or reverse those neuronal deficits. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Other chronic stress paradigms cause similar reductions in dendrite complexity and spine density in prefrontal cortex neurons and CA3 pyramidal cells of the hippocampus.

    “Other chronic stress paradigms (such as restraint stress) cause similar reductions in dendrite complexity and spine density in PFC neurons and CA3 pyramidal cells of the hippocampus (20–22).”

    From Synaptic Dysfunction in Depression: Potential Therapeutic Targets (2012) · cites this paper as [21]

    Section 2 (‘Prefrontal cortex and amygdala’; page unavailable) reports dendritic shortening in medial prefrontal cortex after chronic restraint or immobilization stress. Section 7 (‘Developmental effects’; page unavailable) reports shortened CA3 pyramidal-cell dendrites after chronic restraint stress in normally reared rats. The copy does not report reduced spine density in either population under these stress paradigms. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Studies in rodent models confirm that exposure to stress, like depression, causes atrophy and loss of neurons and glia in the PFC and hippocampus.

    “Studies in rodent models have extended these human studies, and confirm that exposure to stress, like depression, causes atrophy and loss of neurons and glia in the PFC and hippocampus1011,12.”

    From Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants (2016) · cites this paper as [11]

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Research works printed but not linked: 2

  1. Kabbaj M Devine DP Savage VR Akil H 2000b Neurobiological correlates of individual differences in novelty-seeking behavior in the rat: differential expression of stress-related molecules J Neurosci 20 6983 8 10995843 PMC6772801
  2. McEwen BS Lasley EN 2005 The End of Sex as We Know It Cerebrum The Dana Forum on Brain Science Dana Press

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Authors
McEwen, B. S., Eiland, L., Hunter, R. G., & Miller, M. M.
Affiliations
  • Rockefeller University (US)
  • Weill Cornell Medicine (US)
Corresponding author
McEwen, Bruce S.
ORCID
Venue
Neuropharmacology
Publisher
Elsevier BV
Published
2012-01
Volume
62
Issue
1
Pages
3-12
ISSN
0028-3908 (ISSN-L)
DOI
10.1016/j.neuropharm.2011.07.014
PMC
PMC3196296
OpenAlex
W1983494600
Cited by
596
References
150
Citations by year
2026: 26 · 2025: 27 · 2024: 38 · 2023: 26 · 2022: 47 · 2021: 45 · 2020: 35 · 2019: 50 · 2018: 39 · 2017: 36 · 2016: 34 · 2015: 44 · 2014: 65 · 2013: 49 · 2012: 32
FWCI
4.09
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neuropharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
R01 MH41256 and P50 MH58911
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, anxiety, structural plasticity, epigenetic regulation, hippocampus, dendritic remodeling, amygdala, prefrontal cortex, chronic stress, anxiety disorders, neural circuits, maladaptive stress response
MeSH terms
Anxiety, Brain, Humans, Neuronal Plasticity, Stress, Psychological, Epigenesis, Genetic

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