Glucocorticoid actions on synapses, circuits, and behavior: Implications for the energetics of stress
Open accessAbstract
Environmental stimuli that signal real or potential threats to homeostasis lead to glucocorticoid secretion by the hypothalamic-pituitary-adrenocortical (HPA) axis. Glucocorticoids promote energy redistribution and are critical for survival and adaptation. This adaptation requires the integration of multiple systems and engages key limbic-neuroendocrine circuits. Consequently, glucocorticoids have profound effects on synaptic physiology, circuit regulation of stress responsiveness, and, ultimately, behavior. While glucocorticoids initiate adaptive processes that generate energy for coping, prolonged or inappropriate glucocorticoid secretion becomes deleterious. Inappropriate processing of stressful information may lead to energetic drive that does not match environmental demand, resulting in risk factors for pathology. Thus, dysregulation of the HPA axis may promote stress-related illnesses (e.g. depression, PTSD). This review summarizes the latest developments in central glucocorticoid actions on synaptic, neuroendocrine, and behavioral regulation. Additionally, these findings will be discussed in terms of the energetic integration of stress and the importance of context-specific regulation of glucocorticoids.
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Chronic pain is often associated with a cascade of physiological and psychological responses, one of which is altered cortisol levels.
“It is often associated with a cascade of physiological and psychological responses, one of which is altered cortisol levels [130].”
From The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders (2023) · cites this paper as [130]
Section 6 (page unavailable) describes stress responses involving psychological appraisal, peripheral physiological systems, and glucocorticoid secretion. Section 5 (page unavailable) discusses altered cortisol levels in PTSD and depression. Neither passage establishes that chronic pain is often associated with altered cortisol levels, so the chronic-pain-specific part of the claim is unsupported. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe glucocorticoid receptor (GCC) plays a significant role in the regulation of chronic pain.
“The glucocorticoid receptor (GCC), a crucial component of the HPA axis, plays a significant role in the regulation of chronic pain [130].”
From The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders (2023) · cites this paper as [130]
Section 3.1 (Medial Prefrontal Cortex; page unavailable) describes glucocorticoid receptor signaling in HPA-axis regulation, supporting that part of the citing sentence. The paper does not itself state that the receptor regulates chronic pain; pain appears in titles in its References section, not as a finding discussed in the text. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn animals, chronic stress results in prolonged release of glucocorticoids and leads to hypertrophy of the amygdala and nucleus accumbens, atrophy of the hippocampus and prefrontal cortex, and functional impairment of the PFC.
“In animals, chronic stress results in the prolonged release of glucocorticoids and leads to hypertrophy of the amygdala and nucleus accumbens, atrophy of the hippocampus and prefrontal cortex (PFC), and functional impairment of the PFC (44–55).”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [50]
Section 2.1 (page unavailable) reports reduced dendritic complexity in the medial PFC after repeated or chronic stress, and section 4.1 reports impaired PFC-mediated behavior in animals. Section 2.2 describes impaired hippocampal plasticity, but the copy does not establish hippocampal atrophy in animals or hypertrophy of the amygdala and nucleus accumbens. It also does not establish prolonged glucocorticoid release as the cause of that full set of changes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredChronic stress causes dendritic retraction in mPFC, dorsal hippocampus, and dorsomedial striatum but hypertrophy in BLA, vHPC, orbitofrontal cortex, and dorso-lateral striatum and no change in lateral or central subnuclei of the amygdala.
“Chronic stress causes dendritic retraction in mPFC, dorsal hippocampus, and dorsomedial striatum but hypertrophy in the BLA, vHPC, orbitofrontal cortex, and dorso-lateral striatum and no change in the lateral or central subnuclei of the amygdala (3,54,57–61).”
From Chronic Stress Remodels Synapses in an Amygdala Circuit-Specific Manner (2019) · cites this paper as [61]
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References 314 · Cited by 318
- Authors
- Myers, B., McKlveen, J. M., & Herman, J. P.
- Affiliations
- University of Cincinnati (US)
- Corresponding author
- Herman, James P.
- Venue
- Frontiers in Neuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 35
- Issue
- 2
- Pages
- 180-196
- ISSN
- 0091-3022 (ISSN-L)
- PMC
- PMC4422101
- OpenAlex
- W1995322135
- Semantic Scholar
- 983400c1d9dc0170a7057deb18d7dd379c0435c0
- Cited by
- 318
- References
- 314
- Citations by year
- 2026: 24 · 2025: 10 · 2024: 20 · 2023: 29 · 2022: 23 · 2021: 36 · 2020: 46 · 2019: 23 · 2018: 24 · 2017: 23 · 2016: 21 · 2015: 27 · 2014: 12
- FWCI
- 1.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Frontiers in Neuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH049698, MH069860, MH090574, R21MH090574, R01MH069860, F31MH097430, MH049698, MH097430)
- National Institute of Neurological Disorders and Stroke (T32NS007453)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- glucocorticoids, hypothalamic-pituitary-adrenal axis, stress, synaptic plasticity, stress behavior, energy metabolism, depression, post-traumatic stress disorder
- MeSH terms
- Animals, Behavior, Brain, Corticotropin-Releasing Hormone, Glucocorticoids, Humans, Stress, Physiological, Synapses
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