Neural regulation of the stress response: glucocorticoid feedback mechanisms
Open accessAbstract
The mammalian stress response is an integrated physiological and psychological reaction to real or perceived adversity. Glucocorticoids are an important component of this response, acting to redistribute energy resources to both optimize survival in the face of challenge and to restore homeostasis after the immediate challenge has subsided. Release of glucocorticoids is mediated by the hypothalamo-pituitary-adrenal (HPA) axis, driven by a neural signal originating in the paraventricular nucleus (PVN). Stress levels of glucocorticoids bind to glucocorticoid receptors in multiple body compartments, including the brain, and consequently have wide-reaching actions. For this reason, glucocorticoids serve a vital function in negative feedback inhibition of their own secretion. Negative feedback inhibition is mediated by a diverse collection of mechanisms, including fast, non-genomic feedback at the level of the PVN, stress-shut-off at the level of the limbic system, and attenuation of ascending excitatory input through destabilization of mRNAs encoding neuropeptide drivers of the HPA axis. In addition, there is evidence that glucocorticoids participate in stress activation via feed-forward mechanisms at the level of the amygdala. Feedback deficits are associated with numerous disease states, underscoring the necessity for adequate control of glucocorticoid homeostasis. Thus, rather than having a single, defined feedback 'switch', control of the stress response requires a wide-reaching feedback 'network' that coordinates HPA activity to suit the overall needs of multiple body systems.
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The limbic system mediates feedback mechanisms, whereby glucocorticoids and mineralocorticoids act upon receptors in the hippocampus and medial prefrontal cortex, which connect to the PVN via the BNST and lateral septum.
“The limbic system also mediates feedback mechanisms, whereby glucocorticoids and mineralocorticoids act upon receptors in the hippocampus and medial prefrontal cortex, which connect to the PVN via the BNST and lateral septum.”
From Glutamate receptors in domestication and modern human evolution (2020) · cites this paper as Herman et al., 2012
The HPA axis is centrally regulated by the limbic system, primarily through amygdalar processing of perceptual inputs, which are relayed via the bed nucleus of the stria terminalis to the paraventricular nucleus in the hypothalamus.
“The HPA axis is centrally regulated by the limbic system, primarily through amygdalar processing of perceptual inputs, which are relayed via the bed nucleus of the stria terminalis (BNST) to the paraventricular nucleus (PVN) in the hypothalamus.”
From Glutamate receptors in domestication and modern human evolution (2020) · cites this paper as Herman et al., 2012
Feedback also occurs directly on cells in the PVN to inhibit further HPA reactivity.
“Feedback also occurs directly on cells in the PVN to inhibit further HPA reactivity.”
From Glutamate receptors in domestication and modern human evolution (2020) · cites this paper as Herman et al., 2012
Feedforward mechanisms, further potentiating the stress response, are relayed from the amygdala to the PVN via the BNST.
“Feedforward mechanisms, further potentiating the stress response, are relayed from the amygdala to the PVN via the BNST.”
From Glutamate receptors in domestication and modern human evolution (2020) · cites this paper as Herman et al., 2012
GCs promote glutamate release in feedback regions, and the different affinities of mineralocorticoid receptors and glucocorticoid receptors enable the modulation of stress feedback signaling from basal or moderate to acute levels.
“GCs promote glutamate release in these feedback regions, and the different affinities of mineralocorticoid receptors (MRs; bound by GCs at low concentrations) and glucocorticoid receptors (GRs; bound at higher concentrations) enable the modulation of stress feedback signaling from basal or moderate to acute levels (Jankord and Herman, 2008;Herman et al., 2012).”
From Glutamate receptors in domestication and modern human evolution (2020) · cites this paper as Herman et al., 2012
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- Authors
- Herman, J. P., McKlveen, J. M., Solomon, M. B., Carvalho-Netto, E., & Myers, B.
- Affiliations
- University of Cincinnati (US)
- Ministry of Education (BR)
- Venue
- Brazilian Journal of Medical and Biological Research
- Publisher
- FapUNIFESP (SciELO)
- Published
- 2012-04
- Volume
- 45
- Issue
- 4
- Pages
- 292-298
- ISSN
- 0100-879X (ISSN-L)
- PMC
- PMC3854162
- OpenAlex
- W2115117609
- Cited by
- 307
- References
- 45
- Citations by year
- 2026: 17 · 2025: 15 · 2024: 19 · 2023: 19 · 2022: 21 · 2021: 19 · 2020: 29 · 2019: 38 · 2018: 32 · 2017: 23 · 2016: 18 · 2015: 14 · 2014: 29 · 2013: 12 · 2012: 1
- FWCI
- 7.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Brazilian Journal of Medical and Biological Research (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- Americanae (AECID Library) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (MH049698, MH069725, MH069860)
- National Institute of Mental Health (MH066958, R01MH066958, R01MH049698, MH 069725, MH069860, R01MH069860, MH049698, R01MH069725)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- stress response, glucocorticoids, hypothalamic-pituitary-adrenal axis, negative feedback, paraventricular nucleus, glucocorticoid receptor, limbic system, amygdala
- MeSH terms
- Animals, Escape Reaction, Glucocorticoids, Humans, Hypothalamo-Hypophyseal System, Paraventricular Hypothalamic Nucleus, Pituitary-Adrenal System, Stress, Physiological, Feedback, Physiological, Mice, Rats
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