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Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior
Open accessAbstract
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark of major depressive disorder. A number of studies have shown that this dysregulation is correlated with impaired forebrain glucocorticoid receptor (GR) function. To determine whether a primary, acquired deficit in forebrain GR signaling is an etiologic factor in the pathogenesis of depression, we generated a line of mice with time-dependent, forebrain-specific disruption of GR (FBGRKO). These mice develop a number of both physiological and behavioral abnormalities that mimic major depressive disorder in humans, including hyperactivity of the HPA axis, impaired negative feedback regulation of the HPA axis and, increased depression-like behavior. Importantly, a number of these abnormalities are normalized by chronic treatment with the tricyclic antidepressant, imipramine. Our findings suggest that imipramine's proposed activities on forebrain GR function are not essential for its antidepressant effects, and that alteration in GR expression may play a causative role in disease onset of major depressive disorder.
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“Finally, the broad disruption of the GR allele in the CNS [GRNesCre (5)] and its targeted deletion in the forebrain [forebrain-specific GR knock-out; FBGRKO mice] (119), or the PVN all resulted in the disinhibition of the HPA axis (120).”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [119]
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- Barden, N. (2004) J. Psychiatry Neurosci. 29, 185-193.15173895
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Stress and the brain: from adaptation to disease
de Kloet, E. R., Joëls, M., & Holsboer, F. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1683 · Cited by 4,621
“When GR -knockout mice were generated using the α-calcium/calmodulin dependent protein kinase II (αCaMKII) promoter, by deleting the expression of limbic GR (except in the hypothalamic PVN), a robust depression-like phenotype was seen, which was normalized after chronic treatment with the tricyclic antidepressant imip…”
MethodEpigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse
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“Thus, selective knockdown of glucocorticoid receptor expression in the corticolimbic system in rodents is associated with increased HPA activity under both basal and stressful condition”
BackgroundNeural regulation of endocrine and autonomic stress responses
Ulrich-Lai, Y. M., & Herman, J. P. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2647 · Cited by 3,318
“Mice with selective deletion of the GR in the cortex, the hippocampus and the BLA have elevated basal glucocorticoids and prolonged corticosterone responses to psychogenic but not systemic stres”
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New approaches to antidepressant drug discovery: beyond monoamines
Berton, O., & Nestler, E. J. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1846 · Cited by 1,589
“Recently, this neuroendocrine abnormality was reproduced in adult mice with selective deletion of GR2 in the forebrai”
Background
Metadata
- Authors
- Boyle, M. P., Brewer, J. A., Funatsu, M., Wozniak, D. F., Tsien, J. Z., Izumi, Y., & Muglia, L. J.
- Affiliations
- Princeton University (US)
- Corresponding author
- Muglia, Louis J.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-12-27
- Volume
- 102
- Issue
- 2
- Pages
- 473-478
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC544280
- OpenAlex
- W2156404675
- Cited by
- 378
- References
- 40
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 13 · 2023: 9 · 2022: 14 · 2021: 10 · 2020: 15 · 2019: 20 · 2018: 21 · 2017: 15 · 2016: 16 · 2015: 18 · 2014: 29 · 2013: 20 · 2012: 29
- FWCI
- 7.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- glucocorticoid receptor, major depressive disorder, hypothalamic-pituitary-adrenal axis, HPA axis dysregulation, negative feedback regulation, depression-like behavior, imipramine, tricyclic antidepressants, antidepressant mechanism, glucocorticoid signaling
- MeSH terms
- Animals, Corticotropin-Releasing Hormone, Depression, Hippocampus, Hypothalamo-Hypophyseal System, Imipramine, Mice, Inbred CBA, Mice, Inbred C57BL, Pituitary-Adrenal System, Receptors, Glucocorticoid, RNA, Messenger, Time Factors, Prosencephalon, Mice, Knockout, Mice
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