Cited by 378Stress Responses and CortisolTreatment of Major DepressionNeuropeptides and Animal Physiology

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Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior

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Boyle, Maureen P., Brewer, Judson A., Funatsu, Michiyo, Wozniak, David F., Tsien, Joe Z., Izumi, Yukitoshi, Muglia, Louis J.·2005·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0406458102PMC PMC544280

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Abstract

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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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.
ORCID: Brewer, Judson A.
Wozniak, David F.
Izumi, Yukitoshi
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
DOI: 10.1073/pnas.0406458102
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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Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior

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