The DOI matches its Crossref record; 39 of the 40 references it cites were found in a registry or an index.
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]
Citations
Cites
Protective and Damaging Effects of Stress Mediators
McEwen, B. S. (1998) · New England Journal of Medicine · doi:10.1056/nejm199801153380307 · Cited by 6,733
Brain corticosteroid receptor balance in health and disease
de Kloet, E. R., Vreugdenhil, E., Oitzl, M. S., & Joëls, M. (1998) · Endocrine Reviews · doi:10.1210/edrv.19.3.0331 · Cited by 2,614
The Corticosteroid Receptor Hypothesis of Depression
Holsboer, F. (2000) · Neuropsychopharmacology · doi:10.1016/s0893-133x(00)00159-7 · Cited by 2,181
STRESS AND HIPPOCAMPAL PLASTICITY
McEwen, B. S. (1999) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.22.1.105 · Cited by 2,087
Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety
Tronche, F., Kellendonk, C., Kretz, O., Gass, P., Anlag, K., Orban, P. C., Bock, R., Klein, R., & Schütz, G. (1999) · Nature Genetics · doi:10.1038/12703 · Cited by 1,841
Herman, J. P., Figueiredo, H., Mueller, N. K., Ulrich-Lai, Y., Ostrander, M. M., Choi, D. C., & Cullinan, W. E. (2003) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2003.07.001 · Cited by 1,586
Subregion- and Cell Type–Restricted Gene Knockout in Mouse Brain
Tsien, J. Z., Chen, D. F., Gerber, D., Tom, C., Mercer, E. H., Anderson, D. J., Mayford, M., Kandel, E. R., & Tonegawa, S. (1996) · Cell · doi:10.1016/s0092-8674(00)81826-7 · Cited by 1,280
Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment
Pariante, C. M., & Miller, A. H. (2001) · Biological Psychiatry · doi:10.1016/s0006-3223(00)01088-x · Cited by 1,147
Meaney, M. J., Diorio, J., Francis, D., Widdowson, J., LaPlante, P., Caldji, C., Sharma, S., Seckl, J. R., & Plotsky, P. M. (2010) · Developmental Neuroscience · doi:10.1159/000111395 · Cited by 878
Do early‐life events permanently alter behavioral and hormonal responses to stressors?
Anisman, H., Zaharia, M. D., Meaney, M. J., & Merali, Z. (1998) · International Journal of Developmental Neuroscience · doi:10.1016/s0736-5748(98)00025-2 · Cited by 654
Research works printed but not linked: 1
- Barden, N. (2004) J. Psychiatry Neurosci. 29, 185-193.15173895
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Items 301–373 of 373
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Herman, J. P. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-813983-7.00019-7 · Cited by 4
Shiraki, H., Segi‐Nishida, E., & Suzuki, K. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.151729 · Cited by 4
Reelin, the HPA Axis, and Chronic Stress: Implications for the Neurobiology of Depression
Thom, S. A., Halvorson, C. S., Reive, B. S., Sánchez-Lafuente, C. L., Kalynchuk, L. E., & Caruncho, H. J. (2026) · Chronic Stress · doi:10.1177/24705470261427267 · Cited by 3
“…the result of a downregulation of GRs that impairs homeostatic suppression of the HPA axis, resulting in prolonged elevation of circulating GCs. 35,36 Under healthy conditions, GCs act to suppress immune responses primarily through genomic mechanisms including through the repression of activator…”
Laryea, G. N., Arnett, M. G., Wieczorek, L., & Muglia, L. J. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.12.005 · Cited by 3
“Forebrain GR disruption, for instance, increases HPA axis activity, induces anhedonia in the sucrose preference test, causes despair behavior in the forced swim and tail suspension tests, and alters regulation of anxiety behavior (Boyle et al., 2005, 2006).”
Multiple Sclerosis and Depression: A Neuroimmunological Perspective
Arnason, B. G. W. (2010) · Neuroimmune biology · doi:10.1016/s1567-7443(10)70026-0 · Cited by 3
Is the acquired hypothyroidism a risk factor for developing psychiatric disorders?
Brizuela, N. O., Peraza, A. V., Ángel, D. S.-D., García-Martínez, Y., Pacheco-Rosado, J., Pérez‐Sánchez, G., & Sánchez-Huerta, K. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1429255 · Cited by 3
The Neuroimmune System in Psychiatric Disorders
Hassan, Y., ESTEVES, S. C., Leyrer‐Jackson, J. M., & Thomas, M. P. (2024) · Springer eBooks · doi:10.1007/978-3-031-68237-7_56 · Cited by 2
Chronic citalopram treatment does not sensitize the adrenal gland to ACTH (1—24) in rats
Hesketh, S. A., Leggett, J. D., & Henry, D. S. J. (2007) · Journal of Psychopharmacology · doi:10.1177/0269881107078310 · Cited by 3
Genetically Modified Mice as Tools to Understand the Neurobiological Substrates of Depression
Robledo, P., Martín‐García, E., Aso, E., & Maldonado, R. J. (2014) · Current Pharmaceutical Design · doi:10.2174/13816128113196660741 · Cited by 3
“These mice developed impaired negative feedback regulatio n, hyperactivity of HPA axis and increased depression-like behaviour [263, 264].”
Pharmacogenomics and Personalized Medicine in Mood Disorders
Archer, T., Ricci, S., & Ricciardi, M. R. (2013) · Springer eBooks · doi:10.1007/978-81-322-1184-6_16 · Cited by 2
Genetic Transmission of Behavior and Its Neuroendocrine Correlates
Hambsch, B., Landgraf, R., Czibere, L., & Touma, C. (2009) · Elsevier eBooks · doi:10.1016/b978-008088783-8.00084-x · Cited by 3
Traces épigénétiques des carences affectives précoces
Ladha, K., Monhonval, P., & Lotstra, F. (2013) · Cahiers critiques de thérapie familiale et de pratiques de réseaux · doi:10.3917/ctf.049.0205 · Cited by 2
The glucocorticoid hypothesis of depression: history and perspectives
Shishkina, G. T., & Дыгало, Н. Н. (2016) · Vavilov Journal of Genetics and Breeding · doi:10.18699/vj16.155 · Cited by 2
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Pilkay, S. R., & Combs-Orme, T. D. (2020) · Social Work Research · doi:10.1093/swr/svz024 · Cited by 2
3C. 3-Ketosteroid receptors in GtoPdb v.2023.1
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Churilova, A. V., Gluschenko, T. S., Rybnikova, E. A., & Самойлов, М. О. (2019) · Cell and Tissue Biology · doi:10.1134/s1990519x19020044 · Cited by 2
Lee, H. B., Schwab, T. L., Sigafoos, A. N., Gauerke, J. L., Krug, R. G., Serres, M. R., Jacobs, D. C., Cotter, R. P., Das, B. B., Petersen, M. O., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/291914 · Cited by 2
Stolerman, I. P., & Price, L. H. (2015) · Springer eBooks · doi:10.1007/978-3-642-36172-2_200048 · Cited by 2
Niwa, M., Lockhart, S., Wood, D. J., Yang, K., Francis-Oliveira, J., Kin, K., Ahmed, A., Wand, G. S., Kano, S., Payne, J. L., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.10.13.464258 · Cited by 2
Corticosteroid Receptor Genes: Functional Dissection in Mice
Tronche, F. (2007) · Elsevier eBooks · doi:10.1016/b978-012373947-6.00701-7 · Cited by 2
Gavade, S., Wei, Q., Johnston, C. J., Kounelis-Wuillaume, S., Laborc, K. F., Baranwal, S., Akil, H., & Spencer-Segal, J. L. (2022) · eNeuro · doi:10.1523/eneuro.0126-22.2022 · Cited by 1
“Glucocorticoid receptor is widely expressed in the brain, and mice with altered GR expression in forebrain have been developed to improve our understanding of how neuronal glucocorticoid signaling alters vulnerability to stress-related disorders (Wei et al., 2004; Boyle et al., 2005).”
BackgroundSelecting an appropriate stress model of depression in rodents
Lu, X.-X., Tang, H., & Li, X. (2025) · World Journal of Psychiatry · doi:10.5498/wjp.v15.i12.113433 · Cited by 2
Maternal programming of defensive responses through sustained effects on gene expression
Diorio, J. C., & Meaney, M. J. (2007) · Journal of Psychiatry and Neuroscience · doi:10.1139/jpn.0728 · Cited by 2
A Basic and Applied Model of the Body–Mind System
Bernstein, W. M. (2014) · Springer eBooks · doi:10.1007/978-1-4939-1236-0_26 · Cited by 1
Brain Networks, Hormones and Genes Implicated in Depression
Bennett, M. R. (2012) · Springer eBooks · doi:10.1007/978-94-007-5748-6_5 · Cited by 1
The Epigenetics of Parental Effects
Zhang, T., Caldji, C., Diorio, J. C., Dhir, S. K., Turecki, G., & Meaney, M. J. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-391494-1.00004-5 · Cited by 1
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Animal models of stress-based depression
Nabizadeh, M. (2019) · Journal of Neurodevelopmental Cognition · doi:10.29252/jncog.1.1.90 · Cited by 1
“Depression-related cognitive impairment changes with the release of corticosterone and decrease of glucocorticoid receptor regulation [59].”
BackgroundEpigenetics of major depressive disorder
Braun, P., & Potash, J. B. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-823577-5.00002-7 · Cited by 1
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Sarawagi, A., Bhat, U. A., Sinha, S., Iyer, H., Patel, A. B., & Kumar, A. (2022) · Springer eBooks · doi:10.1007/978-981-16-8313-8_11 · Cited by 1
Antidepressant Actions on Glucocorticoid Receptors
Yau, J. L. W., & Seckl, J. R. (2007) · Elsevier eBooks · doi:10.1016/b978-012373947-6.00037-4 · Cited by 1
Depression and corticosteroid receptors
Ago, Y., Takuma, K., & Matsuda, T. (2009) · Folia Pharmacologica Japonica · doi:10.1254/fpj.134.304 · Cited by 1
Perspectives on Neuroscience and Behavior
(2005) · The Neuroscientist · doi:10.1177/107385840501100603 · Cited by 1
Glucocorticoid Receptor Mutant Mice as Models for Stress-Induced Affective Disorders
Gass, P. (2007) · Elsevier eBooks · doi:10.1016/b978-012373947-6.00678-4
Schutsky, K. (2011) · ScholarlyCommons (University of Pennsylvania)
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Leliavski, A. (2014) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-4675
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Bjartmar, L. (2009) · KTH Publication Database DiVA (KTH Royal Institute of Technology)
Morton, S. J. (2015) · CU Scholar (University of Colorado Boulder)
Epigénétique des interactions précoces, de la dépression et de la schizophrénie
de Psychiatrie, D., & Erasme, H. (2012) · Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles)
Linking Molecules to Mood: New Insight Into the Biology of Depression Reviews and Overviews
Krishnan, V., & Nestler, E. J. (2010)
Choi, D. C. (2007) · OhioLink ETD Center (Ohio Library and Information Network)
Hormones and allostasis in brain disease and repair
Hunter, R. G., & McEwen, B. S. (2008) · Cambridge University Press eBooks · doi:10.1017/cbo9781316529898.006
Forbes, C. D. (2017) · doi:10.15760/etd.3401
“glucocorticoids on physiology and behavior (Boyle et al., 2005; Chiba et al., 2012; Korte et al., 1995; Tronche et al., 1999; Welberg et al., 2001).”
Leite, J. A. (2019) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.42.2019.tde-19022019-145239
Exploring Novel Treatment Approaches for Post-Traumatic Stress Disorder
Murkar, A. (2020) · uO Research (University of Ottawa) · doi:10.20381/ruor-24279
“PVN) [124,125], while GR overexpression has the opposite effect on both ACTH and glucocorticoid availability [126,127].”
Background3C. 3-Ketosteroid receptors in GtoPdb v.2021.3
Cain, D. W., Cidlowski, J. A., Edwards, D. P., Fuller, P. J., Grimm, S. L., Hartig, S. M., Lange, C. A., Oakley, R. H., Richer, J. K., Sartorius, C. A., et al. (2021) · IUPHAR/BPS Guide to Pharmacology CITE · doi:10.2218/gtopdb/f98/2021.3
Heilig, M. A. (2009) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.1124335.621983
Hypercortisolism and Behavioral Neuroscience
Vives, A. S., Webb, S. M., & Resmini, E. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-819641-0.00093-1
Grimaud, É. (2019) · Dunod eBooks · doi:10.3917/dunod.marti.2019.01.0043
Jensen, I. (2022) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-9601
Corbett, B. F., Arner, J., Luz, S., Estela-Pro, V., Yan, J. H., Osborne, B., Joannas, L., Henao-Mejia, J., Castro-Vildosola, J., Hala, T., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.09.574910
Castro-Vildosola, J., Bryan, C.-A., Tajamal, N., Jonnalagadda, S. A., Kasturi, A., Tilly, J., Garcı́a, I., Kumar, R., Fried, N. T., Hala, T. J., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.31.606030
“We previously found that S1PR3 is increased by glucocorticoid receptors (GRs) 3 , which are expressed in the mPFC 3,58 and dentate gyrus 59 .”
BackgroundA single glucocorticoid response element regulates sociability in a sex-specific manner
Corbett, B. F., Arner, J., Luz, S., Yan, J. H., Castro-Vildosola, J., Hala, T. J., Taylor, D. M., & Bhatnagar, S. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03158-y
“In rodents, GR knockout from forebrain neurons causes depression-like behavior and heightened activation of the neuroendocrine stress response [69], which is likely attributed to impaired negative feedback of the HPA axis [69, 70].”
Tettey, T. T., Lao, Q., Vaid, S., Kim, S., Varticovski, L., Kolli, V., Merke, D. P., & Hager, G. L. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.12.693739
Functions of the Mineralocorticoid Receptor in the Hippocampus.
Rozeboom, A. M. (2008) · Deep Blue (University of Michigan)
Gatta, E. (2016) · theses.fr (ABES) · doi:10.70675/eb10021dz791ez4d44z8f03zb272dfadb7fb
“Accordingly, studies carried out in GR-knockout mice show that this receptor is required for the extinction of HPA activity in response to stress (Boyle et al., 2005; Furay, Bruestle and Herman, 2008).”
BackgroundImpact of CBG deficiency on emotional and cognitive processes
de Medeiros, G. F. (2016) · theses.fr (ABES) · doi:10.70675/5068781bzb1fez4551z99eez04f240a93ed0 · Cited by 1
Le récepteur 3 de la neurotensine/Sortiline dans la régulation de l’état dépressif
Moréno, S. (2017) · theses.fr (ABES) · doi:10.70675/bd5432bcz3426z4e54z9081zd99b2eb3f712 · Cited by 1
Rôle central des glucocorticoïdes et de leurs récepteurs dans l’étiologie de la Maladie d’Alzheimer
Canet, G. (2020) · theses.fr (ABES) · doi:10.70675/c46cedbczd8bbz4a8eza301z82de5785048c
Etude de la voie de la kynurénine dans la symptomatologie du sujet obèse
Huet, L. (2019) · theses.fr (ABES) · doi:10.70675/ff26d7c8z4c5fz4c86z9e6ezd8d843268447
Models of depression for preclinical drug discovery and development: an update of the literature
Pavlidi, P., Kalampokis, D., Ioannidi, I., Skourti, K., Sotiropoulos, I., Antoniou, K., Dalla, C., & Kokras, N. (2026) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2026.2716135
“While central nervous system (CNS)-wide GR deletion produced paradoxical anxiolytic effects, Boyle et al. subsequently developed inducible forebrain-specific GR knockout (FBGRKO) to investigate GR signaling in emotional regulation and HPA axis function [155].”
InfluentialLi, C., Dong, Q.-M., & Hou, Y.-J. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27219549
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Victoria, N. C. (2022) · Digital Archive @ GSU · doi:10.57709/4563965
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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