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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Background
The Hippocampus as a Neural Link between Negative Affect and Vulnerability for Psychostimulant Relapse
Barr, J. L., Bray, B., & Forster, G. L. (2018) · InTech eBooks · doi:10.5772/intechopen.70854 · Cited by 13
“Knocking out central GR expression (except in the hypothalamus) produces a reliable depression-like phenotype in rodents, which is restored with tricyclic antidepressant treatment [232].”
Background
Activation of TGF-β activated kinase 1 promotes colon mucosal pathogenesis in inflammatory bowel disease
Liu, Z., Kong, F., Vallance, J. E., Harmel-Laws, E., Amarachintha, S. P., Steinbrecher, K. A., Rosen, M. J., & Bhattacharyya, S. (2017) · Physiological Reports · doi:10.14814/phy2.13181 · Cited by 13
“Plasma concentrations of corticosterone were determined by radioimmunoassay from blood collected by retro-orbital phlebotomy as described previously (Boyle et al. 2005).”
Method
LPA1 receptor and chronic stress: Effects on behaviour and the genes involved in the hippocampal excitatory/inhibitory balance
Moreno‐Fernández, R. D., Rosell‐Valle, C., Bacq, A., Zanoletti, O., Cifuentes, M., Pérez‐Martín, M., Gavito, A., Garcia‐Fernandez, M. I., Estivill‐Torrús, G., de Fonseca, F. R., et al. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.107896 · Cited by 13
A possible principal function of corticosteroid signaling that is conserved in vertebrate evolution: Lessons from receptor-knockout small fish
Sakamoto, T., Hyodo, S., & Takagi, W. (2018) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2018.02.011 · Cited by 13
Deletion of exchange proteins directly activated by cAMP (Epac) causes defects in hippocampal signaling in female mice
Aesöy, R., Muwonge, H., Nordhus, K. S., Sabir, M., Witsoe, S. L., Bjørnstad, R., Kopperud, R. K., Høivik, E. A., Døskeland, S. O., & Bakke, M. (2018) · PLoS ONE · doi:10.1371/journal.pone.0200935 · Cited by 12
Deletion of Glucocorticoid Receptors in Forebrain GABAergic Neurons Alters Acute Stress Responding and Passive Avoidance Behavior in Female Mice
Scheimann, J. R., Mahbod, P., Morano, R. L., Frantz, L., Packard, B. A., Campbell, K., & Herman, J. P. (2018) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2018.00325 · Cited by 12
Ontogeny of hypothalamic glucocorticoid receptor-mediated inhibition of the hypothalamic-pituitary-adrenal axis in mice
Laryea, G. N., Arnett, M. G., & Muglia, L. J. (2015) · Stress · doi:10.3109/10253890.2015.1046832 · Cited by 13
“In genetic mouse models of GR deletion in the forebrain (FRGRKO), substantial GR loss does not occur until adulthood, and results in HPA axis hyperactivity, indicating a role for forebrain GR in negative feedback regulation (Boyle et al., 2005, 2006; Furay et al., 2008; Solomon et al., 2012).”
Background
Basic fibroblast growth factor increased glucocorticoid receptors in cortical neurons through MAP kinase pathway
Numakawa, T., Odaka, H., Adachi, N., Chiba, S., Ooshima, Y., Matsuno, H., Nakajima, S., Yoshimura, A., Fumimoto, K., Hirai, Y., et al. (2018) · Neurochemistry International · doi:10.1016/j.neuint.2018.06.009 · Cited by 12
“Furthermore, transgenic mice that have genetically reduced GR expression in their forebrain regions developed both physiological and behavioral abnormalities including impaired negative feedback regulation of the HPA axis and increased depression-like behaviors, which were normalized by antidepressant treatments (Boyl…”
Suppression of glucocorticoid secretion induces a behaviorally depressive state in rotarod performance in rat
Mizoguchi, K., Ikeda, R., Shoji, H., Tanaka, Y., & Tabira, T. (2008) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2008.05.021 · Cited by 12
Prenatal stress changes courtship vocalizations and bone mineral density in mice
Schmidt, M., Lapert, F., Brandwein, C., Deuschle, M., Kasperk, C. H., Grimsley, J. M. S., & Gass, P. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.11.003 · Cited by 11
Effects of pre- and post-natal exposure to bisphenol A on the stress system
Kitraki, E., Nalvarte, I., Alavian‐Ghavanini, A., & Rüegg, J. (2016) · Endocrine Disruptors · doi:10.1080/23273747.2016.1184775 · Cited by 11
Cell-type specialization in the brain is encoded by specific long-range chromatin topologiesPreprint
Winick‐Ng, W., Kukalev, A., Harabula, I., Redondo, L. Z., Szabó, D., Meijer, M., Serebreni, L., Zhang, Y., Bianco, S., Chiariello, A. M., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.04.02.020990 · Cited by 11
HPA axis function in mood disorders
Watson, S., & Mackin, P. (2009) · Psychiatry · doi:10.1016/j.mppsy.2008.11.006 · Cited by 10
Imbalanced glucocorticoid and mineralocorticoid stress hormone receptor function has sex-dependent and independent regulatory effects in the mouse hippocampus
Oakley, R. H., Riddick, N. V., Moy, S. S., & Cidlowski, J. A. (2023) · Neurobiology of Stress · doi:10.1016/j.ynstr.2023.100589 · Cited by 9
“While several studies have reported that loss of GR in the mouse forebrain can lead to dysregulation of the HPA axis (Boyle et al., 2005, 2006; Furay et al., 2008; Solomon et al., 2012), others have observed no alterations in HPA axis activity following depletion of GR in the hippocampus which is…”
Background
Caffeic acid differentially modulates behavior and neurochemicals in chronic unpredictable mild stress and dexamethasone induced models of depression
Hariom, Kumari, P., Chaturvedi, S., Shrivastav, S., Maratha, S. R., & Walia, V. (2024) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2024.173930 · Cited by 9
Molecular mechanism of tuberoinfundibular peptide of 39 on glucocorticoid receptor mediated glutamate/GABA imbalance and cerebral abnormalities against cognitive deficit model
Gunasekaran, V., Sankar, V., & Ramanathan, M. (2019) · Journal of Pharmacy and Pharmacology · doi:10.1111/jphp.13085 · Cited by 9
“However, higher GR occupancy was observed only at elevated corticosterone level in brain.([8]) Chronic stress exposure exhibited over”
Background
Neurochemical Systems Regulating the Hypothalamo-Pituitary-Adrenocortical Axis
Herman, J. P., Figueiredo, H. F., Mueller, N. K., Ostrander, M. M., Zhang, R., Tauchi, M., Choi, D. C., Furay, A. R., Evanson, N. K., Nelson, E., et al. (2006) · Springer eBooks · doi:10.1007/978-0-387-30405-2_13 · Cited by 9
Fresh approaches to antidepressant drug discovery
Anacker, C. (2014) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2014.892071 · Cited by 9
“Accordingly, mice with GR deletion specifically in mature forebrain neurons (GR mice) also exhibit increased glucocorticoid levels, impaired adult hippocampal neurogenesis and depressive behavior [108].”
Background
Differential Regulation of the Glucocorticoid Receptor in a Rat Model of Inflammatory Pain
Ibrahim, S. I. A., Strong, J. A., Qualls, K. A., Ulrich‐Lai, Y. M., & Zhang, J. (2020) · Anesthesia & Analgesia · doi:10.1213/ane.0000000000004652 · Cited by 8
Sildenafil, alone and in combination with imipramine or escitalopram, display antidepressant-like effects in an adrenocorticotropic hormone-induced (ACTH) rodent model of treatment-resistant depression
Saayman, J. L. B., Harvey, B. H., Wegener, G., & Brink, C. B. (2024) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2024.176434 · Cited by 7
Transforming growth factor‐β‐activated kinase 1 resistance limits glucocorticoid responsiveness to Toll‐like receptor 4‐mediated inflammation
Kong, F., Laryea, G. N., Liu, Z., & Bhattacharyya, S. (2014) · Immunology · doi:10.1111/imm.12434 · Cited by 8
Current drug targets for the treatment of depression
Pathak, G., Nigade, A., Anitha, K., & Bhatt, S. (2025) · Brain Disorders · doi:10.1016/j.dscb.2025.100270 · Cited by 7
‘Central’ Actions of Corticosteroid Signaling Suggested by Constitutive Knockout of Corticosteroid Receptors in Small Fish
Sakamoto, T., & Sakamoto, H. (2019) · Nutrients · doi:10.3390/nu11030611 · Cited by 7
“Brain GRs can consistently be considered to be important for regulating hypothalamus-pituitary-adrenal (HPA) axis function independent of pituitary GR activity in mouse models, and the heterozygotic [16] or forebrain-restricted [18] GR knockout also causes depressive behaviors.”
Background
Periconceptional ethanol exposure alters hypothalamic-pituitary-adrenal axis function, signalling elements and associated behaviours in a rodent model
Burgess, D. J., Lucia, D., Cuffe, J. S. M., & Moritz, K. M. (2020) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2020.104901 · Cited by 7
Forebrain corticosteroid receptors promote post-myocardial infarction depression and mortality
Bruns, B., Daub, R., Schmitz, T., Sinno, M. H., Spaich, S., Dewenter, M., Schwale, C., Gass, P., Vogt, M. A., Katus, H. A., et al. (2022) · Basic Research in Cardiology · doi:10.1007/s00395-022-00951-6 · Cited by 7
“An inducible forebrain GR KO was shown to cause CS upregulation and depressive-like behavior in one study [7], whereas findings from Vogt et al.”
Result
Steroid Hormone Signaling Pathways and Sex Differences in Neuroendocrine and Behavioral Responses to Stress
Oyola, M. G., Malysz, A. M., Mani, S. K., & Handa, R. J. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-802114-9.00013-5 · Cited by 7
Obesity and Depression: Shared Pathophysiology and Translational Implications
Huet, L., Delgado, I., Aouizerate, B., Castanon, N., & Capuron, L. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-813333-0.00016-0 · Cited by 8
Regulation of the HPA Axis by Acute and Chronic Stress
Herman, J. P. (2010) · Elsevier eBooks · doi:10.1016/b978-0-08-045396-5.00230-x · Cited by 7
Proteomic analysis of a rat model of depression
Mu, J., Yang, Z., & Xie, P. (2008) · Expert Review of Proteomics · doi:10.1586/14789450.5.2.315 · Cited by 6
Increased antidepressant sensitivity after prefrontal cortex glucocorticoid receptor gene deletion in mice
Hussain, R. J., & Jacobson, L. (2014) · Physiology & Behavior · doi:10.1016/j.physbeh.2014.10.019 · Cited by 6
“Consistent with our results, mice with deletion of forebrain GR, including PFC GR, are more likely than their floxed GR counterparts to respond to chronic imipramine treatment with significant decreases in immobility [26].”
Result
Behavioral effects and inflammatory markers in the brain and periphery after repeated social defeat stress burdened by Opisthorchis felineus infection in mice
Avgustinovich, D. F., Tenditnik, M. V., Bondar, N. P., Marenina, M. K., Zhanaeva, S. Y., Lvova, M. N., Katokhin, A. V., Pavlov, K. S., Evseenko, V. I., & Tolstikova, T. G. (2022) · Physiology & Behavior · doi:10.1016/j.physbeh.2022.113846 · Cited by 7
The JNK signaling pathway as a potential new target for depression
Zhang, J., & Lin, W. (2018) · Chinese Science Bulletin (Chinese Version) · doi:10.1360/n972018-00157 · Cited by 5
Akinetic mutism followed by a manic reaction on introduction of steroid replacement for Addison’s disease
Kalambokis, G., Konitsiotis, S., Pappas, D., & Tsianos, E. V. (2006) · Journal of Endocrinological Investigation · doi:10.1007/bf03345550 · Cited by 6
Corticosteroid Receptor Involvement in the Stress Response
de Kloet, E. R., DeRijk, R. H., & Meijer, O. C. (2011) · Wiley eBooks · doi:10.1002/9781118083222.ch3 · Cited by 6
High emotional reactivity is associated with activation of a molecularly distinct hippocampal-amygdala circuit modulated by the glucocorticoid receptor
Wei, Q., Kumar, V., Moore, S. J., Li, F. R., Murphy, G. G., Watson, S. J., & Akil, H. (2023) · Neurobiology of Stress · doi:10.1016/j.ynstr.2023.100581 · Cited by 5
“The role of brain GR in stress and mood disorders has been investigated in a number of animal models (Arnett et al., 2011; Boyle et al., 2005, 2006; Hartmann et al., 2017; Reichardt et al., 1998; Ridder et al., 2005; Tronche et al., 1999; Wagner et al., 2011).”
Background
The glucocorticoid receptor acts locally to protect dystrophic muscle and heart during disease
OLIVER, T. R., Nguyen, N., Tully, C., McCormack, N. M., Sun, C. M., Fiorillo, A. A., & Heier, C. R. (2024) · Disease Models & Mechanisms · doi:10.1242/dmm.050397 · Cited by 5
Relationships among endocrine and signaling-related responses to antidepressants in human monocytic U-937 blood cells: Analysis of factors and response patterns
Gebhardt, S., Heiser, P., Fischer, S., Schneyer, T., Krieg, J.-C., & Vedder, H. (2008) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2008.07.002 · Cited by 5
“…hand, it is commonly accepted that antidepressants (AD) attenuate HPA axis activity and normalize disturbed relations of endocrine, immune and signal transduction factors (Boyle et al., 2005; Budziszewska and Lason, 1994; Ignatowski and Spengler, 1994; Leonard, 2001; Morley-Fletcher et al., 2004).”
Background
Animal Models in Psychiatric Disorder Studies
Nani, J. V. S., Rodríguez, B., Cruz, F. C., & Hayashi, M. A. F. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.89034 · Cited by 7
Central Nervous System Regulation of the Hypothalamic–Pituitary–Adrenal Axis Stress Response
Herman, J. P. (2011) · doi:10.1002/9781118083222.ch2 · Cited by 5
Sphingosine-1-phosphate receptor 3 activation promotes sociability and regulates transcripts important for anxiolytic-like behavior
Castro-Vildosola, J., Bryan, C.-A., Tajamal, N., Jonnalagadda, S. A., Kasturi, A., Tilly, J., García, I., Kumar, R., Fried, N. T., Hala, T. J., et al. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.12.001 · Cited by 6
Reduced Gene Dosage of the Psychiatric Risk Gene Cacna1c Is Associated with Impairments in Hypothalamic–Pituitary–Adrenal Axis Activity in Rats
Moon, A. L., Mawson, E. R., Gasalla, P., Wilkinson, L. S., Dwyer, D. M., Thomas, K. L., & Hall, J. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26125547 · Cited by 4
“Peripheral hormone levels (Figure 3A,B”
Perinatal glucocorticoid sensitivity in the preterm newborn: molecular mechanisms, endogenous determinants, and clinical implications
Anti, N. A. O., Gheorghe, C. P., Deming, D. D., Adeoye, O. O., Zhang, L., & Mata‐Greenwood, E. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1587891 · Cited by 6

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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