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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Association between Glucocorticoid Receptor Methylation and Hippocampal Subfields in Major Depressive Disorder
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“Glucocorticoid receptors in the forebrain play an important role in depression [6,18].”
Background
Hippocampal Neuronal Nitric Oxide Synthase Mediates the Stress-Related Depressive Behaviors of Glucocorticoids by Downregulating Glucocorticoid Receptor
Zhou, Q., Zhu, L., Chen, C., Wu, H., Luo, C., Chang, L., & Zhu, D. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.0004-11.2011 · Cited by 145
“This has led to a prevailing view that impaired hippocampal GR function is correlated with the hyperactivity of the HPA axis, and could be an etiologic factor in depression (Boyle et al., 2005).”
Background
Treatment-resistant depression: are animal models of depression fit for purpose?
Willner, P., & Belzung, C. (2015) · Psychopharmacology · doi:10.1007/s00213-015-4034-7 · Cited by 153
“To our knowledge, out of all of the mutants so far mentioned, the effects of antidepressant treatments have only been investigated in the FBGRKO mice, revealing normal responses to acute or chronic antidepressants (Boyle et al. 2005; Vincent et al. 2013).”
Background
Are BDNF and glucocorticoid activities calibrated?
Jeanneteau, F. D., & Chao, M. V. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.09.017 · Cited by 150
“Deletion of the Gr gene in the forebrain only recapitulated the disinhibition of the HPA axis but increased anxiety, suggesting that the forebrain structures participate in the maintenance of HPA axis activity (Boyle et al., 2005, 2006).”
The cortisol switch between vulnerability and resilience
de Kloet, E. R., & Joëls, M. (2023) · Molecular Psychiatry · doi:10.1038/s41380-022-01934-8 · Cited by 161
“Collectively, this phenotype suggests a rat model displaying vulnerability to stress [89].”
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Neurobiological Mechanisms of Stress Resilience and Implications for the Aged Population
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“Indeed, the authors reported that in the absence of chronic stress, GABAB(1a) KO and GABAB(1b) KO mice displayed antidepressant-like behavior in the FST, but no difference in the SPT [136] (Table 3).”
BackgroundInfluential
Cyclin-Dependent Kinase 5 Differentially Regulates the Transcriptional Activity of the Glucocorticoid Receptor through Phosphorylation: Clinical Implications for the Nervous System Response to Glucocorticoids and Stress
Kino, T., Ichijo, T., Amin, N. D., Kesavapany, S., Wang, Y., Kim, N., Rao, S., Player, A. N., Zheng, Y., Garabedian, M. J., et al. (2007) · Molecular Endocrinology · doi:10.1210/me.2006-0345 · Cited by 131
Metabotropic Glutamate Receptor Subtype 7 Ablation Causes Dysregulation of the HPA Axis and Increases Hippocampal BDNF Protein Levels: Implications for Stress-Related Psychiatric Disorders
Mitsukawa, K., Mombereau, C., Loetscher, E., Uzunov, D. P., van der Putten, H., Flor, P. J., & Cryan, J. F. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300926 · Cited by 134
“Further, mice with functional downregulation/ablation of these two receptors have altered emotional behaviors relevant to anxiety and depression (Toth, 2003; Urani and Gass, 2003; Boyle et al, 2005).”
Background
Psychological stress increases histone H3 phosphorylation in adult dentate gyrus granule neurons: involvement in a glucocorticoid receptor‐dependent behavioural response
Bilang‐Bleuel, A., Ulbricht, S., Chandramohan, Y., Carli, S. D., Droste, S. K., & Reul, J. M. H. M. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04358.x · Cited by 128
“particular, in the regulation of the hypothalamic–pituitary–adrenocortical (HPA) axis, thereby affecting the levels of circulating glucocorticoid hormones (De Kloet & Reul, 1987; De Kloet et al., 1998; Reul et al., 2000; Boyle et al., 2005).”
Background
Glucocorticoid Signaling in Health and Disease: Insights From Tissue-Specific GR Knockout Mice
Whirledge, S., & DeFranco, D. B. (2017) · Endocrinology · doi:10.1210/en.2017-00728 · Cited by 123
“This promoter is activated at approximately 3 weeks of age in mouse neonates and led to selective deletion of floxed GR in the hippocampus and cortex with intact GR in the ce ntral nucleus of the amygdala, pituitary and the PVN of the hypothalamus (34).”
BackgroundMethod
A cell-autonomous role for the glucocorticoid receptor in skeletal muscle atrophy induced by systemic glucocorticoid exposure
Watson, M. L., Baehr, L. M., Reichardt, H. M., Tuckermann, J. P., Bodine, S. C., & Furlow, J. D. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00512.2011 · Cited by 122
“This approach has been employed successfully in the liver (24, 36, 56), pancreas (16), T cells (6), macrophages (57), osteoblasts (39), and nervous system (5, 23, 55) to determine tissue-specific phenotypes due to reduced GR expression.”
Stress-induced mechanisms in mental illness: A role for glucocorticoid signalling
Cattaneo, A., & Riva, M. A. (2016) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2015.07.021 · Cited by 118
Action control is mediated by prefrontal BDNF and glucocorticoid receptor binding
Gourley, S. L., Swanson, A. M., Jacobs, A. M., Howell, J. L., Mo, M., Dileone, R., Koleske, A. J., & Taylor, J. R. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1208342109 · Cited by 119
“Accordingly, GR deficiency is associated with hypersensitivity to stressors and depressive-like behavior (6), particularly when gene knockout is restricted to the forebrain (7).”
Background
Synaptic regulation of the hypothalamic–pituitary–adrenal axis and its modulation by glucocorticoids and stress
Levy, B. H., & Tasker, J. G. (2012) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2012.00024 · Cited by 153
“…has been suggested that this glucocorticoid resistance could result from a reduced expression of the glucocorticoid receptor (GR; Modell et al., 1997; Boyle et al., 2005), an idea supported by reports of reduced GR expression in post-mortem brain tissue of depressed patients (Webster et al., 2002).”
Background
The Interface of Pain and Mood Disturbances in the Rheumatic Diseases
Goldenberg, D. L. (2009) · Seminars in Arthritis and Rheumatism · doi:10.1016/j.semarthrit.2008.11.005 · Cited by 115
Corticosterone and related receptor expression are associated with increased β-amyloid plaques in isolated Tg2576 mice
Dong, H., Yuede, C. M., Yoo, H.-S., Martin, M. V., Deal, C., Mace, A. G., & Csernansky, J. G. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.05.017 · Cited by 112
“Plasma concentrations of corticosterone were measured using a radioimmunoassay kit from ICN (ICN Pharmaceuticals, Costa Mesa, CA, USA) as previously described (Jacobson et al., 1997; Boyle et al., 2005).”
Method
HPA axis function in mood disorders
Watson, S., & Mackin, P. (2006) · Psychiatry · doi:10.1383/psyt.2006.5.5.166 · Cited by 111
The effect of antidepressant drugs on the HPA axis activity, glucocorticoid receptor level and FKBP51 concentration in prenatally stressed rats
Szymańska, M., Budziszewska, B., Jaworska-Feil, L., Basta‐Kaim, A., Kubera, M., Leśkiewicz, M., Regulska, M., & Lasoń, W. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2008.12.012 · Cited by 112
“…GR expression in the forebrain and limbic system revealed decreased anxiety-like behavior, while mice with elevated GR level showed increased anxiety-like behavior, however, depression-like behavior in the forced swim test was observed in both groups (Boyle et al., 2005; Wei et al., 2004, 2007).”
Genetic approaches to hypothalamic-pituitary-adrenal axis regulation
Arnett, M. G., Muglia, L. M., Laryea, G., & Muglia, L. J. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.215 · Cited by 105
Open questions in current models of antidepressant action
Tanti, A., & Belzung, C. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00585.x · Cited by 115
“Using mice with an acquired forebrain-specific disruption of GR (FBGRKO) Boyle et al. (2005) showed that AD induced a therapeutic effect, but failed to reverse the loss of negative feedback induced by the GR deletion.”
Background
Maternal separation and maternal care act independently on the development of HPA responses in male rats
Macrı̀, S., Chiarotti, F., & Würbel, H. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.03.031 · Cited by 118
Disrupting hypothalamic glucocorticoid receptors causes HPA axis hyperactivity and excess adiposity
Laryea, G., Schütz, G., & Muglia, L. J. (2013) · Molecular Endocrinology · doi:10.1210/me.2013-1187 · Cited by 106
Behavioral Despair and Home-Cage Activity in Mice with Chronically Elevated Baseline Corticosterone Concentrations
Malisch, J. L., Breuner, C. W., Kolb, E. M., Wada, H., Hannon, R. M., Chappell, M. A., Middleton, K. M., & Garland, T. (2008) · Behavior Genetics · doi:10.1007/s10519-008-9246-8 · Cited by 107
“Furthermore, mice with reduced GR in the forebrain have elevated baseline CORT, impaired negative feedback within the HPA axis, and increased ‘‘depression-like behaviors’’ ( Boyle et al. 2005 ).”
Background
Hypothalamic–pituitary–adrenal axis dysregulation and behavioral analysis of mouse mutants with altered glucocorticoid or mineralocorticoid receptor function: Review
Kolber, B. J., Wieczorek, L., & Muglia, L. J. (2008) · Stress · doi:10.1080/10253890701821081 · Cited by 106
“To more precisely define the role of GR in the CNS, some research groups have produced pan-neural GR knockout (GRNesCre; Tronche et al. 1999) and forebrain-specific GR knockout (FBGRKO; Boyle et al. 2005) lines.”
BackgroundMethodInfluential
Depression‐like behavior in the forced swimming test in PACAP‐deficient mice: amelioration by the atypical antipsychotic risperidone
Hashimoto, H., Hashimoto, R., Shintani, N., Tanaka, K., Yamamoto, A., Hatanaka, M., Guo, X., Morita, Y., Tanida, M., Nagai, K., et al. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06168.x · Cited by 105
Alterations in the central CRF system of two different rat models of comorbid depression and functional gastrointestinal disorders
Bravo, J. A., Dinan, T. G., & Cryan, J. F. (2010) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145710000994 · Cited by 106
“1997 ; Vizi & Kiss, 1998), although the hippocampal control of the HPA axis is mostly due to glucocorticoid receptor activation (Boyle et al. 2005; Furay et al. 2008; van Haarst et al. 1997).”
Background
HPA Axis Interactions with Behavioral Systems
Packard, A. E. B., Egan, A. E., & Ulrich‐Lai, Y. M. (2016) · Comprehensive physiology · doi:10.1002/cphy.c150042 · Cited by 138
Genetic Strain Differences in Learned Fear Inhibition Associated with Variation in Neuroendocrine, Autonomic, and Amygdala Dendritic Phenotypes
Camp, M., MacPherson, K. P., Lederle, L. I., Graybeal, C., Gaburro, S., DeBrouse, L., Ihne, J. L., Bravo, J. A., O’Connor, R. M., Ciocchi, S., et al. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.340 · Cited by 103
Glucocorticoid receptor-dependent astrocytes mediate stress vulnerability
Lu, C.-L., Ren, J., Mo, J.-W., Fan, J., Guo, F., Chen, L.-Y., Wen, Y.-L., Li, S.-J., Fang, Y.-Y., Wu, Z.-F., et al. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.11.022 · Cited by 97
“61 GRs in neurons have been shown to modulate depressive-like behaviors in animal studies 62 (15-19).”
Background
Emerging roles of SIRT1 activator, SRT2104, in disease treatment
Chang, N., Li, J., Lin, S., Zhang, J., Zeng, W.-Q., Ma, G., & Wang, Y. (2024) · Scientific Reports · doi:10.1038/s41598-024-55923-8 · Cited by 107
“Research indicates a notable reduction in glucocorticoid receptor (GR) expression in depression animal models’ brain tissues 69,70 .”
Background
The prefrontal–limbic network in depression: Modulation by hypothalamus, basal ganglia and midbrain
Bennett, M. R. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.01.006 · Cited by 98
“…the hypothalamus and the pituitary) lead to slightly elevated baseline levels of corticosterone, failure of dexamethasone to inhibit corticosterone release, and increased depression-like behavior, as well as a 20% increase in corticosterone levels when stressed (Boyle et al., 2005, 2006).”
Forced swim stressor: Trends in usage and mechanistic consideration
Molendijk, M. L., & de Kloet, E. R. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.15139 · Cited by 105
“Forebrain knockout animals (GR- FBKO) showed increased immobility (Boyle et al., 2005) which can be explained by the sparing of hypothalamic, central amygdala and brain stem neurons expressing GR in this model.”
Background
Deletion of forebrain glucocorticoid receptors impairs neuroendocrine stress responses and induces depression-like behavior in males but not females
Solomon, M. B., Furay, A. R., Jones, K., Packard, A. E. B., Packard, B. A., Wulsin, A. C., & Herman, J. P. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2011.12.014 · Cited by 96
Transient Early-Life Forebrain Corticotropin-Releasing Hormone Elevation Causes Long-Lasting Anxiogenic and Despair-Like Changes in Mice
Kolber, B. J., Boyle, M. P., Wieczorek, L., Kelley, C. L., Onwuzurike, C., Nettles, S. A., Vogt, S. K., & Muglia, L. J. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.4470-09.2010 · Cited by 95
“Corticosterone and adrenocorticotropic hormone (ACTH) were analyzed by radioimmunoassay as previously described (Boyle et al., 2005).”
MethodInfluential
Stress and the brain: Solving the puzzle using microdialysis
Linthorst, A. C. E., & Reul, J. M. H. M. (2007) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2007.09.019 · Cited by 98
The hypothalamic-pituitary-adrenal axis as a substrate for stress resilience: Interactions with the circadian clock
Kinlein, S. A., & Karatsoreos, I. N. (2019) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2019.100819 · Cited by 102
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BackgroundInfluential
Maternal Programming of Defensive Responses Through Sustained Effects on Gene Expression
Meaney, M. J. (2007) · Oxford University Press eBooks · doi:10.1093/acprof:oso/9780195306255.003.0007 · Cited by 92
“For example, selective disruption of the glucocorticoid receptor gene in the hippocampus and cortex that is unique to adulthood results in negative feedback impairments and increased HPA activity.(59)”
The immediate early gene early growth response gene 3 mediates adaptation to stress and novelty
Gallitano, A. L., Izumi, Y., Tokuda, K., Zorumski, C. F., Howell, M., Muglia, L. J., Wozniak, D. F., & Milbrandt, J. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.05.050 · Cited by 90
Persistent depressive state after chronic stress in rats is accompanied by HPA axis dysregulation and reduced prefrontal dopaminergic neurotransmission
Mizoguchi, K., Shoji, H., Ikeda, R., Tanaka, Y., & Tabira, T. (2008) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2008.07.002 · Cited by 94

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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