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Cited by 149Stress Responses and CortisolEpigenetics and DNA MethylationNeurotransmitter Receptor Influence on Behavior

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Chronic Stress Induces Sex-Specific Alterations in Methylation and Expression of Corticotropin-Releasing Factor Gene in the Rat

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Sterrenburg, Linda, Gaszner, Balázs, Boerrigter, Jeroen, Santbergen, Lennart, Bramini, Mattia, Elliott, Evan, Chen, Alon, Peeters, Bernard W. M. M., Roubos, Eric W., Kozicz, Tamás·2011·PLoS ONE
DOI 10.1371/journal.pone.0028128PMC PMC3223222
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Abstract

BACKGROUND: Although the higher prevalence of depression in women than in men is well known, the neuronal basis of this sex difference is largely elusive. METHODS: Male and female rats were exposed to chronic variable mild stress (CVMS) after which immediate early gene products, corticotropin-releasing factor (CRF) mRNA and peptide, various epigenetic-associated enzymes and DNA methylation of the Crf gene were determined in the hypothalamic paraventricular nucleus (PVN), oval (BSTov) and fusiform (BSTfu) parts of the bed nucleus of the stria terminalis, and central amygdala (CeA). RESULTS: CVMS induced site-specific changes in Crf gene methylation in all brain centers studied in female rats and in the male BST and CeA, whereas the histone acetyltransferase, CREB-binding protein was increased in the female BST and the histone-deacetylase-5 decreased in the male CeA. These changes were accompanied by an increased amount of c-Fos in the PVN, BSTfu and CeA in males, and of FosB in the PVN of both sexes and in the male BSTov and BSTfu. In the PVN, CVMS increased CRF mRNA in males and CRF peptide decreased in females. CONCLUSIONS: The data confirm our hypothesis that chronic stress affects gene expression and CRF transcriptional, translational and secretory activities in the PVN, BSTov, BSTfu and CeA, in a brain center-specific and sex-specific manner. Brain region-specific and sex-specific changes in epigenetic activity and neuronal activation may play, too, an important role in the sex specificity of the stress response and the susceptibility to depression.

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Figures

Figure 1 Corticosterone titer and body weight after stress. Corticosterone titer in µmol/l (A) and body weight in grams (B) of control and stressed male (m) and female (f) rats. Means and SEM, n = 6 per group, * statistical difference between groups indicated, at P < 0.05.
Figure 1 Corticosterone titer and body weight after stress. Corticosterone titer in µmol/l (A) and body weight in grams (B) of control and stressed male (m) and female (f) rats. Means and SEM, n = 6 per group, * statistical difference between groups indicated, at P < 0.05.CC BY · PubMed Central
Figure 2 Detailed images of immunocytochemistry and in situ hybridization. Images representative for immunocytochemistry of c-Fos (A), FosB (B), for in situ hybridization of CRF mRNA (C) and immunocytochemistry of CRF (D) in the rat brain, taken in the hypothalamic paraventricular nucleus. Scale bars = 20 µm.
Figure 2 Detailed images of immunocytochemistry and in situ hybridization. Images representative for immunocytochemistry of c-Fos (A), FosB (B), for in situ hybridization of CRF mRNA (C) and immunocytochemistry of CRF (D) in the rat brain, taken in the hypothalamic paraventricular nucleus. Scale bars = 20 µm.CC BY · PubMed Central
Figure 3 Paraventricular nucleus of the hypothalamus. Paraventricular nucleus of the hypothalamus in control and stressed male (m) and female (f) rats, with representative images, and numbers per section of neurons stained for c-Fos (A), FosB (B), CRF mRNA (C) and CRF (D), and specific staining density per neuron (SSD) in arbitrary units (a.u.; C and D). Means + SEM, n = 6 per group, * P < 0.05. Scale bars = 50 µm.
Figure 3 Paraventricular nucleus of the hypothalamus. Paraventricular nucleus of the hypothalamus in control and stressed male (m) and female (f) rats, with representative images, and numbers per section of neurons stained for c-Fos (A), FosB (B), CRF mRNA (C) and CRF (D), and specific staining density per neuron (SSD) in arbitrary units (a.u.; C and D). Means + SEM, n = 6 per group, * P < 0.05. Scale bars = 50 µm.CC BY · PubMed Central
Figure 4 Oval bed nucleus of the stria terminalis. Oval bed nucleus of the stria terminalis (BSTov) in control and stressed male (m) and female (f) rats, with representative images, and numbers per section of neurons stained for c-Fos (A), FosB (B), CRF mRNA (C) and CRF (D), and specific staining density per neuron (SSD) in arbitrary units (a.u.; C and D). Means + SEM, n = 6 per group, * P < 0.05. Scale bars = 50 µm.
Figure 4 Oval bed nucleus of the stria terminalis. Oval bed nucleus of the stria terminalis (BSTov) in control and stressed male (m) and female (f) rats, with representative images, and numbers per section of neurons stained for c-Fos (A), FosB (B), CRF mRNA (C) and CRF (D), and specific staining density per neuron (SSD) in arbitrary units (a.u.; C and D). Means + SEM, n = 6 per group, * P < 0.05. Scale bars = 50 µm.CC BY · PubMed Central
Figure 5 Fusiform bed nucleus of the stria terminalis. Fusiform bed nucleus of the stria terminalis (BSTfu) in control and stressed male (m) and female (f) rats, with representative images, and numbers per section of neurons stained for c-Fos (A), FosB (B), CRF mRNA (C) and CRF (D), and specific staining density per neuron (SSD) in arbitrary units (a.u.; C and D). Means + SEM, n = 6 per group, * P < 0.05. Scale bars = 50 µm.
Figure 5 Fusiform bed nucleus of the stria terminalis. Fusiform bed nucleus of the stria terminalis (BSTfu) in control and stressed male (m) and female (f) rats, with representative images, and numbers per section of neurons stained for c-Fos (A), FosB (B), CRF mRNA (C) and CRF (D), and specific staining density per neuron (SSD) in arbitrary units (a.u.; C and D). Means + SEM, n = 6 per group, * P < 0.05. Scale bars = 50 µm.CC BY · PubMed Central
Figure 6 Central amygdale. Central amygdala (CeA) in control and stressed male (m) and female (f) rats, with representative images, and numbers per section of neurons stained for c-Fos (A), FosB (B), CRF mRNA (C) and CRF (D), and specific staining density per neuron (SSD) in arbitrary units (a.u.; C and D). Means + SEM, n = 6 per group, * P < 0.05. Scale bars = 50 µm.
Figure 6 Central amygdale. Central amygdala (CeA) in control and stressed male (m) and female (f) rats, with representative images, and numbers per section of neurons stained for c-Fos (A), FosB (B), CRF mRNA (C) and CRF (D), and specific staining density per neuron (SSD) in arbitrary units (a.u.; C and D). Means + SEM, n = 6 per group, * P < 0.05. Scale bars = 50 µm.CC BY · PubMed Central
Figure 7 Methylation of the Crf gene. Methylation of the Crf gene in the PVN (A), BST (B) and CeA (C) in control and stressed male and female rats. CpGs, cytosine-phosphate-guanine sites. Means±SEM, n = 6 per group, * P < 0.05.
Figure 7 Methylation of the Crf gene. Methylation of the Crf gene in the PVN (A), BST (B) and CeA (C) in control and stressed male and female rats. CpGs, cytosine-phosphate-guanine sites. Means±SEM, n = 6 per group, * P < 0.05.CC BY · PubMed Central
Figure 8 Summary of methylation data. Panel summarizing methylation of the Crf gene at sites in 5′ flanking region, exon 1, intron and exon 2 of Crf, in the PVN, BST and CeA. Dark box: methylation increase compared with respective control. Light gray box: methylation decrease compared with respective control.
Figure 8 Summary of methylation data. Panel summarizing methylation of the Crf gene at sites in 5′ flanking region, exon 1, intron and exon 2 of Crf, in the PVN, BST and CeA. Dark box: methylation increase compared with respective control. Light gray box: methylation decrease compared with respective control.CC BY · PubMed Central

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  1. EJ Nestler, 1999, DeltaFosB: a molecular mediator of long-term neural and behavioral plasticity., Brain Res, 835, 10

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Metadata

Authors
Sterrenburg, L., Gaszner, B., Boerrigter, J., Santbergen, L., Bramini, M., Elliott, E., Chen, A., Peeters, B. W. M. M., Roubos, E. W., & Kozicz, T.
Affiliations
  • Radboud University Nijmegen (NL)
  • University of Pecs (HU)
  • Bar-Ilan University (IL)
  • Weizmann Institute of Science (IL)
Corresponding author
Kozicz, Tamás
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-11-23
Volume
6
Issue
11
Pages
e28128
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0028128
PMC
PMC3223222
OpenAlex
W2159916106
Cited by
149
References
80
Citations by year
2026: 4 · 2025: 3 · 2024: 1 · 2023: 8 · 2022: 11 · 2021: 12 · 2020: 17 · 2019: 10 · 2018: 10 · 2017: 9 · 2016: 16 · 2015: 9 · 2014: 15 · 2013: 13 · 2012: 10
FWCI
4.90
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repository of the University of Granada (University of Granada) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
Funders
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (864.05.008)
  • Magyar Tudományos Akadémia
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
corticotropin-releasing factor, DNA methylation, sex differences, depression, hypothalamic paraventricular nucleus, bed nucleus of the stria terminalis, central amygdala, CREB-binding protein, HDAC5, c-fos, FosB, immediate early genes, epigenetic regulation, stress response
MeSH terms
Animals, Body Weight, Chronic Disease, Corticosterone, Corticotropin-Releasing Hormone, Female, Gene Expression Regulation, Immunohistochemistry, Male, Models, Biological, Paraventricular Hypothalamic Nucleus, Septal Nuclei, Sex Characteristics, Stress, Psychological, Rats, Wistar, In Situ Hybridization, DNA Methylation, Epigenesis, Genetic, Rats

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