Chronic stress induces sex-specific alterations in methylation and expression of corticotropin-releasing factor gene in the rat

Linda Sterrenburg, Balázs Gaszner, Jeroen Boerrigter, Lennart Santbergen, Mattia Bramini, Evan Elliott, Alon Chen, Bernard W M M Peeters, Eric W. Roubos, Tamas Kozicz

Research output: Contribution to journalArticle

86 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere28128
JournalPLoS One
Volume6
Issue number11
DOIs
StatePublished - Nov 23 2011
Externally publishedYes

Fingerprint

corticotropin-releasing hormone
Methylation
Corticotropin-Releasing Hormone
amygdala
Paraventricular Hypothalamic Nucleus
methylation
Rats
Genes
Brain
gender
rats
genes
CREB-Binding Protein
brain
Histone Acetyltransferases
Epigenomics
epigenetics
Messenger RNA
Peptides
Histone Deacetylases

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Chronic stress induces sex-specific alterations in methylation and expression of corticotropin-releasing factor gene in the rat. / Sterrenburg, Linda; Gaszner, Balázs; Boerrigter, Jeroen; Santbergen, Lennart; Bramini, Mattia; Elliott, Evan; Chen, Alon; Peeters, Bernard W M M; Roubos, Eric W.; Kozicz, Tamas.

In: PLoS One, Vol. 6, No. 11, e28128, 23.11.2011.

Research output: Contribution to journalArticle

Sterrenburg, L, Gaszner, B, Boerrigter, J, Santbergen, L, Bramini, M, Elliott, E, Chen, A, Peeters, BWMM, Roubos, EW & Kozicz, T 2011, 'Chronic stress induces sex-specific alterations in methylation and expression of corticotropin-releasing factor gene in the rat', PLoS One, vol. 6, no. 11, e28128. https://doi.org/10.1371/journal.pone.0028128
Sterrenburg, Linda ; Gaszner, Balázs ; Boerrigter, Jeroen ; Santbergen, Lennart ; Bramini, Mattia ; Elliott, Evan ; Chen, Alon ; Peeters, Bernard W M M ; Roubos, Eric W. ; Kozicz, Tamas. / Chronic stress induces sex-specific alterations in methylation and expression of corticotropin-releasing factor gene in the rat. In: PLoS One. 2011 ; Vol. 6, No. 11.
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AU - Sterrenburg, Linda

AU - Gaszner, Balázs

AU - Boerrigter, Jeroen

AU - Santbergen, Lennart

AU - Bramini, Mattia

AU - Elliott, Evan

AU - Chen, Alon

AU - Peeters, Bernard W M M

AU - Roubos, Eric W.

AU - Kozicz, Tamas

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N2 - 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.

AB - 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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