Abstract
BackgroundAlthough the higher prevalence of depression in women than in men is well known, the neuronal basis of this sex difference is largely elusive.MethodsMale 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).ResultsCVMS 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.ConclusionsThe 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.
Highlights
Chronic exposure to stressors can result in psychopathologies, of which depression is ranked second in the global burden of disease [1,2,3,4,5,6,7]
We have supported our hypothesis that chronic stress, induced by the chronic variable mild stress (CVMS) paradigm, recruits corticotropin-releasing factor (CRF)-producing neurons in the paraventricular nucleus (PVN), BSTov, BSTfu and central amygdala (CeA), in a brain center- and sex-specific manner that is clearly different from the responses of these brain centers induced by acute restraint stress [27]
CVMS leaves a brain center- and sex-specific epigenetic footprint that may account for the observed differential responses by these neurons to CVMS
Summary
Chronic exposure to stressors can result in psychopathologies, of which depression is ranked second in the global burden of disease [1,2,3,4,5,6,7]. In depressed people the number of CRF mRNA and CRF peptidecontaining PVN neurons is increased [12,13], which suggests that chronic stressors change the regulatory input system to the PVN Rodent studies underpin this idea, showing that various forebrain centers control HPA-axis activity, of which the central amygdala (CeA) and the oval subdivision of the bed nucleus of the stria terminalis (BSTov) [14,15] are of particular interest. Both play a role in the control of mood [16,17,18,19], host the majority of the brain’s CRF neurons [20,21,22,23] and change their activity upon exposure to chronic stress [24]. The higher prevalence of depression in women than in men is well known, the neuronal basis of this sex difference is largely elusive
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