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

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.

Neurobiological Interactions Between Stress and the Endocannabinoid System

“…It is possible that the discrepancy of these effects could be related to the time point following the cessation of stress when AEA levels were measured; however, an alternate hypothesis is that there are differences between chronic homotypic and heterotypic stressors on CRH signaling. Chronic homotypic stress has been shown to elevate CRH mRNA in the amygdala (Gray et al, 2010), similar to what was seen with sustained exposure to corticosterone (Makino et al, 1994a,b;Swanson and Simmons, 1989), while CUS surprisingly has been found to have little effects on CRH in the amygdala (Kim et al, 2006;Sterrenburg et al, 2011) and actually downregulates CRHR1 in the amygdala (Sandi et al, 2008). As such, the divergence of the effects of homotypic vs heterotypic stress on AEA content could be due to the differential effects of these stress paradigms on CRH signaling; however, given that this relationship has only been established in the amygdala (Gray et al, 2015), this model cannot explain the differential effects in other brain regions.…”

Epigenetics of the Depressed Brain: Role of Histone Acetylation and Methylation

“…In rats that have undergone acute social defeat, H3 acetylation is decreased transiently in the amygdala, although there was no effect of chronic social defeat in rats (Hollis et al, 2011). Another study examining chronic variable stress in rats found reduced HDAC5 levels in the central amygdala in male rats (Sterrenburg et al, 2011), similar to what was observed in NAc after chronic social defeat stress in mice . From a limited number of studies examining the medial PFC, global levels of histone acetylation do not seem to change after acute or chronic stress in rodent models (Covington et al, 2011b;Figure 3.…”

CGRP antagonist infused into the bed nucleus of the stria terminalis impairs the acquisition and expression of context but not discretely cued fear

“…Many of these systems are responsive to stress (c.f., Hokfelt 1991;Hokfelt et al 2000) and, as such, are potential therapeutic targets for stress-related pathologies. A large body of evidence has pointed to corticotropinreleasing factor (CRF) as one such peptide (Chappell et al 1986;Lee and Davis 1997;Nagashima et al 2003;Cooper and Huhman 2005;Hishinuma et al 2005;Choi et al 2006;Sahuque et al 2006;Santibanez et al 2006;Lee et al 2008;Shepard et al 2009;Sterrenburg et al 2011;Lebow et al 2012), and more recent data have suggested an important role for pituitary adenylate cyclase-activating peptide (PACAP) as well (Hammack et al 2009(Hammack et al , 2010; for possible clinical relevance also see Ressler et al 2011;Almli et al 2013;Jovanovic et al 2013).…”