Sex-dependent and differential responses to acute restraint stress of corticotropin-releasing factor-producing neurons in the rat paraventricular nucleus, central amygdala, and bed nucleus of the stria terminalis.

Male and female rodents respond differently to acute stress. We tested our hypothesis that this sex difference is based on differences in stress sensitivity of forebrain areas, by determining possible effects of a single acute psychogenic stressor (1-hr restraint stress) on neuronal gene expression (c-Fos and FosB immunoreactivities), storage of corticotropin-releasing factor (CRF) immunoreactivity, and CRF production (CRF mRNA in situ hybridization) as well as the expression of genes associated with epigenetic processes (quantitative RT-PCR) in the rat paraventricular nucleus (PVN), the oval and fusiform subdivisions of the bed nucleus of the stria terminalis (BSTov and BSTfu, respectively), and the central amygdala (CeA), in both males and females. Compared with females, male rats responded to the stressor with a stronger rise in corticosterone titer and a stronger increase in neuronal contents of c-Fos, CRF mRNA, and CREB-binding protein mRNA in the PVN. In the BSTov, females but not males showed an increase in c-Fos, whereas the CRF mRNA content was increased in males only. In the BSTfu, males and females showed similar stress-induced increases in c-Fos and FosB, whereas in the CeA, both sexes revealed similar increases in c-Fos and in CRF mRNA. We conclude that male and female rats differ in their reactivity to acute stress with respect to possibly epigenetically mediated (particularly in the PVN) neuronal gene expression and neuropeptide dynamics (PVN and BSTov) and that this difference may contribute to the sex dependence of the animal's physiological and behavioral responses to an acute stressor.

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

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.