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

Abstract

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.

Restraint Stress Alters Nociceptin/Orphanin FQ and CRF Systems in the Rat Central Amygdala: Significance for Anxiety-Like Behaviors

“…The electrophysiological and microinjection results clearly point to the specificity of the role of the CeA in N/OFQ function in response to restraint stress exposure. In agreement with our findings, other studies have shown that site-specific microinjection of N/OFQ into the CeA resulted in significant anxiolytic-like actions in the EPM test, supporting the anxiolyticlike effects of this peptide (Uchiyama et al, 2008b). In contrast, N/OFQ effects were observed in rodents that were not subjected to stress procedures (Uchiyama et al, 2008a).…”

“…This is, however, not surprising because the EPM is a paradigm where dose-response relationships are not easily captured. Moreover, this finding is in line with previous studies showing that the EPM effects of N/OFQ are not dose-related (Uchiyama et al, 2008a, b;Economidou et al, 2011).…”

“…In agreement with our findings, other studies have shown that site-specific microinjection of N/OFQ into the CeA resulted in significant anxiolytic-like actions in the EPM test, supporting the anxiolyticlike effects of this peptide (Uchiyama et al, 2008b). In contrast, N/OFQ effects were observed in rodents that were not subjected to stress procedures (Uchiyama et al, 2008a). It is well known that environmental factors, such as housing conditions, have an important impact in the regulation of stress mechanisms.…”

“…On the other hand, the CeA and the BLA showed a reduction in CRF 1 receptor gene expression after restraint. This is consistent with a scenario in which stress leads to the recruitment of the CRF system in specific brain areas, including CeA and PVN (Sterrenburg et al, 2012). This is also in line with what we observed in the N/OFQ system in which NOP transcript overexpression may also be viewed as a physiological compensatory reaction aimed at potentiating N/OFQ signaling within the amygdala nuclei.…”

“…Additional factors may have also contributed to this discrepancy in the anxiolytic effect of intra-CeA injection of N/OFQ in normal nonstressed rats. For example, here the study was conducted in Wistar rats during the dark period of the light dark cycle using a four arm elevated maze, whereas in the study by Uchiyama et al (2008a), Sprague Dawley rats were tested during the light phase of the light dark cycle using a three arm elevated maze.…”