Female responses to acute and repeated restraint stress differ from those in males

Abstract

Chronic stress is implicated in diseases which differentially affect men and women. This study investigated how the activation of neuronal subpopulations contributes to changes in neuroendocrine regulation that predispose members of each sex to stress-related health challenges. Adult male and female rats were restrained in single (acute) or 14 consecutive daily (repeated) 30 min sessions; brain sections were immunohistochemically stained for Fos, arginine vasopressin (AVP) or glucocorticoid receptor (GR) within the paraventricular hypothalamic nucleus (PVH). Acute restraint increased the number of PVH cells expressing Fos, with greater increases in males than females. Habituated responses were seen following repeated stress in both sexes, with no sex differences between groups. No sex differences were found in the number of neurons co-expressing Fos and AVP. Absolute counts of cellular Fos and GR co-localization mirrored Fos expression. In contrast, when doubly-labeled cells were normalized to staining for Fos alone, females showed greater numbers of Fos- and GR-positive cells than males after both acute and repeated stress. These data demonstrate that sex-specific stress responses are evident at the level of neuronal activation, and may contribute to different consequences of chronic stress in females versus males. Females may be more sensitive to glucocorticoid negative feedback, suggesting that sex-dependent differences in the efficiency of initiating and terminating stress responses may exist. Understanding the neural and endocrine pathways that mediate these functions in males and females will inform targeted therapeutic strategies to alleviate stress and the sex-specific afflictions with which it is associated.

Sex-dependent programming effects of prenatal glucocorticoid treatment on the developing serotonin system and stress-related behaviors in adulthood

“…Sex steroid hormones, including E2 and androgens, have been shown to regulate GC receptors in the brain (Ahima and Harlan, 1992, Burgess and Handa, 1993, Kerr et al, 1996, Blanco et al, 2002, Sheng et al, 2003). Sex differences in the GC receptors and GC receptor function in the brain have also been reported (McCormick et al, 1995, Goel and Bale, 2010, Zavala et al, 2011, Bourke et al, 2012, Kikuchi et al, 2015). Thus, the differential levels of sex hormones in males vs females during development may organize the brain GC system in a sex-specific manner.…”

Hippocampal gene expression induced by cold swim stress depends on sex and handling

“…Noticeably, prolonged restraint stress (30-100 min) reportedly leads to stronger Fos increase in males in several brain regions compared to females (Bland et al, 2005;Figueiredo et al, 2002;Zavala et al, 2011). Therefore, it is likely that other peptide hormones or neurotransmitter systems -which respond specifically to the swim stress challenge -are involved in the strong and rapid regulation of Fos, Per1 and Sgk1.…”

Stress-induced sex differences: Adaptations mediated by the glucocorticoid receptor

“…Alternatively, agonism of estrogen receptor β can be anxiolytic and prevent glucocorticoid-induced anxiety-like behavior (Weiser et al, 2010). Sex differences also have been documented in region-specific GR activation: female rats show enhanced activation of the GR in the hypothalamus after both acute and chronic stress compared to males (Zavala et al, 2011). Collectively, these data highlight some of the modulatory effects of the HPG axis on the HPA axis.…”