Sex differences in activated corticotropin-releasing factor neurons within stress-related neurocircuitry and hypothalamic–pituitary–adrenocortical axis hormones following restraint in rats

Abstract

Women may be more vulnerable to certain stress-related psychiatric illnesses than men due to differences in hypothalamic-pituitary-adrenocortical (HPA) axis function. To investigate potential sex differences in forebrain regions associated with HPA axis activation in rats, these experiments utilized acute exposure to a psychological stressor. Male and female rats in various stages of the estrous cycle were exposed to 30 min of restraint, producing a robust HPA axis hormonal response in all animals, the magnitude of which was significantly higher in female rats. Although both male and female animals displayed equivalent c-fos expression in many brain regions known to be involved in the detection of threatening stimuli, three regions had significantly higher expression in females: the paraventricular nucleus of the hypothalamus (PVN), the anteroventral division of the bed nucleus of the stria terminalis (BSTav), and the medial preoptic area (MPOA). Dual fluorescence in-situ hybridization analysis of neurons containing c-fos and corticotropin-releasing factor (CRF) mRNA in these regions revealed significantly more c-fos and CRF single-labeled neurons, as well as significantly more double-labeled neurons in females. Surprisingly, there was no effect of the estrous cycle on any measure analyzed, and an additional experiment revealed no demonstrable effect of estradiol replacement following ovariectomy on HPA axis hormone induction following stress. Taken together, these data suggest sex differences in HPA axis activation in response to perceived threat may be influenced by specific populations of CRF neurons in key stress-related brain regions, the BSTav, MPOA, and PVN, which may be independent of circulating sex steroids.

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

“…Our finding that gene transcription in response to acute swim stress shows a more pronounced increase in females than in males is in line with previous reports (Aloisi et al, 1997;Babb et al, 2013). Data in humans also suggest that women are more susceptible to suffer from neuropsychiatric disorders classically associated with stressful experiences, such as post traumatic stress disorder (Breslau, 2009;Tolin and Foa, 2006) or depression (Parker and Brotchie, 2010).…”

“…The hippocampus is highly sensitive to stress and plays a critical role in the negative effects of stress on cognitive function and on affective disorders (de Kloet et al, 2005). A few studies have demonstrated that the transcriptional response of the immediate early gene Fos is more pronounced after acute stress in females than males (Aloisi et al, 1997;Babb et al, 2013). However, it remains unknown whether hippocampal gene expression is generally more responsive to acute stress challenges in females than males, or if this effect is restricted to Fos.…”

Sex differences in the behavioural and hypothalamic–pituitary–adrenal response to contextual fear conditioning in rats

“…It is unlikely that discrepancies could be due to the phase of the estrous cycle as most results failed to find differences (Babb et al, 2013a;Isawaki-Sekino et al, 2009;Viau and Meaney, 1991). Interestingly, there is evidence to suggest that sex differences in ACTH response may be dependent on the particular type of stressor (Babb et al, 2013b;Spinedi et al, 1994), and this is supported by our present results demonstrating greater sex differences in the ACTH response to shock and conditioning than to novel environments. It is of note that brain corticosterone levels appears to be similar in the two sexes despite higher total levels of corticosterone in females (Droste et al, 2009), probably due to the higher levels of corticosteroid-binding globulin in females (i.e.…”

“…Sex-differences in the endocrine response to fear conditioning are important for two main reasons. First, sex differences in ACTH response to stress in rats appear to be dependent on the particular type of stressor studied (Babb et al, 2013b;Spinedi et al, 1994;Watanobe, 2002). Second, characterization of ACTH response to fear-conditioning can contribute to determine whether or not females are actually less sensitive than males to fear conditioning.…”

Defensive responses of Brandt's voles (Lasiopodomys brandtii) to chronic predatory stress

“…Neural outputs from the medial hypothalamic system target regions of the brain associated with defensive responses. These include the periaqueductal grey (PAG), which is a key site for organizing behavioral defensive responses to psychological stressors like predator odor, and the dorsomedial hypothalamus (DMH), which provides massive projections to the paraventricular hypothalamic nucleus (PVN) and integrates the functions of the endocrine defensive response [4]. The PVN constitutes the central part of the hypothalamo-pituitaryadrenal (HPA) axis especially the periventricular and medial parvicellular parts that contain neurons synthesizing hypophysiotropic corticotropin-releasing hormone, which stimulates the secretion of ACTH [8,11].…”