Sex differences in the traumatic stress response: the role of adult gonadal hormones

Abstract

BackgroundOur previous study revealed that adult female rats respond differently to trauma than adult males, recapitulating sex differences in symptoms of post-traumatic stress disorder (PTSD) exhibited by women and men. Here, we asked two questions: does the female phenotype depend on (1) social housing condition and/or (2) circulating gonadal hormones?MethodsFor the first study, the effects of single prolonged stress (SPS) were compared for females singly or pair-housed. For the second study, adult male and female rats were gonadectomized or sham-gonadectomized 2 weeks prior to exposure to SPS, with half the gonadectomized rats given testosterone. In addition to the typical measures of the trauma response in rats, acoustic startle response (ASR), and the dexamethasone suppression test (DST), we also used two other measures typically used to assess depressive-like responses, social interaction and sucrose preference. Glucocorticoid receptor (GR) expression in the hypothalamus was also examined.ResultsWe now report that the distinct trauma response of female rats is not influenced by social housing condition. Moreover, sex differences in the response to SPS based on ASR and DST, replicated in the current study, are independent of adult gonadal hormones. Regardless of hormonal status, traumatized males show a hyper-responsive phenotype whereas traumatized females do not. Moreover, testosterone treatment in adulthood did not masculinize the response to trauma in females. Notably, both sucrose preference and social interaction tests revealed an effect of trauma in females but not in males, with the effects of SPS on sucrose preference dependent on ovarian hormones. Effects of SPS on GR expression in the hypothalamus also depended on gonadal hormones in females.ConclusionsWe propose that the trauma response for female rats is depressive in nature, recapitulating the female bias in PTSD for internalizing symptoms and major depression in contrast to the externalizing symptoms of males. Presumed core markers of PTSD (enhanced ASR and negative feedback control of corticosterone) are apparently relevant only to males and are independent of adult gonadal hormones. Such sex differences in trauma responding are likely determined earlier in life. We conclude that males and females show fundamentally different responses to trauma that do not simply reflect differences in resilience.Electronic supplementary materialThe online version of this article (10.1186/s13293-018-0192-8) contains supplementary material, which is available to authorized users.

Increased alcohol self-administration following exposure to the predator odor TMT in high stress-reactive female rats

“…For the females, one interpretation of these data is that recruitment of coping strategies such as defensive digging protects against lasting behavioral responsivity in hyperarousal and anxiety-like tests. While a previous study has reported females show hypo-responsiveness of the acoustic startle response following traumatic stress exposure [48] and predator odor stress [25], it is possible that by providing female rats the opportunity to engage in different behavioral coping strategies (i.e., bedding for digging), we were able to separate specific type of responders that represent susceptibility or resiliency to developing lasting behavioral changes in arousal. Conversely, the lack of change in hyperarousal in male rats exposed to TMT remains unclear, but future work could manipulate different startle intensity or examine prepulse inhibition to further dissect this behavioral difference.…”

Roles for androgens in mediating the sex differences of neuroendocrine and behavioral stress responses

“…Administration of PPT impairs the ability of dexamethasone to suppress the diurnal rise and restraint stress-induced release of ACTH and CORT [158]. It is important to note that while androgens are capable of producing these effects via further metabolism and binding of ERα, systemic T generally suppresses stress-induced HPA axis responses and increases negative feedback on the HPA axis [16,159]. This suggests that interactions with other gonadal steroid hormone receptors might negate or diminish any HPA axis enhancing effects of ERα.…”

Sex differences in the hypothalamic–pituitary–adrenal axis: An obstacle to antidepressant drug development?

“…In rats, the use of a single prolonged stress protocol, which models post‐traumatic stress disorder, oppositely regulated GR number in the PVN and the hippocampus of males and females (Pooley et al, ). Stress up‐regulated GR expression in the PVN of male rats but down‐regulated it in the hippocampus, whereas the opposite occurred in stressed females.…”