Sex differences in the traumatic stress response: PTSD symptoms in women recapitulated in female rats

Abstract

BackgroundPost-traumatic stress disorder (PTSD) affects men and women differently. Not only are women twice as likely as men to develop PTSD, they experience different symptoms and comorbidities associated with PTSD. Yet the dearth of preclinical research on females leaves a notable gap in understanding the underlying neuropathology of this sex difference.MethodsUsing two standard measures of PTSD-like responses in rats, the acoustic startle response (ASR) and dexamethasone suppression test (DST), we tested the effects of traumatic stress in adult male and female rats using two rodent models of PTSD, single prolonged stress and predator exposure. We then examined the neural correlates underlying these responses with cFos and glucocorticoid receptor immunohistochemistry in brain regions implicated in the traumatic stress response.ResultsWe now report that adult male and female rats across two models of PTSD show consistent sex-specific responses that recapitulate fundamental differences of PTSD in men and women. Trauma-exposed males showed the well-established hyper-responsive phenotype of enhanced ASR and exaggerated negative feedback control of the hypothalamic-pituitary-adrenal axis, while the same traumatic event had little effect on these same measures in females. Dramatic sex differences in how trauma affected cFos and glucocorticoid receptor expression in the brain lend further support to the idea that the trauma response of male and female rats is fundamentally different.ConclusionsTwo standard measures, ASR and DST, might suggest that females are resilient to the effects of traumatic stress, but other measures make it clear that females are not resilient, but simply respond differently to trauma. The next important question to answer is why. We conclude that males and females show fundamentally different responses to trauma that do not simply reflect differences in resilience. The divergent effects of trauma in the brains of males and females begin to shed light on the neurobiological underpinnings of these sex differences, paving the way for improved diagnostics and therapeutics that effectively treat both men and women.Electronic supplementary materialThe online version of this article (10.1186/s13293-018-0191-9) contains supplementary material, which is available to authorized users.

Voiding Behavior and Efferent Bladder Function Altered in Mice Following Social Defeat but Not Witness Trauma

“…In addition to stressor-specific differences seen in the present study, sex differences in psychological stress-induced bladder dysfunction and brain responses have previously been reported. A recent study identified consistent sex-specific differences in the brain responses to trauma in male and female rats using two models of post-traumatic stress disorder (Pooley et al, 2018). We found a significant increase in voiding frequency in female mice following water avoidance stress (West et al, 2019), an effect that has also been reported in female rats (Smith et al, 2011).…”

Rodent models of post-traumatic stress disorder: behavioral assessment

“…SPS increased the latency of pairhoused Sprague-Dawley females to approach a novel rat in the social preference/avoidance test, implying an anxious phenotype, but decreased the latency of single housed females, implying social support seeking 58 . The dexamethasone suppression test revealed an exaggerated negative feedback control of the HPA axis in SPS-exposed Sprague-Dawley males, but not in females 59 . SPS lacks ecological validity and its stressor intensity cannot be modified.…”

“…While initial acute cat exposure studies assessed overall behavior through tests of risk assessment, anxiety, and arousal 92 , later reports also found avoidance of traumareminder in the open field test 95 , with spatial memory retention impairments in the MWM and radial-arm water maze 93,96 . Like SPS, exposure enhanced dexamethasone suppression of CORT in Sprague-Dawley males, but not in females 59 . In addition, acute ferret exposure in Sprague-Dawley rats produced sensorimotor gating abnormalities in prepulse inhibition 94 .…”

Rats Lacking Dopamine Transporter Display Increased Vulnerability and Aberrant Autonomic Response to Acute Stress

“…Among candidate genes that are related to stress disorders, Dopamine Transporter (DAT) disruptions have captured some attention, particularly with regards to PTSD [ 9 , 10 , 11 , 12 ]. Importantly, within PTSD affected individuals, there is higher incidence and prevalence of stress-related disorders in women [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ], who show more severe symptoms and poorer treatment outcomes than men [ 21 ].…”