Sex differences in corticotropin releasing factor-evoked behavior and activated networks

Abstract

Hypersecretion of corticotropin releasing factor (CRF) is linked to the pathophysiology of major depression and post-traumatic stress disorder, disorders that are more common in women than men. Notably, preclinical studies have identified sex differences in CRF receptors that can increase neuronal sensitivity to CRF in female compared to male rodents. These cellular sex differences suggest that CRF may regulate brain circuits and behavior differently in males and females. To test this idea, we first evaluated whether there were sex differences in anxiety-related behaviors induced by the central infusion of CRF. High doses of CRF increased self-grooming more in female than in male rats, and the magnitude of this effect in females was greater when they were in the proestrous phase of their estrous cycle (higher ovarian hormones) compared to the diestrous phase (lower ovarian hormones), which suggests that ovarian hormones potentiate this anxiogenic effect of CRF. Brain regions associated with CRF-evoked self-grooming were identified by correlating a marker of neuronal activation, cFOS, with time spent grooming. In the infralimbic region, which is implicated in regulating anxiety, the correlation for CRF-induced neuronal activation and grooming was positive in proestrous females, but negative for males and diestrous females, indicating that ovarian hormones altered this relationship between neuronal activation and behavior. Because CRF regulates a number of regions that work together to coordinate different aspects of responding to stress, we then examined more broadly whether CRF-activated functional connectivity networks differed between males and cycling females. Interestingly, hormonal status altered correlations for CRF-induced neuronal activation between a variety of brain regions, but the most striking differences were found when comparing proestrous females to males, particularly when comparing neuronal activation between prefrontal cortical and other forebrain regions. These results suggest that ovarian hormones alter the way brain regions work together in response to CRF, which could drive different strategies for coping with stress in males versus females. These sex differences in stress responses could also help explain female vulnerability to psychiatric disorders characterized by CRF hypersecretion.

What Does Sex Have to Do with It? The Role of Sex as a Biological Variable in the Development of Posttraumatic Stress Disorder

“…Consistent with the current hypotheses that CRF mediates the anxiety response differently in males and females, this study showed that higher doses of CRF resulted in increased anxious behaviors for female rats compared to male rats [29••]. Interestingly, there seems to be an interaction with female gonadal hormones as the female rats in their proestrous phase (higher ovarian hormones) showed even more anxious behaviors than females in the diestrous phase.…”

“…Recent evidence in clinical and preclinical studies have also pointed to sex differences in hypothalamic pituitary adrenal (HPA) axis and autonomic response to threat, contributing to risk for PTSD and post-traumatic stress symptoms in females compared to males [27•, 28••, 29••, 30]. …”

“…There are well-described differences between males and females with respect to their HPA axis response to stress [29••]. Corticotropin-releasing factor (CRF) is implicated in the pathophysiology of disorders that are more common in women; specifically, hypersecretion of this peptide is associated with both major depressive disorder (MDD) and PTSD [31, 32].…”

Sex differences in stress reactivity in arousal and attention systems

“…Another possibility is that ovarian hormones and the effects of CRF interact to impact attention. We performed functional connectivity analyses to assess circuits activated by central administration of CRF (as measured by cFOS) and compared how sex and cycle stage altered these circuits [173,174]. Of relevance for SAT, functional connectivity between the NBM and mPFC in rats treated with CRF is different in proestrous females than in both diestrous females and males.…”

Assessing Subgroup Differences in Posttraumatic Stress Disorder Among Rescue Workers in Japan With the Impact of Event Scale–Revised

“…Almost all Japanese firefighters are men, 69,70 but previous research has shown that the association between corticotropin-releasing factor level and PTSD symptoms differs by gender. 71,72 It is possible that not including gender as a confounding factor (because of the absence of women in the sample) changed the observed associations with PTSD symptoms. Second, this was a crosssectional study, and negative associations observed for rescue operations do not necessarily indicate an effect on probable PTSD symptoms.…”