Sex differences in stress coping and anxiety: role of the brain CRF system
Final Report Abstract
Mood disorders like anxiety and depression are among the most common neuropsychiatric disorders worldwide. In fact, anxiety affects approximately 20 % of the population with the incidence being two times higher in women than in men. Stress is one of the leading causes to develop mood disorders accompanied by maladaptive stressor perception and insufficient adaptation to stress. Interestingly, the major stress neuropeptide corticotropin-releasing factor (CRF) is known to be anxiogenic, pro-depressive and to affect stress coping. Thus, it is a highly intriguing candidate system in research on the treatment of stress-related mood disorders. To date, little is known about sexual dimorphisms in the CRF system and how they affect anxiety in men and women. In the current studies, I focused on basic and context-dependent sex differences in anxiety and CRF’s implications therein, using male and female rats as rodent models. Furthermore, I investigated sex differences in the corticosteroid-binding globulin (CBG), a vital component of an individual’s stress response, and the lack thereof in various behavioral tests and neuroendocrine challenges. In the first project, I showed that males and females robustly differ in their anxiety-related behavior when tested on the elevated plus-maze (EPM) or in the light/dark box (LDB) with females being less anxious than males independent of estrous cycle, sex steroids and housing conditions (group- versus single-housed). On a neuronal basis, exposure to EPM led to higher Fos protein - a marker for neuronal activation - in the dorsal lateral septum in females compared to males. Furthermore, neuronal activity was connected to high levels of anxiety in a variety of forebrain regions of females, but it did not predict anxiety in males. When exposing male and female rats to a psychological stressor, i.e. restraint stress, before testing them on the EPM, an anxiolytic effect is revealed short-term, but does not persist independent of sex or stress duration. When exposing male and female rats to different light conditions in the LDB, i.e. low, non-aversive versus high, aversive light, clear sex differences emerged depending on the aversity of the test; males showed more anxiety in high light conditions while females displayed even less. Interestingly, blocking CRF receptors in this experiment revealed that this effect is not dependent on CRF in males but that the CRF system in females is responsive to changing conditions due to an anxiolytic effect of CRF receptor inhibition under low, but not high, light conditions. Based on this, I tested if males and females do have the same capacities to react to CRF both on a behavioral and neuronal level. I demonstrated that females show faster and more pronounced changes in home cage behaviors such as self-grooming following central CRF injection compared to males. Despite this higher behavioral sensitivity of females, I revealed a higher neuronal sensitivity of males as assessed by Fos protein levels after CRF injection. In the second project, I showed that knocking out CBG in males impaired spatial memory while a reduction of CBG (heterozygous genotype) in females rescued spatial memory in the novel object placement test. No genotype or sex differences were found on the EPM. Acute stressor exposure revealed adapted adrenocorticotropic hormone and corticosterone levels in heterozygous and knockout males and females. Sex steroids were only affected in females where progesterone was lower in heterozygous and knockout rats indicating – along with reduced adrenal weight - a functional change of the adrenals when (partly) missing CBG. In conclusion, I provided evidence that males and females not only robustly differ in their anxiety levels but also their coping strategies and neuronal adaptations. This demonstrates very clearly that in the case of dysregulations and development of mood disorders, treatments must be carefully adapted and optimized to a male or female organism to provide best care and recovery.
