Sex differences in the murine HPA axis after acute and repeated restraint stress

Abstract

Chronic stress and stress-related mental illnesses such as major depressive disorder (MDD) constitute some of the leading causes of disability worldwide with a higher prevalence in women compared to men. However, preclinical research into stress and MDD is heavily biased toward using male animals only. Aberrant activity of the hypothalamic-pituitary-adrenal (HPA) axis has been linked to the development of MDD and several animal models of MDD have been established based on HPA axis dysregulation. In the present study, we compared stress biomarkers and behavior of male and female mice after acute and chronic restraint stress to investigate potential effects of sex differences in the stress response. Further, the validity of the interrupted repeated restraint stress (IRRS) model as an animal model for the HPA axis disturbances seen in MDD was assessed. After acute stress, female mice showed increased corticosterone secretion and changes in molecular markers suggesting increased HPA axis feedback sensitivity. Acute stress-induced signs of anxiety-like behavior were observed in male mice only suggesting that female mice may be more resilient to the anxiogenic effects of acute stress. Males and females responded similarly to IRRS with no sustained perturbations in HPA axis biomarkers. The IRRS model did not adequately translate to the changes reported in MDD with HPA axis overactivity and more severe perturbation models are likely needed. However, in alignment with previous studies, these data support that there are important sex differences in the HPA axis and that these may contribute to the etiology of stress-related psychiatric disorders.

Keywords: HPA axis; Stress; corticosterone; major depressive disorder; restraint stress; sex.