Circadian activity of the hypothalamic–pituitary–adrenal axis is differentially affected in the rat chronic mild stress model of depression

Abstract

The altered activity of the hypothalamic–pituitary–adrenal (HPA) axis is often observed in stress-related disorders. According to the literature, about 60% of patients with major depressive disorder elicit high levels of cortisol. It is still unclear why high cortisol levels are not observed in all patients. In this study, we used the chronic mild stress (CMS) rat model of depression, which is based on continuous exposure to unpredictable stressors, to track longitudinal changes in HPA function using fecal corticosterone metabolites (FCM) as a read out. The dexamethasone suppression test was used to assess negative feedback inhibition of the HPA axis. Our results show (1) a disturbance in diurnal corticosterone rhythm measured as fluctuations of the diurnal FCM peak, (2) differences in corticosterone levels between stress-susceptible and stress-resilient animals, (3) recovery of diurnal corticosterone rhythm after 8 weeks of CMS, and (4) alterations in sensitivity to dexamethasone in negative feedback regulation of corticosterone secretion during the time course of CMS. Thus, a disruption of HPA axis circadian rhythmicity coincides with the initial state in the development of depression-like behavior. This chronobiological abnormality, as well as the hypersecretion of corticosterone, is state, rather than trait, dependent.

Keywords::

• Chronic mild stress
• corticosterone
• depression
• dexamethasone
• hypothalamic–pituitary–adrenal axis
• stress resilience

Acknowledgements

The authors wish to express their gratitude to Kim Henningsen and Stine Dhiin Heide Hansen for running the CMS model of depression and Edith Klobetz-Rassam for excellent technical assistance with EIA. Also, we are grateful to David Farr and Buffy Illum for their careful reading of the manuscript. The project is supported by the regional foundation for the support of basic research in psychiatry (Region Midtjylland, Denmark) and the University of Veterinarian Medicine, Vienna, Austria.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.