The role of pituitary glucocorticoid receptors in hypothalamic-pituitary-adrenal axis regulation following chronic social stress

One of the main physiological systems mediating adaptation to stressful stimuli is the hypothalamic-pituitary-adrenal (HPA) axis. Negative feedback control through glucocorticoids (GCs) is an important mechanism to restore homeostasis after HPA axis activation. GCs act via two receptor types, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). While MRs have been shown to regulate basal and circadian GC levels, GRs play a modulatory role in stressful situations, both acute and chronic. However, the contribution of different physiological subregions in negative feedback control is largely unknown. In this study we investigate the role of negative feedback via GCs on the level of the pituitary by utilizing pituitary-specific conditional GR knockout mice. Following 3 weeks of chronic social defeat, we observed an increase in anxiety-related behavior as well as elevated basal corticosterone levels in control mice. Mice with a GR deficiency in the pituitary show a diminished reaction to chronic stress as indicated by reduced corticosterone levels both basal and after acute stress. These findings are supported by behavioral data that showed decreased anxiety-like behaviour in knockouts compared to controls. In conclusion, we suggest that a lack of pituitary GRs results in a protective effect towards neuroendocrine and behavioral consequences of chronic stress. We hypothesize that this might be due to alterations in postnatal development of GR knockout mice.