Mechanisms of Adaptation of the Hypothalamic-Pituitary-Adrenal Axis in Male Mice in Chronic Social Defeat Stress

The hypothalamic-pituitary-adrenal axis (HPAA) plays an important role in the mechanisms of adaptation to chronic stress. The chronic social stress (CSS) model, based on the experience of defeats in daily agonistic interactions, induces development of a depression-like state in mice, which is generally accompanied by an increase in the blood corticosterone level. We report here studies evaluating changes able to affect the regulation of corticosterone synthesis and its blood concentration occurring in the central (hypothalamus) and peripheral (adrenal glands) compartments of the HPAA axis in conditions of chronic social stress. The experience of chronic social stress increases the relative mass of the adrenal glands, increases the level of Crh gene expression in the hypothalamus, and increases the expression of genes for corticosterone synthesis enzymes – Star , Cyp11a1 , and Cyp11b1 – in the adrenal glands. At the same time, the expression of Fkbp5 and Nr3c1 decreases in the hypothalamus, while that of Crhbp increases; Mc2r and Hsd11b1 expression in the adrenal glands decreases; overall, these changes are aimed at reducing the amount of corticosterone secreted by the adrenal glands and lead to limitation of the glucocorticoid response. Thus, chronic stress leads to an imbalance of the activating and stabilizing mechanisms of HPAA axis regulation and a possible inadequate response to additional stress stimuli.