Chronic Stress Leads to Differentiation of Mice by Glucocorticoid Sensitivity into Groups Characterized by Specific Behavioral Phenotype

Chronic stress alters hypothalamic-pituitary-adrenal (HPA) axis function, influencing corticosterone regulation and adaptive responses. Identifying distinct response patterns can provide insight into individual variability in stress adaptation. This study is aimed to assess variability in HPA axis sensitivity following chronic social defeat stress. Male C57BL6 mice were exposed to chronic social defeat stress (CSDS) for 30 days. In order to evaluate integrity of negative feedback loop of HPA axis dexamethasone suppression test (DST) was used. Corticosterone levels were measured following saline or low-dose dexamethasone administration at 10 and 30 days. K-means clustering by corticosterone levels after saline and dexamethasone administration was applied to identify distinct response profiles. Behavioral testing (open field, elevated plus maze, social interaction test, partition, social defeat, forced swimming test, sucrose preference test) and qPCR analysis of HPA axis-related genes in hypothalamus (Crh, Crhr1, Crhbp, Fkbp5, Nr3c1), pituitary gland (Pomc, Crhr1, Nr3c1, Nr3c2), and corticosterone synthesis genes in adrenal glands (Cyp11a1, Cyp11b1, Hsd11b1, Mc2r, Star, Fkbp5, Nr3c1) was performed. Cluster analysis identified 3 distinct response profiles differing in baseline and dexamethasone-suppressed corticosterone levels. Clusters also exhibited differences in behavioral phenotypes and HPA axis gene expression. Cluster 1 showed low basal corticosterone and an abnormal dexamethasone suppression response, without significant Crh or Crhbp dysregulation in the hypothalamus. Cluster 2 exhibited elevated basal corticosterone, a blunted dexamethasone response, anhedonia, and reduced immobility in the forced swim test; increased Crh and reduced Fkbp5 suggest enhanced glucocorticoid receptor sensitivity and sustained hypercortisolemia. Cluster 3, characterized by normal basal corticosterone and normal dexamethasone response, showed upregulation of Crh and Crhbp, consistent with balanced and potentially adaptive HPA axis regulation under chronic stress. Corticosterone response heterogeneity reflects distinct adaptive trajectories under chronic stress. Identifying behavioral markers of these strategies may improve understanding of stress vulnerability and resilience mechanisms, with implications for stress-related disorders.