Chronic Stress Segregates Mice into Distinct Behavioral Phenotypes Based on Glucocorticoid Sensitivity

Chronic stress alters hypothalamic-pituitary-adrenal (HPA) axis function, affecting corticosterone regulation and adaptive responses. Understanding individual variability in stress adaptation requires identifying distinct HPA axis response patterns. Here, we assessed HPA axis sensitivity in male C57BL6 mice exposed to 30 days of chronic social defeat stress (CSDS). Negative feedback integrity was evaluated using the dexamethasone suppression test (DST), with corticosterone measured after saline or low-dose dexamethasone administration at days 10 and 30. 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 the hypothalamus (<i>Crh</i>, <i>Crhr1</i>, <i>Crhbp</i>, <i>Fkbp5</i>, <i>Nr3c1</i>), pituitary (<i>Pomc</i>, <i>Crhr1</i>, <i>Nr3c1</i>, <i>Nr3c2</i>), and adrenal glands (<i>Cyp11a1</i>, <i>Cyp11b1</i>, <i>Hsd11b1</i>, <i>Mc2r</i>, <i>Star</i>, <i>Fkbp5</i>, <i>Nr3c1</i>) were performed. K-means cluster analysis identified three 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 <i>Crh</i> or <i>Crhbp</i> dysregulation in the hypothalamus. Cluster 2 exhibited elevated basal corticosterone, a blunted dexamethasone response, anhedonia, and reduced immobility in the forced swim test; increased <i>Crh</i> and reduced <i>Fkbp5</i> suggested enhanced glucocorticoid receptor sensitivity and sustained hypercortisolemia. Cluster 3, characterized by normal basal corticosterone and normal dexamethasone response, displayed upregulation of <i>Crh</i> and <i>Crhbp</i>, consistent with balanced and potentially adaptive HPA axis regulation under chronic stress. These results demonstrate that corticosterone response heterogeneity reflects distinct adaptive trajectories under chronic stress. Identifying behavioral and molecular markers of these strategies may advance understanding of stress vulnerability and resilience mechanisms, with implications for stress-related disorders.