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 (Crh, Crhr1, Crhbp, Fkbp5, Nr3c1), pituitary (Pomc, Crhr1, Nr3c1, Nr3c2), and adrenal glands (Cyp11a1, Cyp11b1, Hsd11b1, Mc2r, Star, Fkbp5, Nr3c1) 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 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 suggested enhanced glucocorticoid receptor sensitivity and sustained hypercortisolemia. Cluster 3, characterized by normal basal corticosterone and normal dexamethasone response, displayed upregulation of Crh and Crhbp, 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.

This study investigated how prolonged aggression in male CD1 mice alters responses to chronic LPS-induced inflammation. Aggression experience induced pathological aggression in 36% of mice. Following LPS, aggressors resolved systemic inflammation within five days—evidenced by normalized locomotor activity, WBC, and lymphocyte counts—while controls remained inflamed. LPS did not alter established aggression or anxiety. Furthermore, aggressors demonstrated accelerated inflammation resolution in the brain, showing a higher proportion of resting microglia and a lower percentage of activated microglia following LPS-induced inflammation compared to control animals. Gene expression analysis revealed a more pronounced inflammatory response in the hypothalamus than in the nucleus accumbens. Aggressive mice exhibited a profile associated with inflammation resolution, indicated by increased expression of the Trem2 gene. These differential immune responses may be modulated by the dopaminergic system. Elevated Drd1 gene expression in the hypothalamus likely enhances anti-inflammatory signaling, while changes in nucleus accumbens dopaminergic activity, involving D2 receptor activation, appear linked to the development of pathological aggression. Thus, this study demonstrates that prolonged aggression induces persistent changes in behavioral, neuroimmune, and neuroendocrine systems in male CD1 mice. Aggressive animals develop a distinct neuroimmune phenotype characterized by accelerated resolution of both systemic and brain inflammation following LPS challenge.

Stress-induced mental disorders, including depression and anxiety disorders, constitute a global issue in contemporary society due to treatment complexity and the diversity of manifestations. Understanding the molecular mechanisms of these disorders presents a significant challenge for neurobiology. We investigated the effects of social defeat stress (SDS) of varying durations (10 and 30 days) on behavioral patterns and the H3K4me3 (trimethylation at the 4th lysine residue of histone H3) landscape in the prefrontal cortex of C57BL/6 mice. Furthermore, we compared these data with previously published H3K4me3 landscape data obtained after 15 days of SDS and transcriptomic data collected after 10, 15, and 30 days. We discovered that a 30-day period of stress results in more pronounced depressive-like behavior. SDS induces slight alterations in the H3K4me3 density across numerous nucleosomal peaks. The analysis of differential enrichment peaks of H3K4me3 in promoter regions following varying durations of SDS revealed that the aggregation of multiple H3K4me3 nucleosome peaks in the promoter region functions as a QR code, likely affecting the promoter’s state regarding the accessibility of transcription factors. Furthermore, we identified a cluster of genes in the promoter regions exhibiting differential enrichment peaks of H3K4me3 following SDS of any duration. This cluster includes genes encoding transcription factors such as Mef2c and Nr4a3, as well as postsynaptic density proteins (Shank2, Shank1, and Gria2), which are associated with stress sensitivity and the onset of depression; their protein products are involved in synaptic transmission and signal transduction mechanisms. The comparison of ChIP-seq and RNA-seq data following varying durations of SDS enabled a deeper insight in to the dynamics of SDS-induced changes. Together, these findings provide a better understanding of the molecular mechanisms of SDS in the prefrontal cortex.

This study investigated how prolonged aggression in male CD1 mice alters responses to chronic LPS (lipopolysaccharide)-induced inflammation. Experience of aggression induced pathological aggression in 36% of mice. Following LPS, aggressors resolved systemic inflammation within five days—evidenced by normalized locomotor activity, WBC (white blood cells), and lymphocyte counts—while controls remained inflamed. LPS did not alter established aggression or anxiety. Furthermore, aggressors demonstrated accelerated inflammation resolution in the brain, showing a higher proportion of resting microglia and a lower percentage of activated microglia following LPS-induced inflammation compared to control animals. Gene expression analysis revealed a more pronounced inflammatory response in the hypothalamus than in the nucleus accumbens. Aggressive mice exhibited a profile associated with inflammation resolution, indicated by increased expression of the Trem2 gene. These differential immune responses may be modulated by the dopaminergic system. Elevated Drd1 gene expression in the hypothalamus could possibly contribute to the anti-inflammatory signaling, while changes in nucleus accumbens dopaminergic activity, involving D2 receptor activation, appear linked to the development of pathological aggression. Thus, this study demonstrates that prolonged aggression induces persistent changes in behavioral, neuroimmune, and neuroendocrine systems in male CD1 mice. Aggressive animals develop a distinct neuroimmune phenotype characterized by accelerated resolution of both systemic and brain inflammation following LPS challenge.

Chronic stress produces marked individual differences in behavioral adaptation and glucocorticoid sensitivity, but the molecular basis of this variability remains poorly understood. Here, we examined transcriptional responses to glucocorticoid receptor activation after chronic social defeat stress (CSDS) in male C57BL/6J mice. Based on behavioral responses during social interaction, stressed animals were classified into active coping strategy (AS) and passive coping strategy (PS) phenotypes. A total of 24 h after the final stress session, mice received 2 µg/g of dexamethasone (DEX) or a saline injection, and transcriptomic profiling of the prefrontal cortex (PFC) and dorsal raphe nucleus (DRN) was performed 6 h later using RNA sequencing. Chronic stress induced pronounced phenotype- and region-specific transcriptional alterations. The PFC showed extensive stress-associated gene expression changes, particularly in PS animals, whereas the DRN displayed comparatively fewer differentially expressed genes. Functional enrichment analysis nevertheless revealed substantial pathway-level remodeling in both regions. PS animals exhibited extensive pathway reorganization in the DRN, while AS animals showed broader suppression of enriched biological pathways in the PFC. Acute DEX administration further revealed marked phenotype-dependent differences in glucocorticoid-responsive transcriptional programs, with the strongest response observed in AS animals. Together, these findings demonstrate that chronic stress establishes distinct transcriptional states that shape subsequent DEX-induced transcriptional responses in a phenotype- and brain region-specific manner. Our results provide new insight into the molecular mechanisms underlying heterogeneity in stress adaptation.

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.