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Chronic Stress Segregates Mice into Distinct Behavioral Phenotypes Based on Glucocorticoid Sensitivity
Polina Ritter1,2, Rasha Salman1, Yuliya Ryabushkina1
1Institute of Cytology and Genetics (ICG), Siberian Branch of Russian Academy of Sciences (SB RAS), Prospekt Akad. Lavrentyeva 10, 630090 Novosibirsk, Russia.
International Journal of Molecular Sciences
|December 11, 2025
Summary
Chronic stress creates distinct hypothalamic-pituitary-adrenal (HPA) axis response patterns. Identifying these patterns reveals individual stress adaptation, vulnerability, and resilience mechanisms.
Area of Science:
- Neuroscience
- Endocrinology
- Behavioral Science
Background:
- Chronic stress significantly impacts the hypothalamic-pituitary-adrenal (HPA) axis, altering corticosterone regulation and adaptive capacities.
- Individual differences in stress adaptation necessitate the identification of distinct HPA axis response patterns.
Purpose of the Study:
- To investigate HPA axis sensitivity and identify distinct response profiles in male mice subjected to chronic social defeat stress (CSDS).
- To correlate these HPA axis profiles with behavioral phenotypes and molecular markers of stress adaptation.
Main Methods:
- Male C57BL6 mice underwent 30 days of CSDS, with HPA axis function assessed via the dexamethasone suppression test (DST) and corticosterone level measurements.
- Comprehensive behavioral testing and quantitative PCR (qPCR) analysis of key HPA-axis-related genes in the hypothalamus, pituitary, and adrenal glands were performed.
- K-means cluster analysis was employed to categorize mice into distinct HPA axis response profiles.
Main Results:
- Three distinct HPA axis response clusters were identified, differing in baseline and dexamethasone-suppressed corticosterone levels.
- Each cluster exhibited unique behavioral phenotypes and HPA axis gene expression patterns, indicating varied adaptive strategies.
- Cluster 1 showed low basal corticosterone with abnormal DST response; Cluster 2 displayed elevated basal corticosterone and blunted DST response with anhedonia; Cluster 3 demonstrated normal basal corticosterone and DST response with upregulated stress-related genes.
Conclusions:
- Corticosterone response heterogeneity under chronic stress reflects diverse adaptive trajectories.
- Distinct molecular and behavioral markers are associated with different stress adaptation strategies, offering insights into stress vulnerability and resilience.
- Understanding these varied responses has implications for developing targeted interventions for stress-related disorders.
