Comparative Analysis of HPA-Axis Dysregulation and Dynamic Molecular Mechanisms in Acute Versus Chronic Social Defeat Stress

Organisms respond to environmental stress primarily through the autonomic nervous system and hypothalamic-pituitary-adrenal (HPA) axis, regulating metabolism, psychological states, and immune function and modulating memory, reward processing, and immune responses. The HPA axis plays a central role in stress response, exhibiting distinct activation patterns under acute versus chronic social defeat stress. However, differences in physiological impacts and regulatory pathways between these stress conditions remain understudied. This study integrates RNA sequencing and behavioral analyses to reveal that acute social defeat stress triggers transient anxiety-like behaviors, accompanied by systemic inflammation and immediate-early gene (IEG) activation. In contrast, chronic social defeat stress induces long-term behavioral and physiological alterations, including neurotransmitter imbalance (e.g., reduced GABA and increased glutamate), sustained activation of maladaptive pathways (e.g., IL-17 signaling), and disrupted corticosterone synthesis. These findings highlight the dynamic regulatory role of the HPA axis under varying stress conditions, providing novel insights into mental health disorders such as anxiety and depression. The study identifies potential therapeutic targets to mitigate chronic social defeat stress effects and offers a theoretical foundation for personalized interventions.