Neuroendocrine and circuit remodeling under chronic social stress.

Abstract

Social stress has emerged as one of the most impactful environmental risk factors contributing to psychiatric disorders in modern societies. Although acute stress responses are adaptive mechanisms that promote survival and homeostasis, chronic social stress induces maladaptive neurobiological changes that culminate in pathological behavioral phenotypes. Accumulating evidence from rodent studies demonstrates that chronic social stress reshapes neural circuits and disrupts neuroendocrine regulation. In this review, we summarize and compare major rodent models including early life stress, social isolation, chronic social defeat stress, and chronic subordinate colony housing, and synthesize how these paradigms differentially engage the hypothalamic-pituitary-adrenal axis and monoaminergic systems, including serotonergic, noradrenergic, and dopaminergic circuits, as well as emerging modulators such as endocannabinoids and neuropeptide Y. Because these paradigms engage distinct developmental windows and have been validated predominantly in males, we explicitly evaluate outcomes as a function of age at exposure and sex. We further integrate these neurochemical alterations into a synaptic and cell-type-specific framework of cortico-limbic circuit remodeling linking excitation/inhibition imbalance and astrocytic dysregulation to the divergence between susceptible and resilient phenotypes. We introduce allostatic load as an integrated framework linking cumulative, paradigm-specific stress burdens to vulnerability and resilience, and highlight active, compensatory neuroendocrine and circuit-level mechanisms that confer resilience. We propose that chronic social stress represents not a simple neurotransmitter deficit, but a dysregulation of neural circuits and neuroendocrine plasticity, providing a systems-level perspective of stress-related mental illness.