Beyond the HPA axis: Synaptic circuits of PVN^CRH neurons in stress-related psychiatric disorders

Chronic psychosocial stress is a major risk factor for anxiety, depression and related disorders, yet a hypothalamic-pituitary-adrenal (HPA) axis centric framework alone is insufficient to explain stress-induced vulnerability and phenotypic heterogeneity. Paraventricular nucleus corticotropin-releasing hormone (PVN^CRH) neurons are classically regarded as the neuroendocrine entry point for driving glucocorticoid secretion. However, accumulating evidence indicates that, beyond this endocrine role, they also use fast transmitters and CRH co-transmission to form functional projections to diverse brain regions and pre-sympathetic circuits, thereby regulating stress dimensions that extend beyond HPA axis output, including defensive behaviors, reward and motivation, arousal-sleep regulation, autonomic output and glucose homeostasis. In this review, we integrate anatomical, electrophysiological, and behavioral evidence across representative PVN^CRH pathways, compare their stress-related functional specialization and shared mechanisms across synaptic and endocrine timescales, and discuss translational implications for circuit-informed pharmacological and neuromodulatory strategies in stress-related psychiatric disorders.