Work

Beyond the HPA axis: Synaptic circuits of PVNCRH neurons in stress-related psychiatric disorders

Year: 2026

Type: article

Abstract: 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.

Source: Pharmacological Research

DOI: 10.1016/j.phrs.2026.108179

Authors: Jiayuan Zheng, Na Yue, Zhanzhuang Tian, Jin Yu, Bing Li

Institutions: Shanghai Medical College of Fudan University, Fudan University, Jinshan Hospital of Fudan University, Weifang Maternity and Child Care Hospital, Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function

Language: English

Topic: Stress Responses and Cortisol

Subfield: Behavioral Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,130