Abstract
Chronic stress disrupts skeletal homeostasis, yet central neural mechanisms remain unclear. In this study, we demonstrated that hyperactivation of locus coeruleus noradrenergic (LC(NE+)) neurons was both necessary and sufficient to drive bone loss in a mouse model of chronic social defeat stress (CSDS). Mechanistically, CSDS induced a bidirectional imbalance in the central amygdala corticotropin-releasing hormone (CRH)-expressing (CeA(CRH+)) neurons to LC(NE+) circuit, characterized by enhanced CRH release and suppressed GABAergic transmission. A CeA(CRH+)-LC(NE+)-paraventricular hypothalamic CRH-expressing (PVH(CRH+)) pathway was identified, which propagated stress signals to bone via sympathetic outflows. These findings redefine central bone metabolism control by establishing LC(NE+) neurons as key stress-responsive hubs. Restoration of CRH/γ-aminobutyric acid balance within the CeA(CRH+)-LC(NE+) circuit reversed CSDS-induced bone loss. Targeted inhibition of the CeA(CRH+)-LC(NE+)-PVH(CRH+) pathway effectively mitigated stress-related osteoporosis, suggesting neural pathway-directed interventions as a promising therapeutic strategy for stress-induced bone pathology.