A central CeA-LC-PVH circuit mediates stress-induced osteopenia via skeletal sympathetic nerves in male mice

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.