Work

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

Year: 2025

Type: article

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.

Source: Science Advances

DOI: 10.1126/sciadv.adz9329