A Hypothalamic Oxytocinergic–Sympathetic Axis Couples Anxiety Dysregulation With Impaired Tendon–Bone Repair

Abstract

ABSTRACT Rotator cuff injury (RCI) is frequently accompanied by psychological comorbidities, particularly anxiety‐related symptoms, which predict poor functional recovery, yet the central mechanisms linking affective disturbance to impaired tendon–bone healing remain unclear. Here, by integrating clinical neuroimaging, imaging transcriptomics, and mechanistic animal experiments, we identify hypothalamic paraventricular nucleus (PVN) oxytocinergic (OXT) neurons as a critical central node coordinating emotional regulation and bone–tendon interface (BTI) repair. In patients with RCI, resting‐state fMRI (rs‐fMRI) revealed reduced hypothalamic spontaneous activity that was inversely correlated with anxiety severity. Imaging transcriptomic analyses further linked these functional alterations to spatially concordant gene expression programs enriched in oxytocin signaling. In mouse models, retrograde viral tracing and spatial transcriptomics identified PVNOXT neurons as the predominant labeled population within a polysynaptic PVN–IML–SCG sympathetic pathway connected to the subchondral bone region of the rotator cuff enthesis. In vivo local field potential recordings confirmed a reduction in PVN neuronal activity that peaked at four weeks post‐injury and recovered thereafter, paralleling the behavioral time course. Chemogenetic inhibition of PVNOXT neurons induced anxiety‐like behaviors and impaired BTI healing, whereas their activation alleviated anxiety and enhanced structural and biomechanical recovery. Together, these findings support a working model in which a PVNOXT–sympathetic‐shoulder axis links anxiety dysregulation to musculoskeletal healing through a hypothalamic–sympathetic pathway, providing a framework for integrated neuromodulatory and tissue‐targeted interventions in RCI.