100 Section - Social Isolation Promotes the Burden of α-Synuclein Pathology via Suppressing Oxytocin Signaling and Glymphatic Influx

Social isolation (SI) is associated with an increased risk of Parkinson’s disease (PD), yet the underlying mechanisms remain elusive. Oxytocin (OXT) is a neurohormone critical for social bonding and stress resilience, which is suppressed under conditions of SI. Recent evidence suggests OXT possesses neuroprotective properties and plays a role in regulating glymphatic function. We aimed to investigate whether SI exacerbates αSyn aggregation by impairing glymphatic influx, and to evaluate the therapeutic potential of OXT administration and exercise in counteracting this impairment.

Design: A PD mouse model was generated through unilateral striatal injection of αSyn preformed fibrils (PFFs). Mice were subjected to either chronic SI or group housing. Motor behaviour, PD pathology, and OXT levels were assessed 5 months post-injection. Glymphatic function was evaluated by analysing AQP4 polarity, fluorescent tracer clearance, and in vivo DCE-MRI. Rescue strategies involved intranasal OXT administration and voluntary treadmill exercise.

Results: Compared to PFFs group, the PFFs+SI group exhibited significantly more severe motor deficits, robust αSyn pathology, and approximately 30% greater dopaminergic neuron loss. Furthermore, SI disrupted the normal perivascular localization of AQP4, indicating a loss of AQP4 polarity. This structural impairment was associated with significantly reduced clearance of both fluorescent tracers and fluorescent-labeled αSyn PFFs from the brain parenchyma. ELISA revealed that SI markedly reduced OXT levels in brain regions including the hypothalamus and striatum. Intranasal OXT administration restored both AQP4 polarity and glymphatic tracer clearance, indicating that OXT deficiency mediates SI-induced impairment of glymphatic function. Additionally, voluntary treadmill exercise elevated endogenous OXT levels, reversed AQP4 polarity loss, and improved glymphatic influx in PD mice, as demonstrated by DCE-MRI.

Conclusion: SI exacerbates P</span>D pathology by impairing the glymphatic system in an OXT-dependent manner. Both OXT supplementation and exercise, which boosts endogenous OXT, represent promising therapeutic strategies for rescuing glymphatic function and mitigating disease progression in PD.