Remote Regulation of Molecular Diffusion in Extracellular Space of Parkinson’s Disease Rat Model by Subthalamic Nucleus Deep Brain Stimulation

Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective therapy for Parkinson's disease (PD). However, the therapeutic mechanisms remain incompletely understood, particularly regarding the extracellular space (ECS), a critical microenvironment where molecular diffusion and interstitial fluid (ISF) dynamics are essential for neural function. This study aims to explore the regulatory mechanisms of the ECS in the substantia nigra (SN) of PD rats following STN-DBS. To evaluate whether STN-DBS can modulate ECS diffusion and drainage, we conducted quantitative measurements using a tracer-based magnetic resonance imaging. Our findings indicated that, compared to the PD group, STN-DBS treatment resulted in a decreased diffusion coefficient (<i>D</i>*), shorted half-life (<i>T</i> _1/2), and increased clearance coefficient (<i>k</i>') in the SN. To investigate the mechanisms underlying these changes in molecular diffusion, we employed enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), and microdialysis techniques. The results revealed that STN-DBS led to an increase in hyaluronic acid content, elevated expression of excitatory amino acid transporter 2 (EAAT2), and a reduction in extracellular glutamate concentration. Additionally, to further elucidate the mechanisms influencing ISF drainage, we employed immunofluorescence and immunohistochemical techniques for staining aquaporin-4 (AQP-4) and α-synuclein. The results demonstrated that STN-DBS restored the expression of AQP-4 while decreasing the expression of α-synuclein. In conclusion, our findings suggest that STN-DBS improves PD symptoms by modifying the ECS and enhancing ISF drainage in the SN regions. These results offer new insights into the mechanisms and long-term outcomes of DBS in ECS, paving the way for precision therapies.