Abstract
Efforts to develop disease-modifying treatments for Parkinson's disease (PD) have been hindered by the lack of animal models replicating all hallmarks of PD and the insufficient attention to extra-nigrostriatal regions pathologically critical for the prodromal appearance of non-motor symptoms. Among PD models, 6-hydroxydopamine (6-OHDA) infusion in mice has gained prominence since 2012, primarily focusing on the nigrostriatal region. This study characterized widespread tyrosine hydroxylase-positive neuron and fiber loss across the brain following a unilateral 6-OHDA (20 μg) infusion into the dorsal striatum. Our analysis integrates immunolabeling, brain clearing (iDISCO+), light sheet microscopy, and computational methods, including fMRI and machine learning tools. We also examined sex differences, disease progression, neuroinflammatory responses, and pro-apoptotic signaling in nigrostriatal regions of C57BL/6 mice exposed to varying 6-OHDA dosages (5, 10, or 20 μg). This comprehensive, spatiotemporal analysis of 6-OHDA-induced pathology may guide the future design of experimental PD studies and neurotherapeutic development.