The 6-OHDA Model as a Framework to Study Behavioral and Cellular Biomarkers of Prodromal Parkinson’s Disease

Parkinson's disease (PD) is preceded by a prodromal phase, lasting years before motor symptoms appear, marked by non-motor alterations such as neuropsychiatric manifestations, including anxiety disorders. Although the 6-hydroxydopamine (6-OHDA) model has classically been used to study nigrostriatal degeneration, it remains underexploited as a framework to dissect these early, non-motor stages of PD in different dopaminergic areas outside the nigrostriatal pathway. Our research group has progressively built this framework. We previously showed that bilateral intrastriatal 6-OHDA induces anxiety-like behavior in male rats, detectable as early as 1 week post-lesion and persisting through week 3, alongside dopaminergic neurodegeneration in the ventral tegmental area. Notably, IGF-1 gene therapy attenuated the anxiety-like phenotype without preventing neuronal loss. Identifying the mechanisms through which IGF-1 mediates its behavioral effects represents an important aim of our study. We are now developing a mouse model that combines 6-OHDA lesioning with assessments of BBB integrity and anxiety-like behavior, to test whether BBB disruption underlies the prodromal anxiety phenotype. We propose that integrating peripheral (BBB) and behavioral readouts within the 6-OHDA model offers a translational framework to identify early biomarkers of PD, before dopaminergic degeneration is complete, with implications for early diagnosis and intervention.