Behavioral and functional characterization of early-stage Parkinson's disease models reveals attentional deficits and circuit-level connectivity alterations.

Parkinson's disease (PD) is preceded by a prolonged prodromal phase during which subtle cognitive and behavioral alterations emerge before overt motor symptoms. Experimental models reproducing these early stages are essential for understanding disease mechanisms and identifying early biomarkers. In this study, we performed the multimodal characterization of two toxin-based rat models of prodromal PD induced by bilateral nigral injections of 6-hydroxydopamine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Animals were assessed over 2 months using behavioral testing, functional magnetic resonance imaging (fMRI), and histologic analyses. Both models produced moderate, heterogeneous dopaminergic degeneration within the nigrostriatal pathway, consistent with prodromal stages. Motor impairments remained limited whereas robust attentional deficits were detected. fMRI revealed region-specific connectivity alterations aligned with behavioral impairments, suggesting early circuit-level dysfunction despite the absence of widespread network disruption. To address inter-individual variability, a clinically inspired staging framework was implemented based on dopaminergic lesion severity, attentional performance, and sensorimotor impairment. This phenotype-based classification stratified animals into sham, asymptomatic, early, and advanced stages independent of the toxin used. Together, these findings demonstrate that moderate bilateral dopaminergic degeneration produces early cognitive and circuit-level alterations, and highlight the value of multimodal phenotyping for studying prodromal PD and identifying early functional biomarkers.