UNRAVELING THE CONSEQUENCES OF INDUCED SYNUCLEINOPATHY IN DOPAMINERGIC AND NORADRENERGIC NEURONS

Parkinson’s disease (PD) is a synucleinopathy characterized by α-synuclein aggregation and multisystem dysfunction. While motor impairment is a core feature, anxiety and other non-motor symptoms are prevalent and can shape disability, pointing to interactions between emotional and motor networks. However, most preclinical models emphasize motor-endpoints and lack cell-type specificity, limiting causal links between neuronal populations and symptom domains. To test how synucleinopathy in neuronal populations drives distinct symptom domains, we used a Cre-dependent viral strategy (AAV2/9-CreON-A53T-αSyn) to induce pathology selectively in dopaminergic neurons of the substantia nigra pars compacta (SNc; DAT-Cre mice) or noradrenergic neurons of the locus coeruleus (LC; NET-Cre mice). In both models, histology revealed α-synuclein aggregates and target-cell loss. In standard assays, motor impairment emerged exclusively in DA-targeted mice on the rotarod and in open-field locomotion, whereas NET-targeted mice showed no motor or anxiety-like deficits. To probe anxiety–locomotion coupling, we designed the Opening Track (OT), a walkway with open and enclosed segments to quantify how environmental openness modulates gait. OT uncovered a selective phenotype in NET mice—enhanced context-dependent immobility in enclosed segments—while confirming locomotor impairment in DA-targeted animals. Together, these findings show that cell-type–restricted synucleinopathy yields dissociable affective versus motor outcomes and establish OT as a circuit-informed assay to capture PD-relevant non-motor modulation of gait missed by classical tests. By restricting pathology to DA-SNc or LC–NE neurons and combining behavioral readouts, this framework enables circuit-specific causal mapping of synucleinopathy to motor versus non-motor symptom dimensions and supports evaluation of domain-targeted interventions.