Characterization of motor and non-motor features associated with bilateral nigral degeneration due to A53T alpha-synuclein in female rats

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra (SN), accumulation of alpha-synuclein (a-Syn)-rich aggregates, and the development of both motor and non-motor symptoms. The absence of a cure for PD underscores the critical need for animal models that recapitulate both its molecular hallmarks and the spectrum of behavioral symptoms to elucidate pathogenic mechanisms and advance therapeutic development. While the virus-mediated a-Syn overexpression rat model recapitulates progressive dopaminergic neurodegeneration and motor deficits, its non-motor phenotypic profile remains poorly characterized. In this study, we investigated the behavioral consequences of targeted adeno-associated virus (AAV)-mediated overexpression of aggregate-prone mutant A53T a-Syn within the rat SN bilaterally. We confirmed dopaminergic neurodegeneration within 6 weeks, along with progressive motor impairments evident as reduced locomotion in the open field test and increased foot slips in the grid walking test as early as 3 weeks post-AAV injection. The dopaminergic origin of the motor deficit in the grid walking was confirmed at the 6-week timepoint by its attenuation with L-DOPA treatment. Crucially, animals overexpressing A53T a-Syn exhibited reduced responsiveness to palatable stimulation in the sucrose preference test in the context of advanced neurodegeneration. No changes in anxiety-like behaviors, olfactory function, or recognition memory were observed when compared with age-matched controls. These findings suggest that, in addition to motor impairments, bilateral A53T a-Syn overexpression induces depression-like behavior, providing a valuable tool for studying the pathogenesis and treatment of non-motor affective symptoms in PD.