Altered light-dark phase-dependent behavioral responses and suprachiasmatic nucleus pathology in an α-synuclein rat model of Parkinson's disease.

Disruption of circadian rhythms is a key feature of neurodegenerative diseases and a non-motor feature of Parkinson's disease, which significantly impairs health-related quality of life; yet, the underlying mechanisms are only partially understood. Preclinical animal models with neuropathological and symptomatic significance might contribute to a better understanding of circadian dysfunction. Here, we investigated light-dark phase-dependent modulation of motor and non-motor behavior as well as suprachiasmatic nucleus integrity in α-synuclein-overexpressing rats and wild-type controls. Behavioral testing in 3-month-old animals revealed robust phase-dependent modulation of exploratory activity, locomotion, sucrose preference, and olfaction-guided feeding in wild-type rats, which was absent in their transgenic littermates. Histological analyses demonstrated reduced overall cell density and pronounced α-synuclein accumulation in the suprachiasmatic nucleus of α-synuclein rats, accompanied by altered cellular composition, including altered neuronal, orexinergic, and microglial markers. α-synuclein load was positively correlated with Orexin A+ fibers and Iba1+ cell counts, suggesting a link between protein aggregation, neuroinflammation, and altered light-dark phase-dependent behavior. These findings indicate that α-synuclein rats lack phase-dependent behavioral alternations and exhibit suprachiasmatic nucleus pathology already at an early disease stage with very mild motor impairment, providing a translational model to study different aspects of non-motor symptoms in Parkinson's disease.