Circadian disruption coincides with morphological changes in the suprachiasmatic nucleus in a genetic α-synuclein rat model of early Parkinson's disease

Disruption of circadian rhythms are a key feature of neurodegenerative diseases and a non-motor feature of Parkinson’s disease, which significantly contribute to an impaired 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 circadian modulation of motor and non-motor behavior as well as structural integrity of the suprachiasmatic nucleus in a genetic rat model of Parkinson’s disease with overexpression of human α-synuclein and wild-type controls. Behavioral testing in three month-old animals revealed robust circadian phase–dependent modulation of exploratory activity, locomotion, sucrose preference, and olfaction-guided feeding in wild-type rats, which was absent in their human α-synuclein littermates. Histological analyses demonstrated reduced overall cell density and pronounced α-synuclein accumulation in the suprachiasmatic nucleus of transgenic rats, accompanied by altered cellular composition, including increased proportions of NeuN+ neurons, Orexin A+ fibres, and Iba1+ microglia. Notably, α-synuclein load was positively correlated with Orexin A+ fibres and Iba1+ cell counts, suggesting a link between protein aggregation, neuroinflammation, and altered circadian regulation. Together, these findings indicate that α-synuclein rats exhibit disrupted circadian flexibility at both behavioral and cellular levels already at an early disease stage with very mild motor impairment, providing a translational model to study different aspects of circadian dysfunction in Parkinson’s disease.