α-Synuclein rat model disrupts light-dark phase behaviors and develops suprachiasmatic nucleus pathology

Disruption of circadian rhythms is a significant non-motor symptom in Parkinson's disease (PD), severely impacting patient quality of life. Despite its prevalence, the precise underlying mechanisms linking neurodegeneration to circadian dysfunction remain only partially understood. Current PD treatments primarily target motor symptoms, leaving non-motor aspects like sleep disturbances and altered daily rhythms largely unaddressed. This gap highlights the need for preclinical models that accurately reflect both neuropathological changes and the symptomatic significance of circadian disruption, particularly concerning α-synuclein aggregation and its impact on key brain regions like the suprachiasmatic nucleus (SCN).

Researchers investigated light-dark phase-dependent motor and non-motor behaviors, alongside suprachiasmatic nucleus (SCN) integrity, in α-synuclein-overexpressing rats and wild-type controls. Behavioral testing was conducted in 3-month-old animals, assessing exploratory activity, locomotion, sucrose preference, and olfaction-guided feeding. Histological analyses focused on the SCN, evaluating overall cell density, α-synuclein accumulation, and cellular composition using markers for neuronal, orexinergic, and microglial cells (Orexin A+, Iba1+). The study aimed to correlate α-synuclein load with specific cellular changes and behavioral deficits.

Wild-type rats demonstrated robust light-dark phase-dependent modulation across all tested behaviors, including exploratory activity, locomotion, sucrose preference, and olfaction-guided feeding. In stark contrast, their α-synuclein-overexpressing transgenic littermates completely lacked this phase-dependent behavioral alternation. Histological examination of the suprachiasmatic nucleus (SCN) in the transgenic rats revealed a reduced overall cell density and pronounced α-synuclein accumulation, indicating early neuropathology. These changes were accompanied by an altered cellular composition within the SCN, affecting neuronal, orexinergic, and microglial markers. Specifically, α-synuclein load was positively correlated with both Orexin A+ fiber counts and Iba1+ cell counts. This suggests a direct link between protein aggregation, neuroinflammation, and the observed alterations in light-dark phase-dependent behavior. > The absence of phase-dependent behavioral modulation in α-synuclein rats, coupled with significant SCN pathology, provides a compelling translational model for studying early non-motor symptoms in Parkinson's disease.