Objective: We aimed to investigate the impact of alpha-synuclein aggregation and spreading, and nigrostriatal dopaminergic degeneration on sleep homeostasis and circadian function.

Background: Sleep dysfunction and circadian disturbances are among the earliest non-motor features of PD, proceeding motor manifestations by ~15 years. PD is characterised by the degeneration of the dopaminergic neurons of the nigrostriatal and mesolimbic systems and the occurrence of Lewy bodies containing alpha-synuclein (α-syn). By modelling both hallmarks of the disease, we aimed to dissect the contribution of each pathology to alterations in sleep and circadian functions.

Method: Mice were unilaterally injected into the dorsal stratum with either the neurotoxin 6-hydroxydopamine (OHDA), or preformed fibrils of human α-syn (PFF). EEG radiotelemetry and video recordings were performed under different experimental paradigms and stages of disease progression. To test whether dopaminergic neurodegeneration confined to the nigrostriatal pathway or fibril-related alterations in neuronal functions alter circadian rhythms of physiology and behaviour we assessed the rate of adaptation to changes in geophysical time, the acute effect of light on the central circadian pacemaker, and the circadian free-running period under constant darkness. To assess sleep homeostasis, we recorded sleep over 24-hours and sleep rebound after a 6hr sleep deprivation.

Results: Unilateral degeneration of the nigrostriatal dopaminergic pathway alters brain activity across all vigilant states, including the slowing of EEG, with no apparent changes to centrally regulated circadian output rhythms. In contrast, the PFF mouse model progressively develops changes in its responsiveness to environmental cues (e.g., light), including its adaptability to environmental changes, such as temporal shifts in day/night cycles.

Conclusion: Circadian output pathways that control overt rhythms of behaviour and physiology, including sleep, are progressively altered by α-syn spreading. A partial unilateral nigrostriatal lesion however does not alter sleep regulation or the circadian output.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/utilising-multiple-murine-models-to-investigate-sleep-and-circadian-system-dysfunction-in-pd/