Abstract
Sleep disorders are frequently diagnosed in Parkinson’s disease and manifested in the prodromal and advanced stages of the disease. These conditions, which in some cases affect more than 50% of Parkinson’s disease (PD) patients, include hypersomnia, often manifested as excessive daytime sleepiness, insomnia, characterized by delayed initiation and fragmentation of sleep at night, and disruption of rapid eye movement (REM) sleep, resulting in loss of atonia and dream enactment. Standard dopamine replacement therapies for the treatment of motor symptoms are generally inadequate to combat sleep abnormalities, which seriously affect the quality of life of PD patients. Rodent models still represent a major tool for the study of many aspects of PD. They have been primarily designed to eliminate midbrain dopamine neurons and elicit motor impairment, which are the traditional pathological features of PD. However, rodent models are increasingly employed to investigate non-motor symptoms, which are often caused by degenerative processes affecting multiple monoaminergic and peptidergic structures. This review describes how neurotoxic and genetic manipulations of rats and mice have been utilized to reproduce some of the major sleep disturbances associated with PD and to what extent these abnormalities can be linked to nondopaminergic dysfunction, affecting for instance noradrenaline, serotonin, and orexin transmission. Strengths and limitations are discussed, as well as the consistency of results obtained so far, and the need for models that better reproduce the multisystemic neurodegenerative nature of PD, thereby allowing to replicate the complex etiology of sleep-related disorders.
Highlights
Since their first description two centuries ago, the symptoms of Parkinson’s disease (PD) have been regularly re-assessed to include a large number of nonmotor conditions affecting both the peripheral and the central nervous system (Chaudhuri and Odin, 2010; Lang, 2011)
These findings are in line with some of the disturbances observed in PD patients, who are affected by insomnia at night and daytime sleepiness
The development of rat and mouse models of PD-related sleep disturbances has lagged behind in comparison, for instance, to affective and cognitive symptoms. The reason for this lies in part in the complexity of sleep-related disorders, both with regard to their behavioral manifestation and their relationship to distinct cellular and anatomical substrates
Summary
Since their first description two centuries ago, the symptoms of Parkinson’s disease (PD) have been regularly re-assessed to include a large number of nonmotor conditions affecting both the peripheral and the central nervous system (Chaudhuri and Odin, 2010; Lang, 2011). Sleep analysis has recently been performed in rats injected unilaterally with 6-OHDA in the SNc, which results in a substantial loss of dopamine neurons (Ciric et al, 2019) This intervention leads to increased number and mean duration of wake episodes assessed by cortical and hippocampal EEG during 6 h within the inactive, light-on period (Ciric et al, 2019). The 6-OHDA-lesion rats displayed reduced wake duration and spontaneous activity accompanied by a significant increase of both REM and SWS (NREM) during the dark phase (Sakata et al, 2002) These findings are in line with some of the disturbances observed in PD patients, who are affected by insomnia at night and daytime sleepiness. Aside from the contrasting effects on activity state observed in Thy1-αSyn mice, which may be attributable to different methodological approaches (see above), these inconsistencies are possibly a consequence of distinct genetic strategies (overexpression of α-synuclein as opposed to downregulation of VAMT2), which may produce unique alterations besides those affecting the dopaminergic system
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