Abstract
Disturbances of the daily sleep/wake cycle are common non-motor symptoms of Parkinson's disease (PD). However, the impact of dopamine (DA) depletion on circadian rhythms in PD patients or non-human primate (NHP) models of the disorder have not been investigated. We evaluated alterations of circadian rhythms in NHP following MPTP lesion of the dopaminergic nigro-striatal system. DA degeneration was assessed by in vivo PET ([11C]-PE2I) and post-mortem TH and DAT quantification. In a light∶dark cycle, control and MPTP-treated NHP both exhibit rest-wake locomotor rhythms, although DA-depleted NHP show reduced amplitude, decreased stability and increased fragmentation. In all animals, 6-sulphatoxymelatonin peaks at night and cortisol in early morning. When the circadian system is challenged by exposure to constant light, controls retain locomotor rest-wake and hormonal rhythms that free-run with stable phase relationships whereas in the DA-depleted NHP, locomotor rhythms are severely disturbed or completely abolished. The amplitude and phase relations of hormonal rhythms nevertheless remain unaltered. Use of a light-dark masking paradigm shows that expression of daily rest-wake activity in MPTP monkeys requires the stimulatory and inhibitory effects of light and darkness. These results suggest that following DA lesion, the central clock in the SCN remains intact but, in the absence of environmental timing cues, is unable to drive downstream rhythmic processes of striatal clock gene and dopaminergic functions that control locomotor output. These findings suggest that the circadian component of the sleep-wake disturbances in PD is more profoundly affected than previously assumed.
Highlights
Disturbances of the sleep-wake timing are a prominent feature of non-motor symptoms of Parkinson’s disease (PD), expressed as insomnia, excessive daytime sleepiness and fragmentation of sleep architecture [1,2]
When control animals were released into constant conditions (LL) they expressed a robust free running circadian rhythm with a mean period close to 24 h (23.9960.04 h; Fig. 1A) with 89.460.7% of activity consolidated during the subjective day and a mean amplitude (x2 periodogram) of 4,9836256
3 out of 7 MPTP-treated animals showed a complete loss of circadian rhythmicity (Fig. 1B, 2B–C) with locomotor activity homogenously distributed throughout the 24 h period
Summary
Disturbances of the sleep-wake timing are a prominent feature of non-motor symptoms of Parkinson’s disease (PD), expressed as insomnia, excessive daytime sleepiness and fragmentation of sleep architecture [1,2]. The MPTPtreated NHP is considered a highly appropriate model of PD since, in addition to cognitive and motor deficits, it closely replicates several features of sleep and wake abnormalities, including excessive daytime sleepiness, REM sleep disturbances and altered day-night activity patterns. Many of these precede the appearance of motor symptoms and have been proposed as early biomarkers of the premotor phase of PD [1,16,17]. Because the excitatory and inhibitory influences of light and dark can potentially over-ride circadian clock control, we examined the rest/activity rhythms of MPTP-treated NHP monkey in lighting conditions devoid of any cyclic environmental timing cues to determine the impact of DA neurodegeneration on circadian functions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
