Alteration of daily and circadian rhythms following dopamine depletion in MPTP treated non-human primates.
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 ([(11)C]-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.
Inserm, U846, Stem Cell and Brain Research Institute, Bron, France ; Université de Lyon, Lyon 1, UMR-S 846, Lyon, France.
Karim
K
Fifel
Inserm, U846, Stem Cell and Brain Research Institute, Bron, France ; Université de Lyon, Lyon 1, UMR-S 846, Lyon, France.
Julien
J
Vezoli
Inserm, U846, Stem Cell and Brain Research Institute, Bron, France ; Université de Lyon, Lyon 1, UMR-S 846, Lyon, France.
Kwamivi
K
Dzahini
Inserm, U846, Stem Cell and Brain Research Institute, Bron, France ; Université de Lyon, Lyon 1, UMR-S 846, Lyon, France.
Bruno
B
Claustrat
Inserm, U846, Stem Cell and Brain Research Institute, Bron, France ; Université de Lyon, Lyon 1, UMR-S 846, Lyon, France.
Vincent
V
Leviel
Inserm, U846, Stem Cell and Brain Research Institute, Bron, France ; Université de Lyon, Lyon 1, UMR-S 846, Lyon, France.
Henry
H
Kennedy
Inserm, U846, Stem Cell and Brain Research Institute, Bron, France ; Université de Lyon, Lyon 1, UMR-S 846, Lyon, France.
Emmanuel
E
Procyk
Inserm, U846, Stem Cell and Brain Research Institute, Bron, France ; Université de Lyon, Lyon 1, UMR-S 846, Lyon, France.
Ouria
O
Dkhissi-Benyahya
Inserm, U846, Stem Cell and Brain Research Institute, Bron, France ; Université de Lyon, Lyon 1, UMR-S 846, Lyon, France.
Claude
C
Gronfier
Inserm, U846, Stem Cell and Brain Research Institute, Bron, France ; Université de Lyon, Lyon 1, UMR-S 846, Lyon, France.
Howard M
HM
Cooper
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D002940:Circadian Rhythm; D004298:Dopamine / Q000172:deficiency*; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D009043:Motor Activity; D009479:Neuropeptides / Q000378:metabolism; D000068797:Orexins; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D017440:Photoperiod; D012160:Retina / Q000378:metabolism / Q000473:pathology; D017299:Rod Opsins / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000378:metabolism / Q000473:pathology; D000099210:Melanopsin
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D017299:Rod Opsins; D000099210:Melanopsin