Alteration of daily and circadian rhythms following dopamine depletion in MPTP treated non-human primates

PLoS One. 2014 Jan 23;9(1):e86240. doi: 10.1371/journal.pone.0086240. eCollection 2014.

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 ([(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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Animals
  • Circadian Rhythm*
  • Dopamine / deficiency*
  • Female
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Macaca fascicularis
  • Macaca mulatta
  • Male
  • Motor Activity
  • Neuropeptides / metabolism
  • Orexins
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / metabolism
  • Parkinsonian Disorders / physiopathology*
  • Photoperiod
  • Retina / metabolism
  • Retina / pathology
  • Rod Opsins / metabolism
  • Suprachiasmatic Nucleus / metabolism
  • Suprachiasmatic Nucleus / pathology

Substances

  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexins
  • Rod Opsins
  • melanopsin
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Dopamine

Grant support

Support was provided by the following: Fondation de France, Fondation Caisse d'Epargne Rhône Alpes Lyon, Rhône-Alpes Cible/CMIRA, ANR-09-MNPS-040, Retina France, Volubilis, GDRI Neurosciences, and Cluster Handicap Vieillissement Neurosciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.