title: Loss of dopamine disrupts circadian rhythms in a mouse model of Parkinson's disease.
abstract: Although a wide range of physiological functions regulated by dopamine (DA) display circadian variations, the role of DA in the generation and/or modulation of these rhythms is unknown. In Parkinson's disease (PD) patients, in addition to the classical motor symptoms, disturbances of the pattern of daily rest/wake cycles are common non-motor symptoms. We investigated daily and circadian rhythms of rest/activity behaviors in a transgenic MitoPark mouse model with selective inactivation of mitochondrial transcription factor A (Tfam) resulting in a slow and progressive degeneration of DA neurons in midbrain structures. Correlated with this, MitoPark mice show a gradual reduction in locomotor activity beginning at about 20weeks of age. In a light-dark cycle, MitoPark mice exhibit a daily pattern of rest/activity rhythms that shows an age-dependent decline in both the amplitude and the stability of the rhythm, coupled with an increased fragmentation of day/night activities. When the circadian system is challenged by exposure to constant darkness or constant light conditions, control littermates retain a robust free-running circadian locomotor rhythm, whereas in MitoPark mice, locomotor rhythms are severely disturbed or completely abolished. Re-exposure to a light/dark cycle completely restores daily locomotor rhythms. MitoPark mice and control littermates express similar masking behaviors under a 1h light/1h dark regime, suggesting that the maintenance of a daily pattern of rest/activity in arrhythmic MitoPark mice can be attributed to the acute inhibitory and stimulatory effects of light and darkness. These results imply that, in addition to the classical motor abnormalities observed in PD, the loss of the midbrain DA neurons leads to impairments of the circadian control of rest/activity rhythms.
authors.affiliation: INSERM 846, Stem Cell and Brain Research Institute, Department of Chronobiology, 18 Avenue du Doyen Lépine, 69500 Bron, France; Laboratory of Neurophysiology, Molecular Cell Biology Department, Leiden University Medical Center, PO Box 9600 Mailbox S5-P. 2300 RC Leiden, The Netherlands. Electronic address: fifel-k@hotmail.com.
authors.forename: Karim
authors.initials: K
authors.lastname: Fifel
authors.affiliation: INSERM 846, Stem Cell and Brain Research Institute, Department of Chronobiology, 18 Avenue du Doyen Lépine, 69500 Bron, France. Electronic address: howard.cooper@inserm.fr.
authors.forename: Howard M
authors.initials: HM
authors.lastname: Cooper
mesh_terms: D000203:Activities of Daily Living; D000367:Age Factors; D000818:Animals; D016009:Chi-Square Distribution; D021081:Chronobiology Disorders / Q000209:etiology* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008636:Mesencephalon / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009043:Motor Activity / Q000235:genetics; D010300:Parkinson Disease / Q000150:complications / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D024101:Mitochondrial Proteins; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D004298:Dopamine
keywords: Dopamine; Parkinson; Sleep; Striatum; Suprachiasmatic nucleus