Alteration of Daily and Circadian Rhythms following Dopamine Depletion in MPTP Treated Non-Human Primates

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.

Assessment of subjective sleep quality in iron deficiency anaemia

“…Their findings suggested that the dopamine transporter contributes to homeostatic sleep-wake regulation in humans. Fifel et al 31 , investigated alterations of circadian rhythms in non-human primate models following lesion of the dopaminergic nigro-striatal system.…”

Rhythmic Dopamine: New Emerging Role of The Pleasure Molecule

“…The history of science is rich with such examples of serendipities [1] . Such was the case for the story behind our study published early this year in PlosOne [2] . We have been using infrared captors to monitor the general locomotor activity of individually housed Non-Human Primates (NHP) when we noticed something odd.…”

“…Although such direct evidence is still lacking, epidemiological studies have revealed, a still unexplained, high occurrences of PD in northern compared to tropical latitudes [8] . we propose that the loss of the circadian modulation of DA availability in the brain of PD patients as a consequence of DA neuron degeneration would be the pathophysiological correlate that could explain such trends [2] . The next obvious step towards the confirmation of this hypothesis will be to assess the circadian pattern of sleep in a large number of PD patients settled at different latitudes and link the potential alterations of sleep/wake rhythm with biological markers of DA rhythmicity using for example fMRI and PET technologies.…”

Transplantation in the nonhuman primate MPTP model of Parkinson's disease: update and perspectives

“…Longitudinal and simultaneous multiparametric follow-ups (cognitive and behavioral tasks, motor score, rest-activity cycles, in vivo imaging) should be carried out as much as possible given the NHP PD model chosen in future experiments. Indeed, non-motor symptoms have only been reproduced through repeated low-dose MPTP regimen (Schneider and Kovelowski, 1990;Taylor et al, 1990;Almirall et al, 1999Almirall et al, , 2001Barcia et al, 2003;Decamp and Schneider, 2004;Vezoli et al, 2011;Fifel et al, 2014). Overall, very few studies follow up transplanted monkeys for more than a year Hallett et al, 2015;Aron Badin et al, 2016;Peng et al, 2016).…”

“…The low-dose MPTP monkey model (Bezard et al, 1997) is the model of choice for translational study because it presents a parkinsonian syndrome characterized by all critical aspects of PD, including a slow progressive evolution of symptoms, e.g., it replicates the typical motor symptoms used for primary clinical diagnosis of parkinsonism with response to classical DA therapy (Stephenson et al, 2005), characteristic pattern of nigrostriatal denervation observed in PD patients (Gibb and Lees, 1991;Perez-Otano et al, 1994), early and long-lasting non-motor symptoms (Poewe, 2008;Vezoli et al, 2011;Fifel et al, 2014;Swallow et al, 2016), and increased α-synuclein expression in the pigmented cells of the SN (substantia nigra; Purisai et al, 2005). However, even if those inclusion bodies appears in the same sites as for Lewy bodies in PD, e.g., SN, they do not express typical Lewy body features as found in human PD patients (Forno et al, 1993).…”