Mechanisms of Sleep/Wake Regulation under Hypodopaminergic State: Insights from MitoPark Mouse Model of Parkinson's Disease

Abstract

Sleep/wake alterations are predominant in neurological and neuropsychiatric disorders involving dopamine dysfunction. Unfortunately, specific, mechanisms-based therapies for these debilitating sleep problems are currently lacking. The pathophysiological mechanisms of sleep/wake alterations within a hypodopaminergic MitoPark mouse model of Parkinson's disease (PD) are investigated. MitoPark mice replicate most PD-related sleep alterations, including sleep fragmentation, hypersomnia, and daytime sleepiness. Surprisingly, these alterations are not accounted for by a dysfunction in the circadian or homeostatic regulatory processes of sleep, nor by acute masking effects of light or darkness. Rather, the sleep phenotype is linked with the impairment of instrumental arousal and sleep modulation by behavioral valence. These alterations correlate with changes in high-theta (8-11.5 Hz) electroencephalogram power density during motivationally-charged wakefulness. These results demonstrate that sleep/wake alterations induced by dopamine dysfunction are mediated by impaired modulation of sleep by motivational valence and provide translational insights into sleep problems associated with disorders linked to dopamine dysfunction.

Disrupted sleep-wake regulation in the MCI-Park mouse model of Parkinson’s disease

“…Changes in brain wave activity, as measured by the electroencephalogram (EEG), have been demonstrated in PD patients, who typically exhibit an overall slowing of EEG activity as detected by relative increases in the proportion of lower frequency bands, such as delta and theta, and relative decreases in higher frequency bands, such as alpha, to the EEG spectral profile of different vigilance states 10 – 12 . Similar patterns of EEG slowing have been observed in several mouse models of PD 13 – 15 . Interestingly, particular EEG changes, such as theta power during wake, have been associated with cognitive performance, including in PD 10 , 16 – 19 .…”

“…Mice over-expressing mutant human α -synuclein sleep less, experience increased wakefulness, display altered temporal distribution of sleep, and demonstrate a shift in EEG spectral density to lower frequency bands 14 , 26 ; suggesting a PD-like disfunction in sleep. The MitoPark model exhibits increased fragmentation and reduced REM sleep with overall hypersomnia, particularly during the dark (active) phase of the light cycle 15 . Mice lacking VMAT2 (and degeneration of dopaminergic neurons) have a shorter sleep latency defined behaviorally, but not other features of the PD sleep phenotype 33 .…”

“…Alterations in brain circuitry responsible for PD symptoms and features have been studied primarily in animal models 22 . While some of these models exhibit sleep-wake abnormalities resembling those in PD patients 6 , 13 – 15 , 23 – 28 , no individual model faithfully captures the full spectrum of sleep disturbances present in PD 6 . Moreover, because these mouse models are not progressive, they do not allow for a rigorous dissection of the evolution and temporal dynamics of sleep disturbances as pathology unfolds.…”

Disrupted sleep-wake regulation in the MCI-Park mouse model of Parkinson’s disease

“…Changes in brain wave activity, as measured by the electroencephalogram (EEG), have been demonstrated in PD patients, who typically exhibit an overall slowing of EEG activity as detected by relative increases in the proportion of lower frequency bands, such as delta and theta, and relative decreases in higher frequency bands, such as alpha, to the EEG spectral profile of different vigilance states [10][11][12] . Similar patterns of EEG slowing have been observed in several mouse models of PD [13][14][15] . Interestingly, particular EEG changes, such as theta power during wake, have been associated with cognitive performance, including in PD 10,[16][17][18][19] .…”

“…Alterations in brain circuitry responsible for PD symptoms and features have been studied primarily in animal models 22 . While some of these models exhibit sleep-wake abnormalities resembling those in PD patients 6,[13][14][15][23][24][25][26][27][28] , no individual model faithfully captures the full spectrum of sleep disturbances present in PD 6 . Moreover, because these mouse models are not progressive, they do not allow for a rigorous dissection of the evolution and temporal dynamics of sleep disturbances as pathology unfolds.…”