Abstract
Study objectivesTo search for early abnormalities in electroencephalogram (EEG) during sleep which may precede motor symptoms in a transgenic mouse model of hereditary neurodegenerative Huntington’s disease (HD).DesignIn the R6/1 transgenic mouse model of HD, rhythmic brain activity in EEG recordings was monitored longitudinally and across vigilance states through the onset and progression of disease.Measurements and resultsMice with chronic electrode implants were recorded monthly over wake-sleep cycles (4 hours), beginning at 9–11 weeks (presymptomatic period) through 6–7 months (symptomatic period). Recording data revealed a unique β rhythm (20–35 Hz), present only in R6/1 transgenic mice, which evolves in close parallel with the disease. In addition, there was an unusual relationship between this β oscillation and vigilance states: while nearly absent during the active waking state, the β oscillation appeared with drowsiness and during slow wave sleep (SWS) and, interestingly, strengthened rather than dissipating when the brain returned to an activated state during rapid eye movement (REM) sleep.ConclusionsIn addition to providing a new in vivo biomarker and insight into Huntington's disease pathophysiology, this serendipitous observation opens a window onto the rarely explored neurophysiology of the cortico-basal ganglia circuit during SWS and REM sleep.
Highlights
Huntington’s disease (HD) is a fatal hereditary neurodegenerative disease associated with chorea and motor disturbances
Our previous studies with the R6/1 transgenic mouse model of HD [10] demonstrated enhanced b oscillation and altered striatal activity associated with impaired procedural learning ability [11], and disrupted segregation between active and resting brain states during sleep [12]
To detect early changes in sleep electroencephalogram (EEG) that could be used as a biomarker of the HD pathology, we longitudinally monitored sleep EEG in R6/1 mice throughout disease onset and progression, along with motor symptoms
Summary
Huntington’s disease (HD) is a fatal hereditary neurodegenerative disease associated with chorea and motor disturbances. Expression of the huntingtin protein is ubiquitous, the striatum and cortex in particular are affected early in the disease [2]. The first symptoms of this progressive disease may not be movement disturbances, but deficits in learning and memory [3,4]. Our previous studies with the R6/1 transgenic mouse model of HD [10] demonstrated enhanced b oscillation and altered striatal activity associated with impaired procedural learning ability [11], and disrupted segregation between active and resting brain states during sleep [12]. To detect early changes in sleep electroencephalogram (EEG) that could be used as a biomarker of the HD pathology, we longitudinally monitored sleep EEG in R6/1 mice throughout disease onset and progression, along with motor symptoms
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