Circadian regulation of sleep in a pre-clinical model of Dravet syndrome: dynamics of sleep stage and siesta re-entrainment

Jul 27, 2019Sleep

Daily rhythms controlling sleep patterns and nap timing in an animal model of Dravet syndrome

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Abstract

Dravet syndrome mice exhibit fragmented non-rapid eye movement (NREM) sleep and an elongated circadian period of sleep.

Impairments in circadian sleep regulation are observed in mice with a deletion of the Scn1a gene, which models Dravet syndrome.
DS mice demonstrate a disrupted rhythm of non-rapid eye movement (NREM) sleep.
Re-entrainment of sleep stages and siesta after jet lag occurs normally in DS mice, differing from previous findings in wheel-running activity.
An absence or alteration of the daily 'siesta' is more likely in Dravet syndrome mice.

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STUDY OBJECTIVES: Sleep disturbances are common co-morbidities of epileptic disorders. Dravet syndrome (DS) is an intractable epilepsy accompanied by disturbed sleep. While there is evidence that daily sleep timing is disrupted in DS, the difficulty of chronically recording polysomnographic sleep from patients has left our understanding of the effect of DS on circadian sleep regulation incomplete. We aim to characterize circadian sleep regulation in a mouse model of DS.

METHODS: Here we exploit long-term electrocorticographic recordings of sleep in a mouse model of DS in which one copy of the Scn1a gene is deleted. This model both genocopies and phenocopies the disease in humans. We test the hypothesis that the deletion of Scn1a in DS mice is associated with impaired circadian regulation of sleep.

RESULTS: We find that DS mice show impairments in circadian sleep regulation, including a fragmented rhythm of non-rapid eye movement (NREM) sleep and an elongated circadian period of sleep. Next, we characterize re-entrainment of sleep stages and siesta following jet lag in the mouse. Strikingly, we find that re-entrainment of sleep following jet lag is normal in DS mice, in contrast to previous demonstrations of slowed re-entrainment of wheel-running activity. Finally, we report that DS mice are more likely to have an absent or altered daily "siesta".

CONCLUSIONS: Our findings support the hypothesis that the circadian regulation of sleep is altered in DS and highlight the value of long-term chronic polysomnographic recording in studying the role of the circadian clock on sleep/wake cycles in pre-clinical models of disease.

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Circadian regulation of sleep in a pre-clinical model of Dravet syndrome: dynamics of sleep stage and siesta re-entrainment

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