Disrupted sleep-wake cycles and circadian rhythms in a Drosophila model of C9orf72-FTD

Frontotemporal dementia (FTD) is a neurodegenerative disorder that affects behavior, personality, motor activity, speech, cognition, and sleeping patterns. Previous findings support the idea that disruption of sleep and circadian systems may not only be affected by this disease but also work to actively shape the clinical phenotype of FTD. Thus, understanding how sleep-wake cycles are altered may provide insight into mechanisms that influence both disease progression and quality of life. We studied an established Drosophila model of FTD to investigate changes in the sleep-wake cycle of both young and aging flies. A C9orf72- associated FTD model was chosen, as the most common genetic cause of sporadic and hereditary FTD is a hexanucleotide repeat expansion in intron 1 of the C9orf72 gene. We performed behavioral assays to measure locomotor activity in both a 12 h:12 h light/dark (LD) cycle and complete darkness (free running). From this data, we were able to analyze changes in sleep and activity patterns, as well as circadian rhythms in flies modeling C9orf72 -FTD. Our data suggests that these flies have increased nighttime activity and decreased sleep at night, which becomes more significant as they age. Older flies also displayed decreased sleep pressure during both day and night and lost rhythmicity. Of specific interest, young flies modeling C9orf72 -FTD demonstrated altered day and night sleep latency, decreased sleep depth at night, and reduced rhythmicity in constant darkness. This suggests that changes in their sleep-wake cycle occur early in disease progression and provide an avenue for potential intervention and early diagnostic markers.