Sex-specific sleep disturbances found in juvenile Batten mice
Male mice spend less time asleep than healthy mice during daylight
Sex-specific differences in sleep disturbances have been discovered in a mouse model of juvenile Batten disease, according to the first study of its kind.
During the light period, when mice are primarily asleep, male mice with juvenile Batten-like disease spend less time asleep than healthy mice, while diseased female mice had longer sleep cycles during the early dark period.
“As mice are nocturnal animals, and therefore less active in the light period, our findings of sleep disturbances in the male … mice recapitulate disrupted sleep during the night in [juvenile Batten] disease patients,” the researchers wrote, adding that longer sleep in the early hours of the dark period in female mice mimic daytime sleepiness in people with Batten. “Our work will facilitate future studies into the potential mechanism behind sleep disturbances associated with the disease and the potential treatment strategies.”
The study, “Characterisation of sleep in a mouse model of CLN3 disease revealed sex-specific sleep disturbances,” was published in the Journal of Sleep Research.
Batten is a group of inherited, severe neurological disorders marked by defects in the processes that break down waste products. This leads to the toxic accumulation of lipofuscin, yellow-brown granules composed of digested fats and proteins, inside lysosomes, which arethe components inside cells that break down waste.
Brain cells are susceptible to the effects of lipofuscin building up, which is why people with Batten develop symptoms associated with brain damage, such as vision loss and seizures, as well as progressive cognitive and motor decline.
Juvenile Batten disease, or CLN3 disease, the most common type of Batten, is caused by mutations in the CLN3 gene and symptoms typically arise between the ages of 5 and 10.
Sleep disturbances are among the most common symptoms associated with juvenile Batten. These problems may include difficulty falling asleep, short sleep duration, waking in the middle of the night, nightmares, walking or talking while asleep, and daytime sleepiness.
Exploring sleep disturbances in juvenile Batten disease
Because such sleep problems aren’t fully studied in juvenile Batten and haven’t been described in an animal model, researchers at the University of Kentucky examined sleep in a mouse model of the disease, which lacks the CLN3 gene, called Cln3KO mice.
Unlike humans, who sleep primarily at night over a single seven- to eight-hour period, mice go through several sleep-waking cycles, with fewer cycles during the night than in the daytime.
To continuously track sleep patterns over 24 hours, the researchers used PiezoSleep, a noninvasive, automated motion-sensing system that can distinguish between sleep and wakefulness. Measurements were recorded over two consecutive 12-hour light and dark periods and analyzed separately.
During the light period, when they were generally less active, male Cln3KO mice slept significantly less overall than healthy male mice, as indicated by a lower sleep percentage over time. Cln3KO and healthy female mice had similar sleep percentages.
Even when male Cln3KO mice slept during the light period, the mean time they remained asleep over several sleep cycles was significantly shorter than healthy males. No significant differences were seen between Cln3KO and healthy female mice.
Over the entire 12-hour dark period, when mice are typically more active, the mean time asleep was similar, with or without the CLN3 gene and regardless of sex.
However, during the first six hours of the dark period, the mean sleeping time was considerably longer for Cln3KO female mice than healthy female mice, while Cln3KO and healthy male mice had similar values during this period.
An examination of mice experiencing the top 10% longest sleep bouts during the light period showed that Cln3KO male mice were still deficient in sleep time compared with healthy male mice. Again, Cln3KO and healthy female mice showed no significant differences.
During the dark period, there were no significant differences regarding the top 10% longest sleep bouts, regardless of sex. But during the early dark period, the mean of the top 10% longest sleeping times was significantly longer in Cln3KO mice than in healthy mice, regardless of sex.
Because mice are less active during periods of light, sleep disturbances in the male Cln3KO mice parallel the disrupted sleep patterns at night in juvenile Batten patients, the researchers said. On the other hand, longer sleep cycles for female Cln3KO mice during the early dark period align with daytime sleepiness in patients.
“This is the first study reporting [an abnormal sleep profile] in a mouse model of CLN3 disease,” wrote the researchers, who said their findings “will be useful for future investigations of the mechanisms behind the clinically reported sleep disturbances in CLN3 disease and of potential treatment strategies to recuperate sleep in patients with CLN3 disease, and improve the quality of life for these individuals.”
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