Mouse study links brain’s thermostat to sleep issues in Dravet
Sleeping, body temperature connected through hypothalamus
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Problems with sleep and body temperature regulation in Dravet syndrome are linked through the hypothalamus — the part of the brain that regulates both — and targeting it may help develop better treatments, according to a study in a mouse model of the disease.
“These findings highlight a connection between sleep and thermal dysregulation in [Dravet syndrome], implicating altered neuronal activity of the hypothalamus,” the researchers wrote.
The study, “Disrupted temperature-sleep coupling mechanism in a Dravet syndrome mouse model,” was published in Nature Communications.
Dravet syndrome is caused by mutations in the SCN1A gene. The condition, which typically begins in infancy, involves severe seizures and non-epileptic symptoms, including developmental delays, cognitive impairment, and autonomic dysfunctions like sleep disturbances and impaired body temperature regulation.
While seizures in Dravet have traditionally been linked to the hippocampus, a part of the brain involved in memory and emotions, the exact cause of sleep disturbances and altered body temperature remains unclear.
Sleeping mice and body temperature
Researchers used a mouse model of Dravet syndrome to explore whether sleep and body temperature disturbances are linked. Compared with wild-type (healthy) mice, model mice had a significantly lower core body temperature, which is the internal temperature of the body.
The team recorded brain activity and body temperature using electrocorticography, a technique that measures electrical activity from the surface of the brain, and local field potential recordings, which detect signals from groups of neurons (nerve cells). When healthy mice fell asleep into deep, restorative sleep, their core body temperature dropped. However, model mice did not show this expected change when they transitioned to sleep.
Body temperature control is important for keeping the body balanced, especially before sleep, and “nesting contributes to preserving body temperature during sleep,” the researchers wrote. When given nesting materials overnight, young, healthy mice built complex nests. In contrast, most model mice (75%) did not build nests at all, and those that did made simpler ones, showing “a reduced ability to perform this innate behavior.”
A warmer environment promoted sleep onset, a process called somnogenesis, for healthy mice. But warmth did not help model mice fall asleep, suggesting a break in the normal connection between sleep and body temperature.
To test possible treatments, the researchers used two experimental strategies. First, they used vector-mediated expression of SCN1A, meaning they delivered a healthy copy of the SCN1A gene, which is mutated in Dravet, into brain cells. Second, they used chemogenetic stimulation, which allows specific brain cells to be activated with engineered molecules.
Both strategies targeted the anterior hypothalamus, and both restored warmth-induced sleep in model mice.
“Together, these findings highlight the involvement of dysregulated neuronal activity in the anterior hypothalamus,” the researchers wrote. “Focusing on the transition to sleep, we identified deficits in temperature reduction at the onset of [non-rapid eye movement sleep, the deeper and more restorative stage of sleep] and impaired warmth-induced somnogenesis.”
However, “warmth-induced sleep-promoting features” could be restored “by modulation of hypothalamic neuronal activity by either [vector]-mediated expression of SCN1A or chemogenetic stimulation of anterior hypothalamic neurons,” the researchers wrote, suggesting potential treatment strategies for Dravet syndrome.
