Alcohol use disorder, which affects over 10% of Americans, can lead to persistent and serious insomnia. Difficulties falling asleep and staying asleep can last even after months of sobriety, increasing the risk of relapse. But treating withdrawal-related insomnia is difficult, partly because what's going on in the brain in this condition remains largely mysterious.
Now, research in fruit flies has identified specific brain signals and groups of brain cells that are involved in alcohol-induced insomnia. This work could ultimately lead to targeted treatments for alcohol-related sleep loss, helping people recover from alcohol use disorder.
"The effects of alcohol on sleep seem to be localized to a particular cell type in the brain, which is not something that's ever been shown before," says Maggie Chvilicek, graduate researcher in neuroscience at the University of Utah and lead author on the study. She adds that these cells often do similar things in flies and humans. "The mechanism that we identified is something that very likely could also exist in a mammalian brain."
The results are published in Current Biology.
A rebound effect
The researchers noticed that alcohol affected fruit flies much like it affects humans. When flies received a high dose of alcohol, they took longer to fall asleep and were more likely to wake during the night, even several days after the alcohol left their system.
Crucially, the researchers found, the effects of alcohol on sleep depended on dose—and how one might expect. In both flies and humans, a small amount of alcohol acts like a stimulant, increasing feelings of energy and activity levels, while higher levels slow down thinking and reaction time and can cause unconsciousness. But a smaller alcohol dose that made flies hyperactive didn't prevent them from sleeping normally. In contrast, a bigger dose of alcohol disrupted sleep for days.
This meant that something about the activity-dampening effects of alcohol was interfering with sleep. Chvilicek suspects this may be due to a "rebound" effect, in which reducing brain activity with alcohol causes neurons to become overactive after the fact.
A brain signal called acetylcholine, which plays a key role in memory and motivation, appears to be key to alcohol's negative impacts on sleep, the research team found. When they reduced acetylcholine signaling, it exacerbated the effects of alcohol on sleep, such that even a low dose of alcohol led to long-lasting insomnia.
Targeting specific brain cells
The team used genetic tools to change the activity of specific brain cells, narrowing down on the particular subset of acetylcholine-producing neurons that seem to be implicated in alcohol-induced sleep disruption.
Reducing acetylcholine signaling within this small set of brain cells again made flies more sensitive to low doses of alcohol, taking longer to fall asleep and waking up more often.
The neurons are in a region of the fly brain which is involved in learning and memory. It functions in many ways like the human hippocampus, where acetylcholine signaling also plays a major role.
One important caveat is that turning off that group of cells doesn't cause sleep deficits on its own—flies must also be exposed to alcohol to develop sleep symptoms, meaning that something more complicated must be going on. "It's not just a black-and-white binary of the cells being on or off," Chvilicek says. "It seems like alcohol is playing a specific role in what's happening in those cells."
Toward better treatments
The researchers hope their work ultimately leads to more effective treatments for people in withdrawal. Most sleep medicines act on a broad swath of cells throughout the brain, which increases the risk of addiction and unhealthy side effects. "By identifying a much smaller, more discrete population of cells," Chvilicek says, "we can theoretically develop much more targeted interventions that really focus on the problem that we're trying to address."
Establishing that fruit flies can be used to study alcohol-induced insomnia also allows for much more in-depth study of this condition. "There's so much mechanistic information that can be gleaned because we have this model," Chvilicek says.
As a next step, Adrian Rothenfluh, PhD, associate professor of psychiatry at the University of Utah and senior author on the study, adds that the lab plans to explore which genes are involved in alcohol-induced insomnia. "We've shown multiple times that the same conserved genes regulate alcohol-induced behavior in flies and humans," he explains. "We are now in a prime position to identify genetic mechanisms that affect alcohol-induced insomnia."
