Research conducted on fruit flies has pinpointed specific groups of cholinergic brain cells that contribute to sleep disturbances caused by alcohol. This discovery may eventually lead to focused treatments for insomnia associated with alcohol consumption, aiding individuals in overcoming alcohol use disorder.
Alcohol use disorder, which impacts more than 10% of the U.S. population, can result in severe and persistent insomnia. People may struggle with falling and staying asleep, and these challenges can persist for months even after they stop drinking, which heightens the chance of relapse. However, addressing insomnia linked to withdrawal is challenging because the underlying brain mechanisms are still not entirely understood.
Recent findings in fruit flies have revealed distinct brain signals and particular groups of brain cells that play a role in alcohol-induced sleep disruptions. This research could lead to more effective treatments aimed at alleviating sleep loss related to alcohol, facilitating recovery from alcohol use disorder.
“Alcohol affects sleep in a way that’s localized to a specific type of brain cell, which is a novel finding,” states Maggie Chvilicek, a graduate neuroscience researcher at the University of Utah and lead author of the study. She mentions that the function of these cells is often similar in both flies and humans. “The mechanism we’ve identified likely has parallels in mammalian brains as well.”
A rebound effect
The research team observed that alcohol impacts fruit flies similarly to how it affects humans. Flies administered a high dose of alcohol showed increased time to fall asleep and a greater tendency to awaken during the night, effects that persisted for several days after the alcohol had cleared their systems.
Importantly, the researchers discovered that the influence of alcohol on sleep was dose-dependent. Both flies and humans experience stimulation from a small dose of alcohol, leading to heightened energy and activity, whereas larger amounts slow cognitive processing and may induce unconsciousness. However, lower doses that energized the flies did not hinder their ability to sleep, while larger doses caused sleep disruptions lasting for days.
This indicated that the sleep-disrupting effects of alcohol might be linked to its activity-suppressing impact. Chvilicek hypothesizes that this could lead to a “rebound” effect, where the reduction of brain activity due to alcohol causes neurons to become overly active later.
The study identified acetylcholine, a brain signal crucial for memory and motivation, as central to alcohol’s detrimental effects on sleep. When acetylcholine signaling was diminished, even small doses of alcohol significantly intensified sleep disturbances in the flies, leading to prolonged insomnia.
Targeting specific brain cells
Utilizing genetic techniques, the researchers altered the activity of certain brain cells, zeroing in on a specific subset of neurons that produce acetylcholine, which seem to be associated with alcohol-induced sleep disruptions.
Reducing acetylcholine activity in this particular group of neurons made the flies more sensitive to low alcohol doses, causing them to take longer to fall asleep and leading to more frequent awakenings.
The neurons are located in a brain region of fruit flies responsible for learning and memory, functioning similarly to the human hippocampus, where acetylcholine signaling is also vital.
However, it’s important to note that disabling this specific group of cells does not result in sleep issues by itself; the flies must also be exposed to alcohol to exhibit sleep-related symptoms. “It’s not a simple matter of these cells being either active or inactive,” Chvilicek explains. “Alcohol seems to play a distinct role in what occurs in those cells.”
Toward better treatments
The researchers aim for their findings to pave the way for improved treatments for those experiencing withdrawal. Traditional sleep medications tend to affect a wide range of brain cells, potentially increasing addiction risks and adverse side effects. “By identifying a much smaller and specific group of cells,” Chvilicek states, “we can theoretically create more targeted treatments that directly address the issue at hand.”
Using fruit flies as a model to study alcohol-induced insomnia allows for a deeper understanding of this condition. “This model provides a wealth of mechanistic insights,” Chvilicek adds.
As a follow-up, Adrian Rothenfluh, PhD, an associate professor of psychiatry at the University of Utah and a senior author of this research, shares that the lab plans to investigate the genes involved in alcohol-induced insomnia. “We have established multiple times that the same genes conserved across species regulate alcohol-related behaviors in both flies and humans,” he explains. “We are in an excellent position to uncover genetic mechanisms influencing alcohol-related sleep disruptions.”
This research received support from the Huntsman Mental Health Institute, the University of Utah Molecular Medicine Program, and the NIH: the National Institutes of Diabetes and Digestive and Kidney Diseases (R01DK110358), on Drug Abuse (K01DA058919), and on Alcohol Abuse and Alcoholism (F31AA030209, K01AA029200, R01AA030881, R01AA019536, and R21AA031795).
