Scientists have long recognized the brain's need for energy, but groundbreaking research from the University of Kentucky's Sanders-Brown Center on Aging has now illuminated how the brain's energy utilization significantly influences our sleep patterns.
The study was recently published in The Proceedings of the National Academy of Sciences (PNAS). It discovered certain channels in the brain, called ATP-sensitive potassium (KATP) channels, act as energy sensors and play a pivotal role in maintaining stable sleep-wake cycles and facilitating smooth transitions between cycles.
The research was led by Nicholas Constantino, a doctoral neuroscience student working in the lab of Shannon Macauley, Ph.D. The project was an interdepartmental collaboration between physiology, neuroscience, Sanders-Brown and the Central Nervous System-Metabolism Centers of Biomedical Research Excellence (CNS-Met COBRE).
This research was supported by multiple awards from the National Institutes of Health's National Institute on Aging, National Institute of Neurological Disorders and Stroke, and National Institute of General Medical Sciences. It also received funding from the BrightFocus Foundation and the Alzheimer's Association.
The study delved into the impact of metabolic changes on sleep, particularly the molecular mechanisms connecting metabolism and brain cell excitability, using mouse models lacking KATP channels and advanced techniques like EEG monitoring.
"Our study shows that even small changes in energy usage can profoundly impact behavior," said Macauley, who is an associate professor of physiology in the UK College of Medicine.
These changes impact when we sleep, how we sleep and the overall quality of our sleep. The study identified a previously unknown function of KATP channels in sleep regulation.
"We discovered that KATP channels — key regulators linking metabolism and excitability — play a previously unrecognized role in sleep regulation," said Macauley. "We did not fully appreciate the profound role that fuel utilization has on the integrity of sleep and behaviors while we are awake."
The researchers also discovered that KATP channels on neurons have a daily rhythm.
"We did not know that KATP channels on neurons display a circadian rhythm of expression that suggests a role in regulating sleep," Macauley said. "Additionally, we discovered that KATP channels regulate lactate levels, a key metabolite for transitioning between sleep and wakefulness."
When these channels don't function properly, brain cells can't tell how much energy they need.
"When cells lack the ability to assess their own metabolic needs, essential processes like neurotransmitter synthesis become compromised, which in our study was linked to impaired cognition and increased anxiety," said Macauley. "Most importantly, we found that KATP channels have a profound impact on sleep, particularly in enabling smooth transitions between wakefulness, restorative slow-wave sleep and REM sleep. This is particularly relevant for diseases like Alzheimer's, diabetes and epilepsy, which are associated with both altered KATP-channel activity and sleep disturbances."
Food and Drug Administration-approved drugs targeting KATP channels already exist, so this research suggests a promising new therapeutic approach for restoring sleep in individuals with Alzheimer's, epilepsy or diabetes.
The core message of this research, as stated by the scientists, is the significant impact of fuel sensing and utilization on our sleep and wakefulness.
"Altering the way the body can sense and use fuel can deeply impact the way we sleep and our behaviors while we are awake," said Macauley.
Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers K01AG050719, R01AG068330, R01AG070830, R01AG060056, R01AG062550, and R01AG080589; the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Numbers T32NS115704 and R01NS118558; the National Institute of General Medical Sciences of the National Institutes of Health under Award Numbers P30GM127211 and P20GM148326. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Acknowledgement is made to the donors of Alzheimer's Disease Research, a program of BrightFocus Foundation, for support of this research.
This work was supported by a grant from the Alzheimer's Association ABA-22-972169.
