Fleeting sleep interruptions may help brain reset

Interrupted sleep is typically viewed as a bad thing. Microarousals, for example—3-to-15-second-long awakenings—are associated with a number of sleep disorders.

But these fleeting wake-ups may also have an upside, according to a new Perspective article published today in Neuron. Microarousals in healthy sleep correlate with waste clearance in the brain and memory consolidation, recent rodent studies show. So the disruptions are “crucial for restorative and plasticity-promoting functions of sleep,” suggests a model put forth in the new article.

In mammals, microarousals occur frequently during non-rapid eye movement (NREM) sleep, a phase when the body’s tissues repair themselves and brain activity and heart rate slow down. These arousals track with fluctuations in noradrenaline levels, according to studies from the past five years. And during NREM sleep in mice, the locus coeruleus releases a pulse of noradrenaline about every 50 seconds.

These recent observations were surprising because “usually you associate noradrenaline with the waking brain,” says Anita Lüthi, associate professor of basic neuroscience at the University of Lausanne, who led some of the previous work and co-wrote the new Perspective article with Maiken Nedergaard, professor of neurology at the University of Rochester Medical Center. But coupled with findings Nedergaard and her colleagues published in Cell last week, the results reveal that “the system does not just operate in an all-or-none manner, but it is much more subtle,” she adds.

Overall, the conceptual model of microarousals proposed in the article is “interesting” says Bryce Mander, associate professor of psychiatry and human behavior at University of California, Irvine, who was not involved in the study, but more work is needed to show microarousals are “functional rather than a correlate of another underlying process.”

I

f microarousals help to facilitate waste clearance in the brain, as the article asserts, it would fill in an important blank about the glymphatic system, first described by Nedergaard in a 2012 paper.

Glymphatic clearance—or the flow of cerebrospinal fluid through a network of channels in the brain that removes metabolites and toxins—increases during sleep, Nedergaard and her colleagues showed in 2013, but how sleep influences the flow was unknown. Adding to the mystery, a 2024 study found that glymphatic clearance actually slows during sleep, in contrast to Nedergaard’s findings.

The noradrenaline oscillations from the locus coeruleus during NREM sleep cause rhythmic contractions and expansions in the brain’s blood vessels, according to the Cell study Nedergaard’s team published last week. These pulses lead to oscillations in blood and cerebrospinal fluid volumes that coincide with an uptick in the glymphatic clearance of a fluorescent tracer injected into the cerebrospinal fluid of mice.

“We don’t think it’s directly the microarousals that drive the [glymphatic] cleaning; it’s more likely that we have the norepinephrine at the top as this major conductor of everything,” says study investigator Natalie Hauglund, a postdoctoral researcher at the University of Oxford.

This result “establishes a critical role for noradrenergic activity in sleep, and a way by which fluid dynamics and electrophysiology could actually be connected,” says Lüthi, who was not involved in this study.

It is unclear whether the finding in rodents applies to people, says Laura Lewis, associate professor in the Institute for Medical Engineering and Science at the Massachusetts Institute of Technology, who was not involved in the study but says she has recently thought about exploring the noradrenergic system to explain human patterns of slow-wave sleep. “I think it could help us understand a lot of the dynamics we’re seeing,” such as large waves of cerebrospinal fluid and blood flow that appear during NREM sleep, she says.

I

n addition to their role in glymphatic clearance, microarousals may also facilitate memory consolidation during sleep, according to a 2022 paper from Nedergaard’s lab. But this idea has prompted a back and forth between Lüthi and Nedergaard. Lüthi’s group has cautioned against interpreting all noradrenaline surges during sleep as arousal events, whereas Nedergaard’s group counters that they have used optogenetics to confirm a causal link between the two.

Understanding the specifics of microarousals is critical for parsing what regulates the architecture of sleep, Lüthi says. The locus coeruleus induces two types of arousals during rodent NREM sleep, Lüthi’s group found in a 2024 study. Researchers have traditionally studied “arousals with awakenings” generated in the cortex, but they have neglected what she calls “arousals without awakenings”—a subcortical form that could help researchers better understand arousals in general, she says. Only about one in three noradrenaline surges is accompanied by an awakening, she adds.

Despite their debate, Lüthi and Nedergaard agreed to write the Perspective together to make the case that, based on their independent work, microarousals “are really part of the ongoing dynamics, so they are integral to sleep,” Lüthi says. The pair proposes an inverted U-shaped model to account for the “delicate balance” between microarousals, noradrenaline and sleep benefits. Within this framework, both too few and too many microarousals correlate with too little and too much noradrenaline fluctuation, respectively, which leads to issues with non-restorative NREM sleep.

“There’s a whole literature on microarousals being a feature of disrupted sleep, and I think that there’s a sweet spot where having a certain amount of microarousals is an expression of naturalistic sleep,” Mander says.

Indeed, Lüthi says she is interested in further examining arousals in sleep to learn their function outside of sleep disorders. We know now that microarousals “ride on the wave” of locus coeruleus activity, she says, “but there could be other factors contributing, so we’ll have to figure out how to best manipulate them.”