Star-shaped brain cells impact length and depth of sleep in mice

For something we spend a third of our life doing, we still understand remarkably little about how sleep works – for example, why some people can sleep soundly through a disturbance, while others turn and turn around. regularly for hours every night? And why do we all seem to need a different amount of sleep to feel rested?

For decades, scientists have looked at the behavior of brain neurons to understand the nature of sleep. Now, however, researchers at UC San Francisco have confirmed that another type of brain cell that has been the subject of much less study – astrocytes, named for their star shape – can influence duration and the depth of animal sleep. The findings could open new avenues for exploring sleep disorder therapies and help scientists better understand brain diseases linked to sleep disorders, such as Alzheimer’s disease and other dementias, the authors say.

“This is the first example where someone has done an acute and rapid manipulation of astrocytes and shown that it can actually affect sleep,” said Trisha Vaidyanathan, lead author of the study and graduate student in neuroscience at the ‘UCSF. “It positions the astrocytes as an active player in sleep. It’s really exciting.”

When we are awake our brains are a Babel of disjointed neural voices chatting with each other to enable us to work through the daily tasks of life. But when we sleep, the voices of signaling neurons merge into a unified chorus of bursts, which neuroscientists call slow wave activity. Recent research has suggested that astrocytes, not just neurons, may help trigger this change.

Comprising about 25 to 30 percent of brain cells, astrocytes are a type of so-called glial cell that line the brain with countless bushy tendrils. This coverage allows each individual astrocyte to listen to tens of thousands of synapses, the sites of communication between neurons. The abundant cells connect to each other through specialized channels, which the researchers say could allow astrocytes located throughout the brain to function as a unified network. Hyperconnected and ubiquitous astrocytes may be able to generate synchronized signaling in neurons, as suggested by new study published on March 17, 2021 in eLife.

“This could give us new insights not only on sleep, but also on diseases in which sleep dysregulation is a symptom,” said study lead author Kira Poskanzer, PhD, assistant professor in the department of UCSF biochemistry and biophysics. “Maybe some diseases affect astrocytes in ways we hadn’t thought of before.”

Poskanzer and his team have followed changes in slow wave activity in the brains of mice while manipulating astrocytes using a drug that can activate cells in genetically engineered animals. Slow wave activity can be represented in the same way that the vibrations of an earthquake are scraped on a seismograph. When the brain is awake, the resulting traces are usually a dense scribble of short, jerky movements. But when slow wave activity kicks in during certain stages of sleep, the signal slows down, looping up and down to create a trail with deep valleys and high peaks. The researchers found that igniting astrocytes led to higher slow wave activity – and therefore sleep – in mice.

But the team wanted to take a closer look at the role of astrocytes, asking how these cells exert their influence and what aspects of sleep they manage.

In addition to the specialized junctions that join neighboring astrocytes, these cells are dotted with a variety of receptor molecules that allow them to respond to signals from neurons and other cell types around them. In the study, the team hijacked two of these molecules – called Gi and Gq receptors – and found that they each appeared to control a distinct aspect of sleep. Activation of the Gq receptors made the animals sleep longer, but not deeper, according to slow wave measurements, while the Gi receptors initiated much deeper sleep without affecting sleep duration.

“Depth and duration are aspects of sleep that are often overlooked and lumped together even in neuroscience,” said Vaidyanathan. “But separating these different aspects and how they are regulated will be important down the line in creating more specific sleep treatments.”

The team also found that astrocyte activity has a long range across the brain: triggering astrocytes in one part of the cortex could affect neural behavior at a distant point. Researchers are eager to deepen the extent of this influence and continue to study how different astrocyte receptors work together to impact sleep, Poskanzer says.

“What have people missed because they ignore this group of cells?” she wondered. “The unanswered questions so far in sleep neurobiology – maybe they weren’t answered because we didn’t look in the right places.”