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Twinkling, Star-Shaped Brain Cells May Hold Key to Why and How of Sleep

For centuries, scientists have puzzled over the mystery of why humans sleep and how our brains accomplish this essential task. The answer may lie in star-shaped cells that twinkle and outnumber neurons five to one.

Astrocytes in the brain expressing a fluorescent calcium indicator captured with a two-photon microscope. (Image by Ashley Ingiosi, courtesy of Current Biology)

(CN) — For centuries, scientists have puzzled over the mystery of why humans sleep and how our brains accomplish this essential task. Sleep researchers in recent decades have focused on neurons, the nerve cells that transmit electrical impulses in the brain.

But a different group of brain cells known as astrocytes may be equally important to human sleep, according to a study published Thursday by Washington State University’s Elson S. Floyd College of Medicine.

"What we know about sleep has been based largely on neurons," said lead author and postdoctoral research associate Ashley Ingiosi.

It’s easy to see why neurons captured the scientific imagination. These “basic working units of the brain” literally pulse with electricity as they transmit information to other cells, a process that can be observed through electroencephalography.

In contrast, astrocytes are star-shaped cells long thought to serve a supportive role to neurons in brain function. Instead of electricity, astrocytes interact through a process called calcium signaling, which is harder to observe.

By studying their activity during sleep cycles, researchers discovered that astrocytes, which outnumber neurons by five to one, are just as active as their flashier neighbor cells, according to the study published in the journal Current Biology

The findings may lead to advances in treatment for a series of disorders and neurological diseases ranging from post-traumatic stress disorder and depression to Alzheimer's disease and autism spectrum disorder.

"The findings of our study suggest that we may have been looking in the wrong place for more than 100 years," said senior author and professor of biomedical sciences Marcos Frank. "It provides strong evidence that we should be targeting astrocytes to understand why and how we sleep, as well as for the development of therapies that could help people with sleep disorders and other health conditions that involve abnormal sleep."

Ingiosi and her colleagues used a fluorescent calcium indicator imaged via tiny head-mounted microscopes — a one-of-a-kind methodology that looked directly into the brains of mice behaving normally.

Illustration of how a miniature microscope captures fluorescent astrocytes in the brain (left), with a miniature microscope image of fluorescent astrocytes in the brain shown at right. (Illustration/image by Ashley Ingiosi, courtesy of Current Biology)

“This indicator allowed the team to see calcium-driven fluorescent activity twinkling on and off in astrocytes during sleep and waking behaviors,” according to scientists.

The cutting-edge two-photon microscopy enabled researchers to observe that, just like neurons, astrocyte activity in the frontal cortex “changes dynamically across the sleep-wake cycle.” Most calcium activity occurred at the beginning of the sleep cycle, when the need to sleep is greatest, while such activity tapered off near the end of the cycle, when the need for sleep has lessened.

In the second phase of their research, Ingiosi and her colleagues kept mice awake for the first six hours of their normal rest phase to measure calcium activity. Sleep deprivation increased astrocyte activity, while sleep reduced this activity, researchers discovered.

But how essential are astrocytes to regulating sleep?

To answer this question, researchers studied mice that lack a protein known as STIM1, reducing the amount of available calcium.

“After being sleep deprived, these mice did not sleep as long or get as sleepy as normal mice once allowed to sleep, which further confirmed earlier findings that suggest that astrocytes play an essential role in regulating the need for sleep,” they concluded.

Finally, while the electrical activity of neurons “becomes more synchronized during non-REM sleep and after sleep deprivation,” the opposite is true for astrocytes, indicating that astrocytes do not mirror neurons as suspected, researchers found.

"This indicates to us that astrocytes are not just passively following the lead of neurons," said Ingiosi. "And because they don't necessarily display the same activity patterns as neurons, this might actually implicate a more direct role for astrocytes in regulating sleep and sleep need."

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