Cells that never sleep: How sleep cleans up neurons and keeps them healthy

Important points

• HHMI researcher Amita Sehgal has pioneered the use of Drosophila to understand how genes and cells control sleep, contributing to advances in sleep research.
• The researchers’ recent work suggests that sleep is closely related to the energy needs of brain cells and helps protect the structures within cells that keep neurons functioning properly.
• The research team’s findings could help scientists better understand neurodegenerative diseases like Alzheimer’s disease, which involve some of the same processes and are characterized by sleep disturbances.

Main text:

when HHMI Investigator Amita Sehgal When we began studying sleep 25 years ago, the topic elicited a yawn in most biologists.

“If I had suggested to my department in 2000 that we hire people to work on sleep, they would have laughed at me,” says Sehgal, a molecular biologist and neuroscientist at the University of Pennsylvania. “The idea was that sleep was not something that neuroscientists did, but that psychologists studied sleep and dreams.”

Now, more than 20 years later, sleep science has finally woken up.

Biologists around the world are now studying sleep in everything from fruit flies to jellyfish to understand the basic molecular and cellular mechanisms that promote sleep and answer the age-old question of why we sleep.

“Sleep is widely conserved across the animal kingdom, so there must be a basic function that is the same across species, but what is it?” Sehgal says. “We’re finally getting to the point where we recognize some basic principles about sleep.”

Sleep keeps your brain’s power plant healthy

Sehgal and her team were among the first researchers to use fruit flies to study the cellular and molecular processes that drive the need for sleep.

The team’s recent work suggests that sleep is metabolically driven and that sleep plays an important role in protecting the integrity of mitochondria, the structures that power brain cells.

When we are awake, our neurons are constantly active due to energy produced by mitochondria. A byproduct of this energy production is reactive oxygen species, which can damage mitochondria and the cells that house them.

Sehgal and her team found that sleep helps keep neurons healthy by promoting the transfer of oxidative damage in the form of oxidized lipids to glial cells, a type of supporting cell in the brain. Glia break down some of these lipids to generate energy. It also passes some of the lipids to blood cells, which have specific receptors that receive them.

“In order for these neurons to function, they need a reliable internal source of clean energy,” Sehgal says. “One of the ways sleep helps keep neurons healthy is by moving these lipids around and removing some of the oxidative damage.”

Sleep is the housekeeper of your phone

In addition to these findings, other recent studies by Sehgal and her team have shown that:

• Sleep helps maintain cell health by controlling autophagy, a process that replaces organelles, including mitochondria.
• Sleep facilitates the movement of molecules from the brain to the blood through the blood-brain barrier.
• Neuromodulators (molecules that activate or silence neurons) are affected by changes in sleep, but do not necessarily drive the need for sleep.
• Whether an animal eats or not determines the type of memory it uses: sleep-dependent or sleep-independent.

All of these findings support the team’s hypothesis that sleep is driven by metabolic needs. When you don’t sleep, metabolic waste products build up in your brain, making it impossible for neurons and their energy-producing mitochondria to function properly.

“We’re really excited about the research right now,” Sehgal says. “I feel like we’re really starting to solve the whole sleep problem.”

Association with neurodegeneration

The team’s findings about sleep regulation could help researchers better understand neurodegenerative diseases such as Alzheimer’s disease, which are commonly associated with sleep disorders.

Lipid metabolism and autophagy, two sleep-regulated processes that Dr. Sehgal’s lab showed are also known to contribute to neurodegeneration when gone wrong, and both are inhibited in patients with Alzheimer’s disease.

The research team found that in flies, damage is transmitted from neurons to glial cells via a lipid carrier similar to apolipoprotein E (APOE). In humans, a type of APOE that increases the risk of Alzheimer’s disease is less effective at transporting lipids from neurons to glia, suggesting a possible link.

Understanding how sleep affects these cellular processes may help reveal how disruption of cellular processes also contributes to Alzheimer’s disease.

“In very basic research on sleep, we are discovering processes that are regulated by sleep, that are associated with Alzheimer’s disease, and that are inhibited in Alzheimer’s disease,” Sehgal said. “Sleep disturbances in Alzheimer’s disease may be due to impairments in these two processes.”