Researchers from the University of Toronto have identified a “switch” in the brains of mice that, when activated, induces sleep and acts in balance with other neurons that trigger wakefulness.
The discovery resolves a fundamental question in sleep neurobiology by providing new insight into the circuitry that controls the cycle of sleep and wakefulness.
The switch comprises a collection of neurons called GABA neurons located in a small region of the primordial part of the brain known as the brainstem. Because these neurons are also found in humans, the researchers are confident the same mechanism is at work in humans.
The finding also points the way to potential treatments for narcolepsy, a sleep disorder that affects millions of people worldwide and is characterized by excessive sleepiness during the day, sudden sleep attacks and a loss of muscle control known as cataplexy.
“We already knew that cells known as orexin neurons trigger wakefulness,” says Professor Jimmy Fraigne, a neurobiologist in the Department of Cell & Systems Biology (CSB) in the Faculty of Arts & Science and co-author of a paper describing the discovery.
“Now, we’ve identified inhibitory neurons that trigger sleep,” he says. “This is new.
“We didn’t have any notion before that these cells could do what we observed, nor that this region of the brain had anything to do with the balancing act between sleep and wakefulness.”
The paper, “GABA neurons in the sublaterodorsal tegmental nucleus suppress wakefulness in healthy and narcoleptic mice,” was published in the journal PLOS Biology. Fraigne’s co-authors are CSB’s Professor John Peever, and Hanhee Lee, a former member of Peever’s lab.
Neural circuits in our brains work together to control our daily cycle of wakefulness, rapid eye movement (REM) sleep during which we dream and process memories, and non-REM sleep during which our brain is less active than during REM sleep.
“Sleep affects everybody in the world,” says Fraigne. “We all need sleep; we spend a third of our lives sleeping. So trying to understand what the brain is doing to regulate sleep and wakefulness is fascinating and fundamental. Finding that these neurons play this role is a breakthrough in our understanding of that balance.
“Plus, we now have clear evidence that these neurons are an underlying problem when it comes to narcolepsy,” says Fraigne.
“Narcolepsy sufferers fall asleep at any time of the day — in the middle of a sentence as they’re speaking or while eating. If you don’t suffer from it, it’s hard to imagine how debilitating it is. Yet current treatments primarily manage symptoms rather than address underlying mechanisms.”
By identifying this group of neurons as a main cause of narcoleptic symptoms, Fraigne and his collaborators have identified it as a potential therapeutic target and provided a roadmap for developing effective new treatments.
What’s more, other sleep disorders involve untimely intrusions of sleep or wakefulness, and understanding how these neurons work may lead to treatments for conditions ranging from insomnia to extreme daytime sleepiness known as hypersomnia.
Having identified GABA neurons and the role they play, the researchers plan to investigate the cells further in order to understand what distinguishes them from other cells in the brain and whether they can be controlled. The long-term goal is to fully understand this underlying mechanism with the hope of discovering a treatment.
“The more information we gather about how these cells work, the more effectively we can target them for treatment,” says Fraigne.
“There’s still quite a bit of work to do to understand these complex dynamics,” he says. “But that’s what we’re trying to do.”
This story by Christopher Sasaki was originally published on the Arts & Science website.