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Researchers have spotted a chemical brain process that may explain why some people fall asleep without warning. The research was done in mice, but as this ScienCentral News video reports, it helps explain what regulates our normal sleep patterns and may lead to future treatments for people with narcolepsy.
At the end of a long day, when fatigue comes wafting over our limbs and starts to tip our lids shut it seems blatantly obvious why we need sleep - we're tired. But surprisingly, why we need sleep and what exactly happens in the brain to trigger sleep is one of the greatest mysteries of neuroscience.
Yanagisawa and his colleagues combined two established scientific techniques to identify and map, for the first time, a prominent sleep circuit in the brains of mice. They say the circuit helps balance sleep patterns in all mammals, including people, though they still don't know what tips that balance to either wake us up or put us to sleep. Yanagisawa hopes his team's map will at least shed new light on sleep's dark mysteries as well as lead to new treatments for people with narcolepsy. "We believe that our research will open up the future avenue for devising a new way of treating various sleep disorders," he says.
Narcoleptic mice image: Masashi Yanagisawa
Yanagisawa's team focused their research in an area of the brain known to regulate sleep, called the hypothalamus. The hypothalamus is packed with different sleep regulating neurons (nerve cells). The researchers wanted to disentangle one specific set known as "orexin neurons." Orexin neurons are informally called "wake up" neurons because they are brain cells that release a hormone, called orexin, that help keeps people awake. Orexin is a chemical messenger (also known as a neurotransmitter) that travels to different parts of the brain to keep those areas awake, keeping us from falling asleep all the time. People with narcolepsy actually have weak orexin signaling systems.
The research team already knew where these orexin neurons sent their signals, but they didn't know what activated them. To determine their power source, the researchers used a fluorescent green protein, normally found in jellyfish and developed by researchers in France as a tracer molecule. Much like a homing device, if the fluorescent molecule is injected into the brain it will "swim upstream," says Yanagisawa, through the synapses of one orexin neuron to another until it finds the original power source. But because so many different neurons are "just scattered around and completely intermixed" within the tight space of the hypothalamus they needed something even more specific. So the research team genetically modified mice to express the fluorescent molecule wherever orexin neurons were located.
They reported in the journal Neuron that they could finally see a three-part circuit under a fluorescent microscope. The circuit ran between orexin neurons that wake us up and keep us going, histamine neurons that also help keep us awake, and a third group called "cholinergic neurons" or sleep neurons that are active when we are asleep. When the orexin and histamine neurons are active, they turn off the cholinergic or "sleepy neurons," as Yanagisawa calls them. But when the "sleepy neurons" are active they inhibit the orexin and histamine neurons.
The three part chemical brain circuit that balances sleep and wakefulness.
"So there is a triangular flip flop or seesaw switch mechanism in our brain which regulates wakefulness and sleep," Yanagisawa explains.
The researchers say this mechanism is important for maintaining sleep homeostasis - basically giving us stable periods of being awake and asleep - but the answer to the big question, what flips the switch on sleep and why we need sleep, is still unknown. They think something builds up in the brain when we are awake, "something we call sleep debt or sleep pressure," says Yanagisawa.
Future Narcolepsy Treatment
In the meantime, the researchers hope their new understanding of this three-part circuit will yield new treatments for people with narcolepsy. Yanagisawa says we may be able to repair failed orexin neurons "with drugs so that in the absence of those functional neurons [they] can still keep awake."
Stasia Wieber, director of the Center for Sleep Medicine at Mount Sinai School of Medicine, in New York, agrees that understanding the orexin signaling system is critical to treating narcolepsy. "Now that we understand a little bit about the feedback mechanisms and loops involved in orexin will only help to be able to use it clinically," she says.
But Wieber also stresses that this research was done in mice and has yet to be reproduced in people. She says it may be five to seven years before it could turn into a medication. For his part, Yanagisawa adds, "We [still] don't know the trigger" for sleep and says finding it will be his next step.