Insomniac flies and the brain’s sleep switch
Scientists supported by the Wellcome Trust have identified the mechanism that tells the brain to sleep, a ‘pressure switch’ that controls the activity of sleep-promoting nerve cells in the brain. Ryan O’Hare finds out more.
Most of us probably aim to get at least seven hours of shut-eye a night, meaning almost a third of our lives will be spent asleep. Yet many will have lain awake at one point or other, asking “why can’t I fall asleep?”
For those with sleep disorders, this inability to switch off at night often bleeds into waking life –affecting their work, memory, decision making, and potentially damaging their long-term health. Questioning why we need to sleep, and uncovering the mechanisms that control sleep, are crucial to better understanding and treating such disorders.
Scientists supported by the Wellcome Trust are doing just that, and uncovering the biological mechanisms which shepherd the brain into the murky world of sleep. By studying fruit flies (Drosophila melanogaster) a team at the University of Oxford’s Centre for Neural Circuits and Behaviour (CNCB) have discovered the ‘switch’ in the brain that sends us to sleep.
Sleep is controlled by a combination of two systems; the circadian clock, which keeps track of the day and night cycle; and a second, lesser known master control, called the sleep homeostat.
Although circadian rhythms have been well studied, scientists know relatively little about the sleep homeostat, which keeps track of how much sleep we’re getting, or lacking.
“The [circadian] clock is an adaptive mechanism that ensures you sleep at the most opportune time,” says Professor Gero Miesenböck, Director of the CNCB.
“The core regulator of sleep is the second system, the sleep homeostat. It’s the device in the brain that somehow keeps track of waking time. Once that waking time exceeds a certain amount, it puts us to sleep.”
The moment when the brain changes state, and we fall asleep, is controlled by a combination of the two. “The body clock says it’s the right time, and the sleep switch has built up pressure during a long waking day,” explains Professor Miesenböck.
The group discovered that deep in the brains of fruit flies, a handful of sleep-promoting cells are at the heart of the homeostat. It’s these neurons which keep track of sleep history. After an extended period of being awake the cells stir from their quiet resting state and fizzle with electrical activity. As the neurons start to fire, they raise the alarm call of ‘go to sleep!’ signalling the need for the brain to go offline. The signal builds until it crosses a threshold, at which point the flies nod off.
The activity of these neurons is regulated by a protein that regulates the opening of ion channels in the cell membrane, changing the cells’ electrical activity. Without this molecule, the neurons are permanently stuck in the quiet state and the flies have trouble falling asleep.
Just like humans, bleary-eyed flies that were kept awake overnight, needed more sleep in the following 24 hours, to try and catch up on what they lost. As the sleep debt increases, so does the activity of the neurons. But mutant flies, in which the protein was broken, weren’t able to sleep, even when they needed to, and displayed levels of cognitive impairment comparable to those seen when normal flies are deprived of sleep.
Can research in fruit flies teach us about the human brain? Although the tiny insects may seem a world away from us, many of the same processes are conserved across species, and model organisms like Drosophila provide scientists with an invaluable tool for studying these fundamental processes.
This work in flies can be used as a stepping-stone to design experiments in mammals, and then carried on to the next link in the chain. All of which allows us to better understand the human brain.
Within the last two decades, researchers have established that groups of sleep-active neurons are also found in the human brain, and that these neurons are the target of general anaesthetics. Modulating their activity could possibly provide a new therapeutic avenue to explore for treating people with chronic sleep conditions.
“This is fundamental neuroscience,” says Dr John Williams, Head of neuroscience and mental health for the Wellcome Trust. “It’s laying the groundwork for those who work on mammalian systems to gain new insights, and feed back into [fruit flies] to probe at a fundamental and molecular level. By linking across species, we can begin to gain insight into the complexity of human decision making and human brain function.”
It is clear that sleep has restorative function – a chance to carry out repairs and maintenance, process the information gathered during the day, and possibly to clear out the molecular garbage accumulated. There is also mounting evidence suggesting that a chronic lack of sleep in humans may be linked to a range of health problems, such as heart disease, diabetes, and could even be a potential trigger for psychotic episodes in schizophrenia and bipolar disorder.
Whilst discovering the sleep switch may take us a step closer to understanding the ‘how’ of sleep, the ‘why’ remains more elusive. But researchers are now looking closer at the neural circuitry of the brain and turning their focus to the next level of control – what influences the sleep switch? Is it the build up of a waste product, a change in the strength of synapses, or a need to declutter the brain of half-formed memories from the waking day?
Dr Diogo Pimentel, one of the lead researchers, comments: “If we knew what happens in the brain during waking that requires sleep to reset, we might get closer to solving the mystery of why all animals need sleep.”
Image credits: Tim Ellis, Guy Tear, Audio Visual, LSHTM, all via Wellcome Images