Wake up during the night? Oscillatory sleep states are actually best for your brain
Deep in the bowels of “sleep’s engine room”, Danish researchers have now identified oscillations crucial to memory, suggesting novel targets for improving sleep.
This discovery was made by an international research team headed by sleep experts from the University of Copenhagen. In addition to improving our understanding of sleep, the finding also indicates a need to design novel medicines for treating sleep disorders.
Just has you can be as fresh as a daisy, as fast as lightening or as slow as a snail, you can sleep like a log.
Lots of us will say we “slept like a log” when we’ve had a really good night’s sleep. And then we might add with a grin: ‘I didn't wake up once.’
The experience of having had a good night’s sleep is genuine – and is usually underpinned by a feeling of having gained energy from the sleep. However, on closer inspection, the claim not to have woken up “a single time” doesn't wash. And this is one of the key points of a new research article published in Nature Neuroscience, one of the world’s most prestigious neuroscience journals.
The story is complex in many ways, involving the deciphering of existing brain activity using microscopic optic fibres implanted in mouse brains. These optic fibres communicate with genetically engineered receptors capable of measuring the incidence of biochemical substances and lighting up like tiny party lanterns.
And the story also contains ideas for the design of novel medicine for treating sleep disorders.
Hormone swings and the dynamics of sleep
The article was authored by a team of Danish and Chinese researchers, headed by three sleep experts from the Centre for Translational Neuroscience at the University of Copenhagen: Professor Maiken Nedergaard, Assistant Professor Celia Kjærby and PhD student Mie Andersen who all received funding from the Lundbeck Foundation.
The article describes a previously unknown phenomenon: significant variations in the concentration of the norepinephrine hormone and neurotransmitter in the brains of mammals both regulate sleep patterns and consolidate memory.
One of the consequences of this regulation during the sleep phase is that the brain actually wakes up countless times during the night. The new research article shows that, at times, the brain will wake up once or twice a minute – much more frequently than previously thought.
And by measuring the electrical activity of the brain, the researchers found that the sleeper is usually unaware of this. It is assumed that the sleeper fails to register that they are awake because each awakening is extremely brief, representing the crest of an ongoing, wave-like sleep pattern driven by norepinephrine. There is then a rapid descent from the crest of the wave to a deep valley of sleep. Here, other measurements of the brain’s electrical activity indicate that it is now soundly asleep. As soon as it passes through this valley, the brain heads for the next crest and briefly wakes up again.
The sleep pattern and the dynamic it creates continue in this way – provided, of course, that the sleeper is experiencing non-rapid eye movement (NREM) sleep. Approximately 75-80% of a night’s sleep is NREM sleep when we do not dream.
It is a well-established fact that there is a connection between NREM sleep and memory. Celia Kjærby explains that this type of sleep consolidates in our memory the impressions and information we gather during our waking hours. She and Mie Andersen are the first authors of the scientific article in Nature Neuroscience:
‘But until now we’ve lacked information about the details of this consolidation and the role norepinephrine plays in this context. This is where we can contribute new knowledge by demonstrating that norepinephrine also plays an essential role while we sleep.’
Norepinephrine is closely linked to the waking hours of our lives – the hours when we are active – and it is also a so-called stress hormone, released when we experience fear or tension. Therefore, in sleep research circles it has been assumed that norepinephrine is relatively calm when we are asleep – because, otherwise, it would stop us from sleeping. Celia Kjærby says:
‘But we were able to prove that this is not the case. And the finding is very exciting because it gives us a better understanding of how NREM sleep helps us store things in our memories.’
Experiments with mice produced answers
In many respects, the experiments needed to map the role of norepinephrine in the regulation of sleep and the consolidation of information in memory required the researchers to delve so deeply into sleep’s engine room that, for purely ethical reasons, the experiments could not be conducted with people as subjects.
Mice were used instead. They were suitable for the purpose because both mice and humans are mammals, and the mechanisms the researchers wished to study are basic biological mechanisms. Celia Kjærby explains: ‘The experiments were designed in such a way that we were able to assume with a high degree of probability that the results would also apply to humans.’
But how did the researchers conduct the various measurements?
Here’s the answer in layman’s terms, and in a highly condensed format: The researchers took a number of laboratory mice and anaesthetised them one by one. They then implanted microscopic optic fibres into the brains of the mice. The optic fibres were connected to wires which could be run to different types of laboratory equipment, such as an LED light source, via small holes drilled into the skulls of the animals. At the same time, the researchers injected a number of genetically engineered receptors, equipped with a flashlight function, into the brains of the mice via the drilled holes.
Celia Kjærby, a human biologist, and Mie Andersen, a molecular biomedical scientist, then performed an array of tests on the mice. Some of these tests involved measuring the real-time level of norepinephrine while the mice slept and comparing this with the electrical activity in their brains. And this was when they realised that norepinephrine is extremely active when mammals are asleep.
They also performed a range of tests relating to memory. From these, the researchers were able to demonstrate that when they increased the amplitude of the norepinephrine oscillations during the sleep phase, they could improve the animals’ memory. Celia Kjærby explains: ‘When we tested the animals a few hours later, we could see that they remembered much better than a control group of mice that had not been subjected to the manipulation. It’s fair to say that, momentarily, the mouse models had a kind of super memory.’
Sleep medicine
The wave-like sleep pattern norepinephrine creates during NREM sleep is crucial to memory. Among other things, it controls the formation of so-called sleep spindles. These are brief, intense outbreaks of brainwave activity that promote storage of information in the memory.
‘We could see this because we were able to conduct real-time measurements of the biochemical conditions in the brain using LED light to manipulate the device in the brains of the mice – at the same time, cranking the animals’ own norepinephrine production either up or down. This enabled us to influence the amplitude of the norepinephrine oscillations,’ Celia Kjærby explains.
In other words, the level of norepinephrine, and the sleep oscillations this hormone and neurotransmitter creates, must be correct for the memory to work at its best. And there is yet another point to this discovery – linked to sleep medicine.
The drugs given today by healthcare professionals to patients with difficulty sleeping aim to produce long, unbroken NREM sleep. To achieve this effect, these drugs impact, among other things, the locus coeruleus – the centre in the brain responsible for norepinephrine production. And they lower this production.
In many cases, this can ensure that the patient gets a fairly good night’s sleep, but, as Celia Kjærby explains, it comes at a price: ‘When we inhibit norepinephrine oscillations in this way, we also interfere with the formation of sleep spindles. This has a negative effect on memory because less information is stored. And our project demonstrates this.’
The research team believes that a logical step would therefore be to attempt to design novel sleep medicines which do not inhibit the norepinephrine cycle that plays a major role in controlling sleep and memory consolidation in mammals.
The article is part of the Lundbeck Foundation's thematic series on sleep and health: While you sleep