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Friday, August 12, 2022

Sleep allows neural connection shrinking: crucial for learning

For as long as life has existed, everything alive has slept. Surely, the purpose of something as essential as sleep is fully understood in the scientific community. However, the “why” of sleep is what keeps scientists like Chiara Cirelli up at night. Cirelli, a UW-Madison professor of psychiatry, became passionate about discovering the purpose of sleep since she first learned about it while obtaining her dual doctorate in neuroscience from the University of Pisa.

“From the very beginning when I started medical school, I went into a sleep lab and I was hooked. It’s such a fascinating topic about which we know so little, so it’s easy to get buried in it,” said Cirelli.

Cirelli has worked on this topic for over two decades, using meticulous approaches and various animal models to better illuminate the shadowy world of sleep science.

“Over the last 20 years, we’ve been doing very different experiments with subjects from flies to mice to people to rats, but all this time, it’s been to test one idea, one hypothesis. This is the synaptic homeostasis hypothesis,” said Cirelli.

The synaptic homeostasis hypothesis (SHY) is an elegant explanation of our need to sleep. The hypothesis balances new learning and old knowledge. When we are awake and learning new things, the connections between neurons, or synapses, get stronger and therefore larger. This enlargement of the synapses is essential to assimilate new knowledge. However, what happens when there’s no more space for the neurons to grow? Cirelli believes sleep is the answer.

“Everyone in neuroscience in general accepts and understands that when you learn, you overall strengthen the connections [between neurons]. That creates this need for renormalization because otherwise there would be no space and the existing connections would saturate,” said Cirelli.

Renormalization is the shrinking of some connections in order to accommodate for the new larger synapses that form following learning. Cirelli believes this process happens during sleep, and is the reason we can learn new things.

During the day, the net strength and size of our synapses that we use for learning increase. As we sleep, they are renormalized to make room for the next day. As logical as this idea sounds, figuring out how it actually works is no easy feat.

“It’s not easy to test, because there is no single way of measuring the strength of the connections. There are many ways, some better than others, but there’s not just a single experiment to say ‘yes you are right.’ That’s why we’ve been doing this for almost 20 years,” said Cirelli.

Measuring the content of synaptic proteins in the brains of fruit flies is one of the methods Cirelli used to study sleep. A neurotransmitter is a chemical messenger. Neurons use these to communicate with one another. The neuron sending the message, or the pre-synaptic neuron, will release neurotransmitters into the synapse.

These neurotransmitters are taken in by the neuron receiving the message, or the post-synaptic neuron. They instruct this neuron on what kind of message to continue communicating or act upon. Both pre- and post-synaptic neurons use specific proteins to release the neurotransmitter and respond to it.

“[We] extract from the brain all of the proteins in the synapses and just measure the quantity. If the synapses are bigger, then there should be more of these proteins after wake than after sleep. This is what we measured in flies,” said Cirelli.

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Cirelli’s lab is also working on a brain imaging study in flies similar to a study they did in mice. Cirelli anticipates the fly study will be less time consuming because fly brains are much smaller than mice brains. Cirelli’s lab hopes to confirm the same results that they produced from mice.

The original mouse study was a high risk study that paid off majorly. They kept mice awake or let them sleep, then sacrificed the mice and imaged their brains using electron microscopy, which can visualize the synapses and measure their size. Cirelli sorted through hundreds of mouse brain images to evaluate the synaptic strength.

“At the end, we broke the code and figured out which animals were which. When we ran the statistics [on the size of the connection versus whether the animal was asleep or awake], it was extremely significant and clear that the sleep and wake groups were distinct,” said Cirelli.

Although the study helped Cirelli conclude that sleep does help reduce the size of synaptic connections, she took a huge risk in taking on a study this time-consuming.

“This is a study that heavily depended on the hard work of undergraduate research assistants that work part-time in the lab while they go to school, because it is very long and very risky. That’s another challenge of these projects, is finding the right people,” said Cirelli.

Now, Cirelli’s next step is to find a way to prove that SHY applies to humans as well. Cirelli and her team find promise in transcranial magnetic stimulation for researching sleep-dependent synaptic renormalization in humans.

“It’s just a coil and a piece of metal that you put on the scalp. It sends a little signal and you are able to record a wave that is the response. This is measuring not just one connection, but millions! For the same amount of stimulation, since the number of connections does not change from one day to the next, if overall those connections got stronger, then the signal I record would be bigger after wake than after sleep,” said Cirelli. In other words, the wake brain, full from a day’s learning, will be expected to send a stronger signal than one that has been renormalized to make more room for more learning the next day.

“We still don’t know what the exact mechanism is. How, through the strengthening of neurons, do you induce this need for sleep? But we know that this mechanism does exist,” said Cirelli.

Cirelli stressed the importance of sleep in continued learning and how vital it is to sustain life. With so many people not getting enough sleep (including Cirelli’s undergraduate research assistants), the simple answer would be to use sleeping pills and medication to induce sleep. Cirelli, however, warns against the long term use of these medications.

“Sleeping pills are not a solution and should never be used in the long term. There is no pill that can mimic all of the aspects of sleep... every pill just stimulates a pathway or enhances a neurotransmitter. But sleep is a mixture of modifications of many different pathways. So, when the pills act only one way, you can get that state of sleep, but it’s not true physiological sleep,” said Cirelli.

Along with starting from the assumption that sleep is important, Cirelli says learning more about sleep may teach us how to maximize it.

“There’s no easy fix. But recent studies have shown that very mild levels of acoustic stimulation during sleep enhances the depth of sleep, so for the young people getting only a few hours of sleep at night, this could be helpful. Ideally, someday you can have a power nap for one hour and be refreshed, but it has to be so carefully balanced,” said Cirelli.

The importance of staying stimulated during the day isn’t usually an issue for young people who don’t sleep enough, but the sleeplessness in older adults can be directly related to how they use their time awake.

“Older people complain about not being able to sleep as much as when they were young. We know that one of the treatments that works the best long term is behavioral therapy ... this means you have to teach people to continue to live a full life and be engaged during the day. This way you will induce this stimulation of neurons. The more you do that, then the more the need for sleep and the pressure for sleep increases,” said Cirelli.

Sleep problems won’t be corrected overnight, but our capacity to learn is invaluable, so sleep will continue to be important as we improve our understanding of learning and renormalization.

As Cirelli and her team continue to learn about the science of sleep, they’ll view the process from more angles than anyone before her. They plan to look into how early development changes the renormalization and sleep process. Perhaps someday, the reason we need sleep every night will no longer be a topic scientists lose sleep over.

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