Study reveals the complexity of sleep machinery

Sleep machinery is not as simple as we think it is


Hypocretin (Hcrt), also known as orexin, neuropeptide signaling stabilizes sleep and wakefulness in all vertebrates. A lack of Hcrt causes the sleep disorder narcolepsy, which is a decreased ability to stay awake during the day. Increased Hcrt signaling has been speculated to cause insomnia, which is a decreased ability to fall asleep at night.

Many pharma companies focus on hypocretin to treat sleep disorders, and it has recently attracted a lot of attention within sleep research. This is because of the suspected role of hypocretin in both insomnia and narcolepsy.

Researchers also suspect hypocretin to play a role in depression, ADHD, and other mental disorders.

A lot is already known about the hypocretin system in the brain. There is even a new drug for insomnia countering the effect of hypocretin, the latest introduced in Canada in 2018.

As the signaling pathways of hypocretin are relatively well-described, the intracellular mechanisms that regulate its expression remain unclear, and it’s a matter of attention for researchers.

Therefore, Associate Professor Birgitte Kornum and her colleagues set out to shed light on the issue in a new study, which has recently been published in the reputed journal PNAS.

The study combines tests on mice, zebrafish, and human cells, and the researchers cooperated with their neighbors at the University of Copenhagen’s Department of Cellular and Molecular Medicine, among others.

People with a genetic variation of this molecule have a higher risk of suffering from daytime sleepiness.

MicroRNA associated with sleep regulation

The researchers have spent several years studying one of the cellular mechanisms that affect hypocretin levels.

Here they have focussed on a small molecule called microRNA-137 (miR-137).

“We discovered that miR-137 helps regulate hypocretin. To experience normal sleep, you need to have the right amount of hypocretin in the brain at the right time, and miR-137 helps with that. Though MiR-137 is also found in other parts of the body, it is especially pronounced in the brain,” Birgitte Kornum says about the new study, which she has headed together with Assistant Professor Anja Holm from Aalborg University.

MicroRNA regulates various cellular processes, including hypocretin levels. Therefore, there is considerable research interest in microRNAs, as they could be targeted in order to regulate such processes.

Previously, the scientists knew very little about the role played by miR-137 in the brain, but now Birgitte Kornum’s research team has demonstrated that it is associated with hypocretin regulation and thus with sleep.

“This is the first time a microRNA is associated with sleep regulation. Drawing on the UK Biobank, we discovered some genetic mutations in miR-137 which cause daytime sleepiness. The study demonstrates this connection in both mice and zebrafish, and we are able to prove the connection with hypocretin. Our discovery shows just how complex the machinery of sleep is. Imagine inheriting a variant of miR-137 that puts you at higher risk of feeling sleepy during the day,” says Birgitte Kornum.

Hypocretin affects sleep stages

Hypocretin also affects the order of the sleep stages.

Our sleep is usually divided into four stages. The stages follow a specific order, and this order is vital to the quality of our sleep.

“Narcolepsy patients suffering from low levels of hypocretin experience muddled sleep stages. We know this from mice tests demonstrating that hypocretin affects the order of these stages,” explains Anja Holm from Aalborg University, who is the first author of the study and who did the tests together with Birgitte Kornum.

Sleep and immune system

Existing research suggests that we need to gain more knowledge of hypocretin regulation to solve the problem. The Danish researchers point to a different but equally important piece of the puzzle, namely the immune system.

“Most people know that when you are ill you often feel tired. And when you have a fever and the immune system is hard at work, you often suffer from poor sleep. So we know that something happens to the hypocretin level when the body is trying to fight off a virus infection, for example, and we are trying to understand this process,” says Birgitte Kornum.

“In the study, we show that one of the immune system’s transmitter substances, IL-13, has a special effect on hypocretin. We can tell that when we add IL-13, it affects miR-137 and thus also the level of hypocretin in the body. We still do not know why, though, but we are currently doing tests that may be able to give us an answer.”

Futuristic view of study

  1. The interaction reported between miR-137, hypocretin, and sleep regulation could therefore play an important role in several neurological and neuropsychiatric diseases featuring disturbed sleep-wake patterns and could pave the way for treatments.
  2. The MIR137 locus has a strong genetic association with schizophrenia and has also been suggested to be involved in the etiology of other neuropsychiatric disorders. miR-137 expression is dysregulated in schizophrenia and Rett-syndrome.

Journal Reference

  1. Anja Holm, Marie-Laure Possovre, Mojtaba Bandarabadi, Kristine F. Moseholm, Jessica L. Justinussen, Ivan Bozic, René Lemcke, Yoan Arribat, Francesca Amati, Asli Silahtaroglu, Maxime Juventin, Antoine Adamantidis, Mehdi Tafti, Birgitte R. Kornum. The evolutionarily conserved miRNA-137 targets the neuropeptide hypocretin/orexin and modulates the wake to sleep ratio. PNAS 119 (17) e2112225119 DOI: 10.1073/pnas.2112225119
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