Study reveals complexity of sleep machinery

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

Many pharmaceutical companies are focusing on hypocretin to treat sleep disorders, and it has recently garnered a lot of attention in sleep research. This is due to the presumed role of hypocretin in insomnia and narcolepsy.

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

Much is already known about the hypocretin system in the brain. There’s even a new insomnia drug against the effect of hypocretin, the latest introduced in Canada in 2018.

Since hypocretin signaling pathways are relatively well described, the intracellular mechanisms that regulate its expression remain unclear, and this is a subject of attention for researchers.

Therefore, Associate Professor Birgitte Kornum and her colleagues set out to shed some light on the matter in a new study, which was recently published in the reputable journal PNAS.

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

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

MicroRNA associated with sleep regulation

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

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

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

The microRNA regulates various cellular processes, including hypocretin levels. Therefore, there is considerable interest in research on microRNAs, as they could be targeted to regulate these processes.

Previously, 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 the regulation of hypocretin and therefore with sleep.

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

Hypocretin affects sleep phases

Hypocretin also affects the order of sleep phases.

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

“Patients with narcolepsy with low levels of hypocretin experience confused sleep stages. We know this from tests in mice showing that hypocretin affects the order of these stages,” says Anja Holm from the Aalborg University, who is the first author of the study and who carried out the tests with Birgitte Kornum.

Sleep and the immune system

Existing research suggests that we need to learn more about 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’re sick, you often feel tired. And when you have a fever and the immune system is under strain, you often suffer from poor sleep. So we know that something is happening at the level of hypocretin when the body is trying to fight off a viral infection, for example, and we are trying to understand this process”, explains Birgitte Kornum.

“In the study, we show that one of the immune system’s transmitter substances, IL-13, has a particular effect on hypocretin. We can say that when we add IL-13 it affects miR-137 and therefore also the level of hypocretin in the body. However, we still don’t know why, but we are currently running some tests that might give us an answer.

Futuristic vision of the study

  1. The reported interaction between miR-137, hypocretin and sleep regulation could therefore play an important role in several neurological and neuropsychiatric diseases characterized by disturbances of the sleep-wake rhythm and could open the way to 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. Evolutionarily conserved miRNA-137 targets the neuropeptide hypocretin/orexin and modulates the sleep/wake ratio. PNAS 119 (17) e2112225119 DOI: 10.1073/pnas.2112225119

Sharon D. Cole