Authors: Sharon Salt, Editor
The genetics behind circadian rhythms has been well studied in recent years, however, much less is known about the genes that regulate how much sleep our bodies require.
In a recent study published in Neuron, researchers from the University of California, San Francisco (CA, USA) examined a family with several members who require significantly less sleep than average (approximately 6 hours) and identified a new gene that they believe has a direct impact on how much someone sleeps.
“It’s remarkable that we know so little about sleep, given that the average person spends a third of their lives doing it,” commented Louis Ptáček (University of California, San Francisco), co-senior author of the paper. “This research is an exciting new frontier that allows us to dissect the complexity of circuits in the brain and the different types of neurons that contribute to sleep and wakefulness.”
The gene, termed ADRB1, was identified using genetic linkage studies and whole-exome sequencing, which revealed a novel and very rare variant.
To decipher the role of the gene variant, the team studied its protein in the test tube and determined whether these mutations caused any functional alterations in comparison with the wild type. “We found that this gene codes for β1-adrenergic receptor, and that the mutant version of this protein is much less stable, altering the receptor’s function. This suggested it was likely to have functional consequences in the brain,” explained co-senior author Ying-Hui Fu (University of California, San Francisco).
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Several experiments were then conducted in mice carrying a mutated version of the gene. The researchers revealed that, on average, these mice slept 55 minutes less than regular mice. According to the team, humans with the gene sleep 2 hours less than average. Further analysis demonstrated that high levels of gene expression was present in the dorsal pons, which is known to be involved in activities such as respiration, eye movement and sleep.
In addition to this, the investigators revealed that normal ADRB1 neurons in this region were active during wakefulness but also during REM sleep. However, they were quiet during non-REM sleep. Furthermore, they found that these mutant neurons were more active than normal neurons, likely contributing to the short sleep behavior.
“Another way we confirmed the role of the protein was using optogenetics,” stated Fu. “When we used light to activate the ADRB1 neurons, the mice immediately woke up from sleep.”
Ptáček acknowledged the limitations of the study, which included using mice to study sleep as they exhibit different sleep patterns in comparison with humans. He also noted that studying sleep in humans also comes with challenges, as sleep is a behavior as well as a function of biology. “We drink coffee and stay up late and do other things that go against our natural biological tendencies,” he noted.
In future, the team plan to study the function of the ADRB1 protein in other parts of the brain, in addition to looking at other families for additional genes that are likely to be important. “Sleep is complicated. We don’t think there’s one gene or one region of the brain that’s telling our bodies to sleep or wake. This is only one of many parts,” Ptáček concluded.
Sources: Shi G, Xing L, Wu D et al. A rare mutation of β1-adrenergic receptor affects sleep/wake behaviors. Neuron doi:10.1016/j.neuron.2019.07.026 (2019) (Epub ahead of print); www.eurekalert.org/emb_releases/2019-08/cp-ria082119.php