Identification of mechanisms which increase deep sleep could lead to novel treatments which promote the restorative effects of sleep.
Uygun et al. show that knockdown of the α3 GABAA-receptor subunit from parvalbumin neurons in the thalamic reticular nucleus using CRISPR-Cas9 gene editing increased the thalamocortical delta oscillations which are implicated in many health-promoting effects of sleep. Image credit: Sweet Briar College.
Healthy sleep is a basic physiologic need. In its absence, a myriad of processes in the body can go terribly awry.
Chronic sleep problems have been linked to mental health disorders, cardiovascular disease, type 2 diabetes, and obesity, among other conditions.
Yet, consistently achieving the deep, restorative sleep necessary for optimal physiologic health and peak cognitive performance can be difficult due to lifestyle, environmental, and biologic factors.
One of the most confounding questions in sleep biology has been how deep sleep is regulated by the brain. The answer could help illuminate new ways to mitigate sleep problems.
In a new study in mice, Dr. Radhika Basheer of VA Boston Healthcare System and Harvard Medical School and colleagues identified an area in the brain that regulates the oscillations of delta waves — electrical signals transmitted across neurons that arise during the deepest phases of relaxation. They are a hallmark of restorative sleep.
The researchers homed in on neurons in the thalamus, a region of the brain that regulates sleep and wakefulness, among other functions.
Using CRISPR-Cas9 gene editing, they disrupted a gene that codes for a protein that binds the inhibitory neurotransmitter GABA. This protein is a target of drugs that promote sleep.
Disruption of this gene in mouse models boosted the activity of delta waves and enhanced deep sleep in the animals.
If replicated in further animal models, the findings could lay the groundwork for designing therapies that precision-target this protein to induce deep sleep.
“Our findings represent an important step forward in pinpointing the molecular basis of sleep regulation and point to an alternative pharmacologic strategy for promoting natural, restorative sleep,” Dr. Basheer said.
New therapies are sorely needed. Commonly used insomnia medicines, while an important tool for treatment of persistent insomnia, have well-known drawbacks.
Many of these medications work by getting people to fall asleep fast, but they also tend to dampen the activity of restorative delta waves.
Thus, while such medications promote falling asleep, the slumber they induce is not necessarily restorative.
“We believe our findings set the stage for developing a new class of sleep medicines that can achieve this all-important maintenance of deep sleep by boosting delta wave oscillations,” Dr. Basheer said.
The findings were published in the journal Nature Communications.
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D.S. Uygun et al. 2022. Knockdown of GABAA alpha3 subunits on thalamic reticular neurons enhances deep sleep in mice. Nat Commun 13, 2246; doi: 10.1038/s41467-022-29852-x
