Sleep, a physiological activity anchored in human genes, accounts for one-third of human life. According to a survey by the World Health Organization, about 27% of the world’s population has sleep disorders, and in China, the incidence of adult insomnia is as high as 38%! According to the “2022 China Healthy Sleep Survey White Paper” released by the China Sleep Research Association in 2022, nearly three-quarters of people have experienced sleep disturbances, and difficulty falling asleep has become the number one problem. Among them, the average sleep time of minors is only 7 hours; People between 25 and 60 years old, the sleep time gradually decreases with age, and the proportion of sleep time more than 6 hours also gradually decreases /span>——For young adults, “bad sleep” can be mainly attributed to “great stress”; for the elderly, poor health may be the main reason for affecting sleep. 
(Source: China Sleep Research Association)In addition to sleep duration, sleep quality also affects our sleep experience. We often have the “disorienting experience” of waking up exhausted after a long sleep. This is because there is not enough deep sleep. As an important part of sleep, deep sleep is called “golden sleep”, accounting for 25% of the entire sleep time. It can relieve people’s fatigue for a day, promote the metabolism of the human body, and is of great benefit to the body. So how does the brain regulate the human body to enter deep sleep? Scientists have been working on this problem for years in an attempt to find effective ways to alleviate sleep problems. A recent study published in Nature Communications by researchers at Harvard Medical School provides a key clue to this longstanding mystery: They found that by increasing the Knockout of the GABAA alpha3 subunit can effectively enhance deep sleep in mice. 
(Image source: Nature Communications)
As we all know, sleep can be mainly divided into two types, one is REM sleep(REM sleep), and the other is non-REM sleep(NREM sleep) . The REM sleep stage is the most important period of dreaming; the stages other than REM sleep are collectively referred to as NREM sleep. According to the depth of sleep, NREM sleep can be divided into stage 1, stage 2 and stage 3. Stages 1 and 2 are collectively referred to as “light sleep,” and stage 3 is called “deep sleep.” When entering deep sleep, deep, slow brain waves called “delta waves” begin to appear in the brain. At this stage, noise and activity may not respond to people, which is commonly known as “sleep.” 
Changes in sleep stages overnight An area of the brain responsible for regulating functions such as sleep and wakefulness. Using gene editing techniques, the researchers disrupted a protein that encodes a protein that binds inhibitory neurotransmitters, GABAA, a family of proteins that are targeted by sleeping pills, commonly used (such as non-benzodiazepines) and benzodiazepines, etc.)can improve sleep by activating GABAA receptors. However, activated GABAA activity reduced delta oscillations, suggesting that GABAA receptors prevent the human body from entering deep sleep, which means that the sleep quality of sleeping pills is not high. In this study, the researchers knocked out the GABAA α3 gene in the mouse thalamus (because the α3 isoform is predominant in the reticular thalamus), to study the effect of GABA A receptors on thalamic reticular neurons on delta oscillations in NREM to reflect the quality of deep sleep. Interestingly, α3 knockout mice had higher NREM Delta oscillatory power compared to baseline (BL) recordings. 
NREM Delta oscillation power (Image source: Nature Communications)In humans, delta oscillations are most prominent in N3, the deepest stage of NREM sleep, and arousal thresholds also increase with the depth of NREM sleep. Given that humans are more likely to wake up from the lighter N1 or N2 phases, the researchers analyzed the delta oscillations preceding the NREM → REM and NREM → wake transitions. Unexpectedly, the researchers found that after α3 knockout, only the period of NREM → REM significantly increased the delta oscillation; while there was no significant difference between NREM → pre-awake. 
Delta power (Image source: Nature Communications)In addition to this, before transition to REM, delta oscillations occur throughout the NREM cycle The frequencies all maintained a high level, and GABAA α3 was inhibited, and the delta oscillation level was higher. There is also a significant linear relationship in this process: with the longer NREM duration at the NREM→REM transition, the greater the increase in the delta oscillation frequency. This has researchers excited. To reconfirm that this improvement in deep sleep was due to inhibition of the GABAA α3 subunit, they performed histological examination of the reticular nucleus of the thalamus and determined that GABAA α3 was indeed knocked out in most regions of the thalamus. From this, the researchers came to an important conclusion that the inhibition of GABAA α3 gene in the reticular nucleus of the thalamus determines the increase of delta oscillatory power during NREM and induces deep sleep in the body. 
Cas9-sgRNA distribution detection (Source: Nature Communications)Although the commonly used sleeping pills have good efficacy in the treatment of insomnia, But there are also well-known drawbacks: many drugs make people fall asleep quickly, but at the same time inhibit the activity of the restorative Delta wave of the brain. Taking sleeping pills to fall asleep is not necessarily restorative, and the quality of sleep will be greatly reduced. “Our findings represent an important step toward pinpointing the molecular basis of sleep regulation and point to an alternative pharmaceutical strategy for promoting natural, restorative sleep,” said Senior Investigator Radhika Basheer “We believe our findings lay the groundwork for the development of a new sleep drug — one that could achieve the maintenance of deep sleep critical to deep sleep by promoting delta wave oscillations,” said Dr. Life is in deep sleep. It is hoped that this new type of sleeping pill will be developed as soon as possible, so that people with sleep disorders can also have a fast and sweet “spring”~References[1] Uygun DS, Yang C, Tilli ER, Katsuki F, Hodges EL, McKenna JT, McNally JM, Brown RE, Basheer R. Knockdown of GABAA alpha3 subunits on thalamic reticular neurons enhances deep sleep in mice. Nat Commun. 2022 Apr 26;13(1):2246. doi: 10.1038/s41467-022-29852-x.
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