Clues in the puzzle of sleep

summary: Using genetic modification to disrupt a gene in the hypothalamus that encodes a GABA-binding protein enhanced delta-wave activity and promoted deep sleep in mouse models.

source: Harvard

Healthy sleep is a basic physiological need. In its absence, a myriad of processes in the body can deviate terribly. Chronic sleep problems have been linked to mental health disorders, cardiovascular disease, type 2 diabetes, and obesity, among other conditions.

However, achieving the deep, rejuvenating sleep necessary to consistently achieve optimal physiological health and peak cognitive performance can be challenging due to lifestyle, environmental and biological factors.

One of the most vexing questions in sleep biology has been how the brain regulates deep sleep. The answer could help shed light on new ways to alleviate sleep problems.

Now, a newly published study led by Harvard Medical School researchers at the VA Boston Healthcare System provides important clues in this long-standing puzzle.

The work was performed on mice and published on April 26 in Nature Communications, identifies a region in the brain that regulates vibrations of delta waves – electrical signals sent through neurons that arise during the deepest phases of relaxation. It is the hallmark of restorative sleep.

The research team settled on neurons in the thalamus, an area of ​​the brain that regulates sleep and wakefulness, among other functions. Using CRISPR-Cas9 gene editing, the researchers disrupted a gene that codes for a protein that binds the inhibitory neurotransmitter GABA.

Protein is a target for sleep-promoting drugs. Disruption of this gene in mouse models enhanced delta-wave activity and deep sleep in the animals.

If replicated in other animal models, the findings could lay the groundwork for designing treatments that precisely target this protein to induce deep sleep.

“Our findings represent an important step forward in identifying the molecular basis of sleep regulation and pointing to an alternative pharmacological strategy to promote rejuvenating natural sleep,” said study senior author Radhika Bashir, associate professor of psychiatry at HMS and VA Boston.

This shows a sleeping woman
Now, a newly published study led by Harvard Medical School researchers at the VA Boston Healthcare System provides important clues in this long-standing puzzle. The image is in the public domain

New treatments are urgently needed. Commonly used insomnia medications, although an important tool for treating persistent insomnia, have known drawbacks. Many of these medications work by making people fall asleep quickly, but they also tend to suppress restorative delta waves activity. Thus, while such medications are conducive to sleep, the sleep they induce is not necessarily a restorative factor.

Bashir, who co-led the study with colleague Richie Brown, associate professor of psychiatry at HMS, added.

HMS co-authors include David Uigun, Chun Yang, Fumi Katsuki, Eric Hodges, James McKenna, and James McNally. Elena Tilly of Stonehill College was a co-author on the study.

Financing: This work was supported by VA Biomedical Research and Development Service Merit Awards and NIH grants R01 NS119227, R21 NS079866, R01 MH039683, T32 HL07901, K01 AG068366, R21 MH125242.

Disclosures: Uygun, McKenna, McNally, Brown, and Basheer are research health scientists at the VA Boston Healthcare System. The contents of this work do not represent the views of the US Department of Veterans Affairs or the US government. McKenna has received partial salary compensation and funding from Merck MISP (Merck Investigator Supported Programs) but has no conflict of interest with this business.

About this sleep research news

author: Ekaterina Besheva
source: Harvard
Contact: Ekaterina Besheva – Harvard
picture: The image is in the public domain

original search: open access.
Knockdown of GABAA alpha3 subunits on retinal thalamic neurons promotes deep sleep in miceWritten by Radhika Bashir et al. Nature Communications


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Knockdown of GABAA alpha3 subunits on retinal thalamic neurons promotes deep sleep in mice

Identifying the mechanisms that increase deep sleep could lead to new treatments that enhance the restorative effects of sleep.

Here, we show that knockdown of α3 GABAaThe receptor subunit of parvalbumin neurons in the retinal-thalamic nucleus using CRISPR-Cas9 gene editing increased thalamocortical delta oscillations (1.5-4 Hz) that is involved in several health-promoting effects of sleep. Inhibitory synaptic currents in thalamic retinal neurons were significantly reduced in vitro.

Further analysis revealed that delta strength in long NREM shifts before NREM-REM transitions was preferentially affected by deletion of α3 subunits.

Our results identify a role for GABAa Receptors on neurons of the reticular thalamic nucleus suggest antagonism of α3 subunits as a strategy to enhance delta activity during sleep.