Mice help scientists understand genetics of sleep

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Through a genetic study of sleep defects in mice, researchers at UT Southwestern Medical Center recently discovered two genes that could help unlock the mysteries of sleep.

The study produced two pedigrees, called Sleepy and Dreamless. While mice with the Sleepy mutation need approximately 21 hours of sleep, 50 percent more than a normal mouse, Dreamless mice have a severe reduction in rapid-eye movement, or REM, sleep. According to Joseph Takahashi, chairman of the Department of Neuroscience at UT Southwestern Medical Center and a researcher in the study, these mutant mice could greatly improve scientists’ overall understanding of sleep.

“Sleep in mice and in humans is almost identical,” Takahashi said. “So the mouse is actually a very good model organism. If we understand sleep in mice, that knowledge will likely transfer almost directly to human sleep.”

To introduce the sleep defects, the researchers used a chemical that randomly changed a single base pair in the mouse’s DNA. Takahashi said a typical mouse in the study had about 50 of these changes made to its genes. 

Because these changes were random, the researchers had no way of knowing beforehand whether they would cause sleep defects. Instead, they used an electroencephalogram, or EEG, to measure the brainwaves of the mice. According to Takahashi, this was a labor-intensive process.

“The reason no one has done this before is because you have to hook up electrodes to every single mouse,” Takahashi said. “It requires surgery, and we screened about 8,000 mice. The procedure takes about an hour. Maybe an expert could do six to eight mice a day — that’s pretty slow.”

Once they attached the electrodes to the mice, the researchers measured a continuous baseline for two days. Then, they placed the mice into cylindrical cages that rotated randomly, depriving the mice of sleep for a day. Finally, they measured their recoveries from the sleep deprivation.    

At this point, Takahashi said they had to breed the mice to make sure the offspring could have the defect as well, proving the defect was due to genetics. The offspring were then put through a process called linkage analysis which showed the specific genes that caused the defect.

The gene modified by the Sleepy mutation encodes a type of protein called a kinase that modifies other proteins by adding phosphate to them. According to Takahashi, Sleepy mice have a kinase protein that does not carry out this function, but he is not sure how this relates to increased sleep.

“We don’t really understand why they need more sleep, but this gives us the first clue,” Takahashi said. “This protein could be a target for drug development, if human patients have defects that cause too much sleep or not being able to sleep.” 

Linkage analysis on Dreamless mice revealed that their mutation affects sodium channels in the brain, causing neurons to fire more than usual and reducing REM sleep. Takahashi said this might also be a potential target for drugs in the future. 

Takahashi said that moving forward, he would like to determine whether the Dreamless mice have other abnormal tendencies due to loss of REM sleep and discover how the kinase protein that was modified in Sleepy mice affects sleep. He also said the researchers are working on producing different types of sleep defects in the mice, which would reveal different genes associated with sleep.

“We need to get a much better picture of the genetic underpinnings of sleep,” Takahashi said. “Typically when you find many genes, you begin to see connections. That’s a very important goal for us, to understand how different genes work together to control sleep.”