The first two core genes that regulate
the amount of deep sleep and dreaming have been identified by researchers. This finding is a key development that could lead to the discovery of a network of related genes controlling
The study from the Peter O'Donnell Jr. Brain Institute
demonstrates in mice that a single gene controls the amount of non-REM
(rapid eye movement) sleep, which includes deep sleep. A second gene
controls the amount or need for REM sleep, associated with vivid
dreaming. The findings provide a critical molecular entry point to
explain how sleep works and to identify potential targets to better
treat sleep disorders.
‘A newly identified gene controls the amount of non-REM (rapid eye movement) sleep, which includes deep sleep, while the second one controls the amount or need for REM sleep, associated with vivid dreaming.’
"This research is just the beginning. We believe that these two genes
are the first of many that regulate sleep," said study co-author Dr. Joseph S. Takahashi,
Chairman of Neuroscience with the O'Donnell Brain Institute at UT
Southwestern Medical Center and Investigator in the Howard Hughes
Previous research has identified genes that regulate the switch between wakefulness and sleep. But until this latest study in Nature
, scientists have not known what mechanisms control the drive or need for non-REM sleep, nor the amount of REM sleep.
To find out, researchers used a forward-genetic approach in which
they screened for sleep disorders in 8,000 mice using electroencephalogy
(EEG) to monitor brain waves. They found two distinct pedigrees of
- A mouse they called Sleepy
had 50% more non-REM sleep than normal mice without any other obvious defects, caused by a mutation in the Salt-Inducible Kinase 3 Sik3 (Sik3)
- A mouse researchers called Dreamless
severely deficient in the amount of REM sleep, a stage of rest
characterized by rapid eye movements and vivid dreams. This deficit was
caused by a mutation in the Sodium Leak Channel Non-selective
Researchers introduced these same mutations into normal mice and saw their sleep behaviors change accordingly.
"We hope this is the entry door to the black box that explains how our sleep is regulated," said the senior co-author Dr. Masashi Yanagisawa,
an Adjunct Professor of Molecular Genetics at UT Southwestern and
former HHMI Investigator. He now directs the International Institute for
Integrative Sleep Medicine (IIIS) at the University of Tsukuba in
Japan, where most of the mice were screened.
Normal sleep patterns include short durations of REM sleep surrounded
by longer stretches of non-REM sleep and account for about a quarter of
a night's rest in most young adults. Many forms of sleep disorder
distort these patterns. Because the Sik3
genes have just been identified, no evidence yet exists to link them directly to known sleep disturbances in humans.
However, while the role and importance of REM sleep remains a point
of debate, many scientists agree this stage of rest is involved in the
formation of emotional memories and coping with negative experiences.
Thus, a lack of REM sleep may contribute to conditions such as
posttraumatic stress disorder (PTSD).
"At least in theory, this study opens up future possibilities to
create new sleep-regulating drugs, but doing so will occur in the
distant future," said Dr. Yanagisawa, noting that the proteins produced
could possibly be molecular targets for new medicines.
Dr. Takahashi used a forward-genetic approach two decades ago to make a landmark discovery of the Clock
that regulates the body's biological clock. The finding led his team to
discover a network of more than 20 other related genes.
Dr. Takahashi said he expects the screen for sleep genes will lead to
more genes, forming perhaps a much larger group than the clock genes
because sleep affects more parts of the brain.
What's unclear is how big a part the other genes in that network play in regulating sleep. The Takahashi lab found that only a handful of the clock genes have a crucial role in the larger network.
"If the same is true for sleep, this is going to be a simplifying,
illuminating discovery," said Dr. Takahashi, holder of the Loyd B. Sands
Distinguished Chair in Neuroscience and 2016 recipient of the Peter
Farrell Prize in Sleep Medicine.
Dr. Takahashi said he had wanted to conduct such a genetic screen for
sleep mutants for many years but had to overcome logistical issues to
conduct a large-scale effort. Most mouse studies involve no more than a
few dozen animals, but Dr. Yanagisawa rapidly scaled up and optimized
his lab's ability to screen large numbers of mice initially at UT
Southwestern and now at his institute in Japan.
"To be able to screen 8,000 mice is something that most people would
say is too much work," said Dr. Takahashi, explaining that each mouse
had to be surgically wired for the EEG readings, among other steps.
"Technically, this project was very challenging."