The third "short sleep gene"
A mutation in the neuropeptide S receptor reduced the need for sleep and protected the memory of mice
Doctors have found another mutation that allows its carriers to sleep 4.3-5.5 hours a day and get enough sleep, according to Science Translational Medicine (Xing et al., Mutant neuropeptide S receptor reduces sleep duration with preserved memory consolidation). Moreover, it seems to protect against memory disorders associated with lack of sleep — at least, this happens in mice. Animals with the mutation that were not previously allowed to sleep were better than mice from the control group passed a test that checks the work of contextual memory.
According to doctors, people from 18 to 65 years old, on average, need to sleep 8-8.5 hours a day. Those who sleep too little or, conversely, too much, have an increased risk of cardiovascular diseases. Lack of sleep can lead, among other things, to cognitive impairment, depression, and decreased immunity.
The duration of sleep depends on circadian rhythms and homeostasis. Genetic factors also affect sleep. Some people sleep for 4-6 hours a day all their lives, but at the same time they feel well and they do not develop disorders and disorders associated with chronic lack of sleep. Ten years ago, neurophysiologists and physicians led by Ying-Hui Fu from the University of California at San Francisco found a mutation in the DEC2 gene in a mother and daughter who got enough sleep in six hours. The protein DEC2 regulates the production of the hormone orexin, which maintains a state of wakefulness. Recently, the same group of researchers described a mutation in the β1-adrenoreceptor gene. Its carriers got enough sleep, on average, in 5.7 hours.
In a new study, Fu-led scientists described a mutation in the neuropeptide S receptor 1 gene (NPSR1). Neuropeptide S, to which the receptor binds, modulates awakening and falling asleep. Scientists found a mutation (the amino acid tyrosine in the 206 position of the protein chain was replaced by histidine) in a father and son who had enough sleep for 4.3-5.5 hours for a full rest. Such a replacement is extremely rare, in one person out of four million.
To test the effect of the mutation, the authors constructed genetically modified mice carrying the mutant NPSR1 gene.Mutant animals compared to mice from the control group were more active and moved more, both during the day and at night. Studies using electroencephalography and electromyography (recording muscle activity) have shown that animals with the mutation slept 71 minutes less day and night on average (P<0.0001) than normal mice. They had reduced the duration of slow sleep both during the day and at night, and the time of rem sleep was reduced only in the dark. In mice with a mutation in the NPSR1 gene, compared with animals from the control group, the need for sleep was less (P<0.01), despite the fact that they slept less. They recovered faster after six hours of sleep deprivation. And even after deprivation, their need for sleep was less (P=0.0013) than in normal mice.
Then the authors decided to find out whether a mutation in the NPSR1 gene changes the physiological activity of neuropeptide S receptor 1. It is formed in the brain and, in turn, affects the formation of the CREB protein that regulates the transcription of some genes. Normal and mutant mice were injected with neuropeptide S into the brain, and then the concentration of CREB protein was measured in the brain lysate. In mutant mice, it was even higher (P<0.001) than in normal animals, so the researchers decided that the activity of the receptor persists even in the presence of a mutation.
Moreover, it turned out that neurons on the surface of which the mutant protein NPSR1 is located are more sensitive to the action of neuropeptide S (P<0.0001) than neurons with a conventional protein. Scientists injected a neuropeptide into the brain to activate the NPSR1 receptor protein. And then the activity of neurons in the central part of the thalamus, where the protein is formed, was monitored using calcium imaging. For comparison, they monitored the activity of neurons in the lateral region of the hypothalamus. This part of the brain is also involved in the regulation of sleep, and the NPSR1 protein is formed there, but in smaller quantities compared to the thalamus. Nevertheless, the introduction of neuropeptide S into the hypothalamus included a mutant protein there as well.
Chronic lack of sleep leads to cognitive impairment in most people. But carriers of some mutations that allow them to sleep less do not suffer from such disorders. To find out whether cognitive impairments appear in carriers of a mutation in the NPSR1 gene, the authors conducted a test for contextually conditioned fear in an experimental and control group of mice. This test involves the memory of past events. The rodents who were not allowed to sleep shortly before taking part in the test had worse test results than the animals who slept freely. But mice with a mutation in the NPSR1 gene passed the test after 6 hours of sleep deprivation no worse than animals from the control group who slept enough time, and better (P=0.0179) than ordinary mice who were not allowed to sleep before participating in the test.
"The NPSR1 gene not only reduces sleep duration, but also prevents memory problems that are usually the result of sleep deprivation," notes Ying—Hui Fu in a press release of the 'Short Sleep' Gene Prevents Memory Deficiencies Associated with Sleep Deprivation. "This is the first gene found that protects against one of the adverse effects of sleep disorders."
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