Journey to the bottom of a brain that does not sleep

human brain
Image of a mouse brain. DEISEROTH LABORATORY

Two pioneering studies are immersed in the brains of animals today to try to answer a seemingly simple but complicated question in detail: Why do we need sleep?

There is abundant evidence that sleep is a disconnection from the reality necessary to consolidate memory, learn and give the body time to do its cleaning functions at the molecular level. The proof that sleep is essential is that its lack is related to cardiovascular, neurological and obesity diseases . To this is added the evidence that when the circadian clock that dictates periods of activity and rest in daily cycles of about 24 hours stops working , the basic logistics of the body breaks down and a multitude of ailments appear, including cancer. Although the restorative effect of sleep has been studied in different organs, until now it has been almost impossible to do the same with the organ organ, the brain, especially to understand what happens at the molecular level during the hours of sleep.

The two works, published Thursday in Science, provide the first answers to these questions. “We have tried to simulate the rhythm of life that humans have in mice,” summarizes Charo Robles, a Spanish researcher at the University of Munich (Germany) and lead author of the two studies. His team has analyzed protein transcription and phosphorylation – the biochemical process that transports energy where it is needed – in the brain for 24-hour cycles. A group of animals slept all their hours – about 12 a day – and others were deprived of sleep at different times of day or night – four hours in total. The researchers analyzed individual neurons and sequenced the molecules produced at every moment of the day in the frontal part of the brain that includes the cerebral cortex and the hippocampus, epicenters of learning and memory.

The results reveal that the brain follows very marked rhythms of activity and rest in which two peak moments stand out: dawn and dusk, which coincide with the onset of sleep and wakefulness in mice, respectively, because mice are animals nocturnal The work also demonstrates that these cycles are completely disrupted if there is a lack of sleep. One of the molecules studied is messenger RNA, in charge of traveling where it is necessary to start the process of producing proteins, for example neurotransmitters that allow intensifying brain activity or depress it when it is necessary for the brain to rest.

The molecular biologist Charo Robles, in the center, along with the rest of his team at the University of Munich (Germany).
The molecular biologist Charo Robles, in the center, along with the rest of his team at the University of Munich (Germany). CR

“The process of activity and inactivity is marked in part by the internal clock that we all carry inside and that determines circadian rhythms every 24 hours or so,” explains Robles. “What we see is that the brain seems to anticipate the activity it will have the next day and sends the messenger RNA molecules to the synapses, the connections between neurons, which are responsible for thought, memory and other cognitive functions. Once there the RNAs begin the process of protein production with those activity peaks concentrated at dawn and dusk, ”he details. Mice that do not get enough sleep have all the RNAs in place, but for unknown reasons the molecules do not initiate the production of proteins, necessary to generate awareness and thought during the day or relax neurons during sleep. The second work, whose first author is also Spanish, researcher Sara Noya, from the University of Zurich (Switzerland), highlights that lack of sleep paralyzes phosphorylation that allows energy to be taken from where it is where it is needed. Mice that do not sleep lose 98% of all this capacity, a brain blackout.

“The brain of a mouse and that of a human are very different, but we believe that these results confirm the hypothesis that sleep is essential to restore neuronal stability after one day of activity and in preparation for the next,” explains Robles.

Understanding the very complex dream of the brain at the molecular level – one of the works has analyzed about 8,000 proteins – is a first step towards a possible drug that allows to undo the negative effects of lack of sleep in the brain, admits Robles, “although it is something that is still far, ”he says. Its next objective is to extend molecular mapping to more areas of the brain of mice. “There are still many questions to answer, for example, the cerebral cortex is very active during the day and less at night, but there are other areas of the brain that are only excited during sleep,” he says.

“These studies are very important to know that these phenomena take place in mice, it is something that was unknown,” says María Llorens, a researcher at the Severo Ochoa Molecular Biology Center in Madrid. Now the big challenge is “to have non-invasive techniques to assess whether these changes take place in humans,” something very complicated for now, but that “does not detract from the discovery,” he says. Llorens’ laboratory discovered this year that the human brain continues to produce new neurons throughout life , even in old age. Who knows if that regenerative capacity also depends intimately on the hours we sleep each day.

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