“The most is that the world can’t stay, Zhu Yan’s words and trees.”
Beauty is a dream that countless people cannot reach. However, scientists have found that the human brain has a “switch” that controls metabolism, and turning this “switch” on can slow down metabolism, thereby playing a role in treating disease and delaying aging.
Recently, the team of Professor Chen Hong of Washington University in St. Louis in the United States published a paper in Nature Metabolism and found a “remote control” to turn on the metabolic switch of the human brain. Using ultrasound stimulation of preoptic area (POA) neurons in the hypothalamus, the researchers successfully induced mice and rats into a state of “hibernation.” This means that mankind is one step closer to retaining youth, treating stubborn diseases, and prolonging life.
Ultrasound stimulates the deep part of the brain. Photo courtesy of interviewee
The hypothesis of ultrasound “remote control” of neurons is proposed
“The highlight of this study is the control of brain neurons through ultrasound to put the mice into a sting-like state with low body temperature and low metabolism. In this type of neuron, we found ion channels that sense ultrasound, which in turn explains the underlying mechanism of this technique. Chen Hong told China Science News.
In nature, some animals can go into hibernation during winter or when food is scarce. They lower body temperature, slow metabolic rate and energy expenditure, and spend months without eating or drinking. In addition, some animals can also temporarily sleep (torpor) — entering a state of low body temperature, heart rate and metabolic rate while suppressing other physical activities.
For humans, hibernation or sting is undoubtedly mysterious and full of temptation. Space travel, healthcare, we have too many important scenarios that urgently need to have this capability.
Scientists’ understanding of the mechanism of hibernation is also constantly being refreshed, and it was initially thought that hibernation is caused by endogenous components in the blood. In 2020, American and Japanese scientists published “back-to-back” papers in the journal Nature, pointing out that special neurons that regulate hibernation are found in the preoptic area of the hypothalamus of mice, and these neurons are artificially activated through optogenetic or chemical genetic means, which can make mice enter a reversible state of hibernation or hibernation.
“When we saw these two papers in Nature, we were very inspired.” Yang Yaoheng, the first author of the paper and a postdoctoral fellow at Washington University in St. Louis, told China Science News, “This confirms that hibernation is controlled by a specific brain region of the hypothalamus, which is equivalent to knowing that there is such a switch in the brain to control hibernation, depending on whether we can find the ‘remote control’ to turn it on.” ”
Chen Hong’s team has long been committed to the study of ultrasound, which is the only non-destructive physical wave known that can penetrate the human skull and reach and act on deep brain regions.
Soon, a hypothesis of using ultrasound to “remotely control” hibernate to control neurons was proposed.
Illustration of ultrasound-induced artificial hibernation. Photo courtesy of interviewee
Finding the critical 1°C, the “big fish” came too suddenly
At the beginning of 2021, Chen Hong’s team officially launched the study after preliminary research. Their idea is clear: focus ultrasound on the brain area that controls hibernation to see if it can cause changes in body temperature and metabolic rate in laboratory mice.
At first, they were not sure, and at that time, the new crown epidemic was tight, and it was inconvenient to purchase various experimental equipment and materials, so they decided to use some simple equipment to conduct pre-experiments to see if the direction was correct.
In February 2021, researchers purchased infrared thermometers and other equipment online and built a simple system to start pre-experiments.
Despite some preparation and research, setbacks came uninvited.
Yang Yaoheng said, “Preliminary research found that in the brain area of mice that control hibernation, there are indeed proteins that can feel ultrasound, so we think the hypothesis should be true, but during the pre-experiment, it was found that ultrasound stimulation seemed to have no effect.” ”
Until the team was ready to give up, Yang Yaoheng suddenly found that he had made a “low-level mistake” – not shaving the mouse.
The pre-experiment is just to verify the idea, so the infrared thermometer purchased has a low sensitivity. The mouse hair will block the infrared detection signal completely.
After discovering the problem, Yang Yaoheng found the electric razor used by his assistant during the epidemic, anesthetized the mice and performed “shaving”, and began the experiment immediately after the mice woke up.
“At that time, we saw that the results were very robust (strong, obvious). As soon as we turned on the ultrasound, the body temperature of the mice immediately dropped by more than 1°C, and Teacher Chen Hong and we were very excited. Recalling that critical moment, Yang Yaoheng’s tone was still excited, “Because, because, how to say well, we have seen such a robust result for the first time, and it is in a lossless way to remotely control mice into such a state.” ”
Although the direction has been clear, the road to the goal is still difficult. In fact, Chen Hong’s team has long opened up territory in the field of ultrasonic research; Yang Yaoheng has also been deeply engaged in this field for 10 years.
From inspiration to pre-research, pre-experimentation, to the fortunate observation of definitive results. Yang Yaoheng believes that seizing opportunities or seizing inspiration is like fishing, and the brain’s thoughts are the sea, “We usually receive a lot of information, and there are also many new ideas that slip out of our thoughts.” What researchers have to do is to spend a long time weaving a ‘fishing net of knowledge’, and only when this net is big and dense enough can they catch the ‘big fish’ of inspiration.”
Chen Hong (front right) team. Photo courtesy of interviewee
From mice to rats, one step closer to human hibernation
In the experiment, the team combined the ultrasonic emission device with the automation system to build a closed-loop feedback device: a single emission of ultrasonic pulses lasting 10 seconds can reduce the core body temperature of mice by 3°C to 4°C, slow down the heart rate by 47%, significantly reduce oxygen consumption, and become inactive. At the same time, the metabolic pathways of these mice also changed: from using carbohydrates and fats to produce heat, to using only fat, indicating that the mice have entered a low-energy dormant state.
After 90 minutes, the mice’s body temperature gradually rises, and once the 34°C is reached, the mouse’s sleeping state threshold, the device emits ultrasonic pulses again. In this way, mice can always maintain a low body temperature and low metabolic state.
The experiment lasted 24 hours, during which time the body temperature of the mice remained at 32.95?±0.45°C without physical damage or abnormalities.
“We haven’t done any longer experiments at the moment, mainly because the device is a small wearable helmet that emits ultrasonic waves on the heads of mice. But it needed a gel-like medium that was exposed for too long and produced bubbles to attenuate the ultrasound, so the experiment was not carried out for a longer period of time. Yang Yaoheng explained.
After completing the mouse experiments, the researchers conducted experiments on rats.
Here’s the problem, though. There are neural circuits in the mouse brain that control hibernation, but rats hardly enter any state similar to hibernation, so does it have neural circuits to control hibernation? Scientists don’t know.
“We actually face a basic scientific problem, which is not knowing whether rats retain these neural circuits during evolution.” Yang Yaoheng said, “If there is no such neural circuit, there is no way to talk about control.” ”
Fortunately, they found in follow-up studies that the neural circuit may still exist even in non-hibernating animals, but it remains closed. This opens up the possibility for humans to achieve artificial hibernation.
“Compared with the previous literature, we found that the ultrasound-induced artificial hibernation state is very close to the hibernation state of animals in nature.” Yang Yaoheng added, “But this is only a series of changes in the body indicators of mice observed, and how close it is to the natural hibernation state needs further study.” ”
Yang Yaoheng. Photo courtesy of interviewee
Figuring out the mechanism may solve the “ultimate problem”
After discovering the phenomenon of hibernation in mice and rats, the researchers were eager to know the mechanism of this. They wanted to figure out which proteins in the brain could sense ultrasound and act as switches on and off.
To this end, the team collaborated with bioinformaticiologists and experts in the field of metabolism to sequence cells using the latest biotechnology, screening out neuronal cells activated by ultrasound, and then analyzing all the protein RNA sequences on the cell to detect which protein or ion channel was overexpressed.
It’s been another difficult journey. Single-cell sequencing experiments, data processing, optimizing experimental design, and eliminating interference factors are like “finding a needle in a haystack”. After more than two years of work, they found this protein ion channel called trpm2, confirming that it can sense ultrasound and activate neurons.
“Knowing whether humans have neural pathways that control hibernation is critical for scientific research.” Chen Hong said, “If artificial hibernation is feasible in people, this ultrasound technology can improve the survival chances of critically ill patients by delaying their metabolism and vital activities, and buying more treatment time for critically ill patients.” ”
For patients with myocardial infarction and stroke, every minute of rescue at the onset of the disease is a matter of life and death. If patients can be put into a state similar to hibernation to delay the metabolic process, they can fight for more chances of survival. Looking ahead, artificial hibernation can even keep “terminally ill” patients in a low-metabolism state for a long time, waiting for new drug development or medical technology progress.
“This focused ultrasound technology is non-invasive, so it’s easier to translate clinically, which in turn helps us solve these ultimate problems.” Chen Hong said. (Source: Zhang Shuanghu, China Science News)
Related paper information:https://doi.org/10.1038/s42255-023-00804-z