In order to conserve energy in cold weather or when there is a lack of food, some mammals can temporarily lower their body temperature and their metabolism. Researchers have now succeeded in artificially imitating this so-called torpor state. When they stimulated the brains of mice using ultrasound, the animals' body temperature dropped by several degrees Celsius. With continued stimulation, this state could be maintained for 24 hours, with the animals waking up undamaged within a few hours after the stimulation was switched off. The process could possibly be helpful in medicine or aerospace.
In hostile environmental conditions such as cold or lack of food, some mammals such as mice, bats and small primates can activate a type of energy-saving mode called torpor. Similar to hibernation, they lower their body temperature and metabolism so that they use less energy and can sometimes survive for up to several weeks without eating.
Since the 1960s, people have tried to mimic this condition - for example for astronauts on long-term space flights or to increase the chances of survival of stroke patients. The brain regions involved in mice are now known, and researchers have actually already succeeded in inducing an artificial torpor-like state in mice through injections into the relevant brain regions or through genetic manipulation. However, all previous procedures were so invasive that transmission to humans was unthinkable.
Neuromodulation via ultrasound
A team led by Yaoheng Yang from Washington University in Saint Louis has now managed to achieve such a condition using a non-invasive procedure for the first time. To do this, the researchers equipped mice with portable ultrasound transmitters that send targeted ultrasound pulses to the preoptic area of the hypothalamus in the mouse brain at the push of a button. This region is involved in the regulation of body temperature and metabolism and has been identified in previous studies as the region responsible for torpor.
“Ultrasound is the only available form of energy that can penetrate the skull non-invasively and can be focused with millimeter precision on any part of the brain without using ionizing radiation,” the researchers explain. "This makes ultrasound a promising technology for neuromodulation in small animals, non-human primates and humans." In fact, the ultrasound stimulation in the mice had the desired effect: Immediately after the stimulation, the body temperature and the activity level of the animals began to drop lost weight. After a few minutes, the body temperature had dropped by more than three degrees Celsius, the heart was beating more slowly and metabolic measurements showed that the animals were consuming less oxygen.
Complete recovery after long-term use
If there were no further ultrasound impulses, the animals' body temperature began to rise again after about an hour and after two hours they had fully recovered. Further experiments showed that the strength and duration of the ultrasound impulses determine how much the body temperature drops and how quickly it returns to normal. The research team extended the torpor phases with an automatic feedback controller: whenever the body temperature of the mice began to rise again, the controller emitted ultrasonic pulses again. "In this way, we were able to keep the body temperature of the mice at 32.95 degrees Celsius for 24 hours," reports Yang's colleague Hong Chen. "After switching off the ultrasound, the metabolism and body temperature returned to normal."
Subsequent brain studies revealed that it is indeed the neurons of the preoptic area of the hypothalamus that induce torpor in response to the ultrasound. With the help of genetic sequencing, Yang and his team discovered that certain ion channels in the nerve cells, the so-called TRPM2 channels, are activated by the ultrasound and then set in motion a signal chain that downregulates body temperature and metabolism.
Transferable to other living beings
To test the transferability of the method to other animals, the research team used the same technique on rats. Unlike mice, torpor does not occur naturally in these animals. "We also found a significant decrease in body temperature in the rats as a result of the ultrasound stimulation," reports the team. "Although the extent of the decrease in rats was lower than in mice, these data show that the method can also be used in living beings without natural torpor." From the researchers' point of view, this could indicate that the technique could also be used in humans .
"This study may seem like a small step for this research group, but it promises to be a giant leap for mankind to use torpor-like states in medicine and possibly in space travel," write Martin Jastroch of Stockholm University and Frank van Breukelen from the University of Nevada in a commentary accompanying the study, also published in the journal Nature Metabolism.
Source: Yaoheng Yang (Washington University in St. Louis, USA) et al., Nature Metabolism, doi: 10.1038/s42255-023-00804-z