Chen’s team used ultrasound to safely and non-invasively induce a state of torpor in mice and rats.

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Hong Chen, an associate professor at Washington University in St. Louis, and a multidisciplinary team induced a state of torpor in mice by using ultrasound to stimulate the preoptic area of ​​the hypothalamus in the brain, which helps regulate body temperature and metabolism. In addition to the mouse, which naturally goes into torpor, Chen and his team induced torpor in a rat, which doesn’t. Their findings, published on May 25, 2023, in nature metabolism, show the first non-invasive and safe method to induce a torpor-like state by targeting the central nervous system.

Chen, an associate professor of biomedical engineering at the McKelvey School of Engineering and of radiation oncology at the School of Medicine, and her team, including Yaoheng (Mack) Yang, a postdoctoral research associate, created a portable ultrasound transducer to stimulate neurons in the preoptic area of ​​the hypothalamus. When stimulated, the mice showed a drop in body temperature of about 3 degrees C for about an hour. In addition, the mice’s metabolism showed a switch from using carbohydrates and fat for energy to just fat, a key feature of torpor, and their heart rates dropped by about 47%, all while at room temperature.

The team also found that as acoustic pressure and ultrasound duration increased, so did the depth of lower body temperature and slower metabolism, known as ultrasound-induced hypothermia and hypometabolism (UIH).

“We developed a closed-loop automatic feedback controller to achieve stable and long-lasting ultrasound-induced hypothermia and hypometabolism by controlling the ultrasound output,” Chen said. “The closed-loop feedback controller set the target body temperature to be less than 34°C, which was previously reported to be critical for natural torpor in mice. This feedback-controlled UIH maintained the mouse’s body temperature at 32, 95 °C for about 24 hours and recovered to normal temperature after the ultrasound was turned off.”

To learn how ultrasound-induced hypothermia and hypometabolism are activated, the team studied the dynamics of activity of neurons in the preoptic area of ​​the hypothalamus in response to ultrasound. They observed a steady increase in neural activity in response to each ultrasound pulse, which aligned with changes in the mice’s body temperatures.

“These findings revealed that UIH was triggered by ultrasound activation of neurons in the preoptic area of ​​the hypothalamus,” Yang said. “Our finding that transcranial stimulation of the preoptic area of ​​the hypothalamus was sufficient to induce UIH revealed the pivotal role of this area in orchestrating a torpor-like state in mice.”

Chen and his team also wanted to find the molecule that would allow these neurons to fire with ultrasound. Through genetic sequencing, they found that ultrasound activated the TRPM2 ion channel in neurons in the preoptic area of ​​the hypothalamus. In a variety of experiments, they demonstrated that TRPM2 is an ultrasound-sensitive ion channel and contributed to the induction of UIH.

In the rat, which does not naturally go into torpor or hibernation, the team sent ultrasound to the preoptic area of ​​the hypothalamus and found a decrease in skin temperature, particularly in the region of brown adipose tissue, as well as a drop of about 1 degree. C in the nucleus. body temperature, resembling natural lethargy.

This multidisciplinary team includes Jonathan R. Brestoff, MD, PhD, assistant professor of pathology and immunology in the School of Medicine; Alexxai V. Kravitz, associate professor of psychiatry, anesthesiology and neuroscience in the School of Medicine, and Jianmin Cui, professor of biomedical engineering in the McKelvey School of Engineering, all at Washington University in St. Louis. The team also includes Michael R. Bruchas, professor of anesthesiology and pharmacology at the University of Washington.

“UIH has the potential to address the long-sought goal of achieving safe, non-invasive induction of the torpor-like state, which has been pursued by the scientific community since at least the 1960s,” Chen said. “Ultrasound stimulation possesses a unique ability to non-invasively reach deep regions of the brain with high spatial and temporal precision in human and animal brains.”

This work was supported by the National Institutes of Health (R01MH116981, UG3MH126861, R01EB027223, and R01EB030102). JRB is supported by the NIH (DP5 OD028125) and the Burroughs Wellcome Fund (CAMS #1019648).