科学家使用超声波脑刺激诱导类似冬眠的状态

根据一项研究，位于圣路易斯的华盛顿大学的科学家们已经开发出一种利用大脑超声波刺激来诱导哺乳动物进入类似冬眠状态的方法。 自然新陈代谢. 这种非侵入性技术可用于太空飞行等场景，或用于患有严重健康状况的患者以节约能源和热量。

一些哺乳动物和鸟类有一种通过进入冬眠状态来保存能量和热量的聪明方法，在这种状态下，它们的体温和新陈代谢率会下降，从而使它们能够在极端寒冷或食物匮乏等环境中的致命条件下生存下来。 虽然在 1960 年代为进行太空旅行的科学家或患有危及生命的健康状况的患者提出了类似的条件，但安全地诱发这种情况还有很长的路要走。

圣路易斯华盛顿大学副教授 Hong Chen 和一个多学科团队通过使用超声波刺激大脑的术前区域，诱导小鼠进入类似冬眠的状态，这有助于调节体温和新陈代谢。 除了自然冬眠的老鼠，陈和她的团队还诱导老鼠冬眠，而老鼠却没有。 他们的发现发表在 5 月 25 日的《自然》杂志上 自然新陈代谢展示了第一种通过靶向中枢神经系统来诱导类似冬眠状态的非侵入性和安全方法。

Chen 的团队使用超声波安全且无创地诱导小鼠和大鼠进入类似冬眠的状态。 图片来源：圣路易斯华盛顿大学陈实验室提供的视频

医学院 McKelvey 工程与放射肿瘤学院生物医学工程助理教授 Chen 和她的团队，包括博士后研究员 Yaoheng (Mack) Yang，创造了一种可穿戴超声换能器来刺激细胞神经。下丘脑。 刺激后，小鼠体温下降约 3 度[{” attribute=””>Celsius for about one hour. In addition, the mice’s metabolism showed a change from using both carbohydrates and fat for energy to only fat, a key feature of torpor, and their heart rates fell by about 47%, all while at room temperature.

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

“We developed an automatic closed-loop feedback controller to achieve long-duration and stable ultrasound-induced hypothermia and hypometabolism by controlling of the ultrasound output,” Chen said. “The closed-loop feedback controller set the desired body temperature to be lower than 34 C, which was previously reported as critical for natural torpor in mice. This feedback-controlled UIH kept the mouse body temperature at 32.95 C for about 24 hours and recovered to normal temperature after ultrasound was off.”

To learn how ultrasound-induced hypothermia and hypometabolism is activated, the team studied the dynamics of the activity of neurons in the hypothalamus preoptic area in response to ultrasound. They observed a consistent increase in neuronal activity in response to each ultrasound pulse, which aligned with the changes in body temperature in the mice.

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

Chen and her team also wanted to find the molecule that allowed these neurons to activate with ultrasound. Through genetic sequencing, they found that ultrasound activated the TRPM2 ion channel in the hypothalamus preoptic area neurons. In a variety of experiments, they showed 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 delivered ultrasound to the hypothalamus preoptic area and found a decrease in skin temperature, particularly in the brown adipose tissue region, as well as about a 1 degree C drop in core body temperature, resembling natural torpor.

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

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

Reference: “Induction of a torpor-like hypothermic and hypometabolic state in rodents by ultrasound” by Yaoheng Yang, Jinyun Yuan, Rachael L. Field, Dezhuang Ye, Zhongtao Hu, Kevin Xu, Lu Xu, Yan Gong, Yimei Yue, Alexxai V. Kravitz, Michael R. Bruchas, Jianmin Cui, Jonathan R. Brestoff and Hong Chen, 25 May 2023, Nature Metabolism.
DOI: 10.1038/s42255-023-00804-z

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