Project Summary/Abstract Hibernation is one of the most remarkable physiological traits observed across a spectrum of animal species. Hibernating mammals reside primarily in a state known as torpor, characterized by lowered metabolism and reduced body temperature to conserve energy and survive harsh conditions. This natural phenomenon has inspired the concept of artificial hibernation (AH), which seeks to mimic the reduction in metabolism and body temperature using artificial means. Hypometabolism induced by AH in humans has the promise to impact broad medical domains, including enhancing survival rates during critical health events such as stroke and heart attacks, inhibiting the proliferation of cancer cells, extending the viability of organs for transplantation, and promoting longevity. However, noninvasive and safe induction of AH has remained within the realm of science fiction. My group recently discovered that stimulating specific neurons in the hypothalamus using ultrasound could noninvasively, safely, and reversibly reduce metabolism and body temperature in mice. We found this effect was associated with ultrasound-sensitive ion channels in torpor-associated neurons in the hypothalamus. While mice naturally enter torpor under food deprivation and cold exposure, we showed the feasibility of inducing AH through ultrasound in non-hibernating rats. Building on these promising discoveries, we propose the audacious hypothesis that neural pathways critical for metabolism regulation are conserved across mammals and can be activated by ultrasound. Our overarching goal is to pioneer a platform technique that harnesses ultrasound for the noninvasive and safe induction of AH, thereby catalyzing disruptive medical innovations. To achieve this ambitious goal, we will utilize an interdisciplinary approach that combines ultrasound engineering, system neuroscience, physiology, molecular biology, brain functional imaging, and behavior assays to address three pivotal questions: 1) What are the molecular, cellular, neural circuit, and system-level mechanisms that underpin ultrasound-induced AH in mice and rats? 2) How effective is ultrasound-induced AH in treating stroke, as demonstrated using rat stroke models? 3) Is the technique translatable to non-human primates as a critical step toward human application? Our proposed research program is innovative because it is expected to offer a disruptive technique to induce AH, provide an unprecedented opportunity to elucidate the complex role of the nervous system in metabolism regulation, pioneer the evaluation of ultrasound-induced AH in diseased models, and tackle the pivotal question of AH feasibility in humans. If successful, this high-risk, high-reward project could redefine the landscape of metabolism research and revolutionize the therapeutic manipulation of metabolic states. It could provide compelling evidence for the clinical translation of ultrasound-induced AH and turn what was once a science- fiction...