Therapeutic hypothermia protects the brain after cardiopulmonary arrest. Innate fear has evolved to orchestrate protective effects in life-threatening situations. Thus, strong fear perception may induce a specialized life-protective metabolism based on hypothermia/hypometabolism; however, such phenomena and their inducers are yet to be elucidated. Here, we report that thiazoline-related fear odors (tFOs), which are TRPA1 agonists and induce robust innate fear in mice, induced hibernation-like systemic hypothermia/hypometabolism, accelerated glucose uptake in the brain, and suppressed aerobic metabolism via phosphorylation of pyruvate dehydrogenase, thereby enabling long-term survival in a lethal hypoxic environment. In contrast to hibernation, during which immune functions are generally suppressed, tFO-stimulation induced a crisis-response immune state characterized by potentiated innate immune functions but suppressed inflammation with anti-hypoxic ability. Collectively, these responses exerted potent therapeutic effects in cutaneous and cerebral ischemia/reperfusion injury models. Whole brain mapping and chemogenetic activation revealed that sensory representation of tFOs orchestrate survival fate via brain stem Sp5/NST to midbrain PBN pathway. TFO-induced strong crisis perception maximizes latent life-protective effects by shifting metabolism to a crisis response mode characterized by hypothermia, hypometabolism and crisis immunity.

中文翻译：

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噻唑啉相关的TRPA1激动剂增香剂协调小鼠的生存命运

低温治疗可保护心肺停搏后的大脑。天生的恐惧已演变为在威胁生命的情况下协调保护作用。因此，强烈的恐惧感可能会基于体温过低/代谢不足而诱发特殊的保护生命的新陈代谢；但是，这种现象及其诱因尚未阐明。在这里，我们报告说，噻唑啉相关的恐惧气味（tFOs）是TRPA1激动剂，在小鼠中引起强烈的先天恐惧，诱发像冬眠的系统性体温过低/代谢不足，加速了大脑中葡萄糖的摄取，并通过丙酮酸的磷酸化抑制了有氧代谢脱氢酶，从而可以在致命的低氧环境中长期存活。与通常抑制免疫功能的冬眠相反，tFO刺激诱导了危机响应的免疫状态，其特征是先天免疫功能增强，但具有抗缺氧能力，抑制了炎症。这些反应共同在皮肤和脑缺血/再灌注损伤模型中发挥了有效的治疗作用。全脑定位和化学发生激活表明，tFO的感觉代表通过脑干Sp5 / NST到中脑PBN通路来协调生存命运。TFO引起的强烈危机感通过将新陈代谢转变为以体温过低，低代谢和危机免疫为特征的危机应对模式而最大化了潜在的生命保护作用。这些反应在皮肤和脑缺血/再灌注损伤模型中发挥了有效的治疗作用。全脑定位和化学发生激活表明，tFO的感觉代表通过脑干Sp5 / NST到中脑PBN通路来协调生存命运。TFO引起的强烈危机感通过将新陈代谢转变为以体温过低，低代谢和危机免疫为特征的危机应对模式而最大化了潜在的生命保护作用。这些反应在皮肤和脑缺血/再灌注损伤模型中发挥了有效的治疗作用。全脑定位和化学发生激活表明，tFO的感觉代表通过脑干Sp5 / NST到中脑PBN通路来协调生存命运。TFO引起的强烈危机感通过将新陈代谢转变为以体温过低，低代谢和危机免疫为特征的危机应对模式而最大化了潜在的生命保护作用。