Chilling time with synthetic torpor

休眠可以被认为是一种短期的冬眠。这是许多不同物种（包括小鼠）在环境挑战（例如暴露于低环境温度和/或食物短缺和/或疾病）期间保存能量的保护性生理策略。迟钝的动物会主动和深刻地降低它们的代谢率（高达90%）和温度（略高于环境温度）。值得注意的是，动物从这种状态中平静地出现，而不会对它们自己或它们的器官系统造成伤害。除了创造对氧气和营养物质输送减少的恢复能力外，麻木还调节免疫系统，使其能够耐受感染，促进对辐射的抵抗力并阻止肿瘤生长。由于这些非凡的特征，人们对麻木的研究已经有几十年了，尽管在理解上取得了一些进展，但触发和调节这种状态的复杂生理机制在很大程度上还是未知的。由于自然的麻木在哺乳动物物种（包括一些灵长类动物）中广泛存在，因此有理由假设存在共同的脑回路，存在于所有动物中，但只有少数动物活跃。这表明，同样的神经回路可能在没有表现出麻木的动物（如大鼠或人类）中被人为激活，从而使它们能够被诱导将体温降低到正常的37摄氏度以下。最近的进展已经开始确定负责小鼠下丘脑中与温度调节有关的区域的麻木的脑回路。这个区域的特定神经元的激活可以触发Torpor，而不需要外部动机（如食物短缺或寒冷的环境温度）。这些神经元可以使用遗传策略选择性地靶向表达特定药物或光敏蛋白的工程受体，从而允许在小鼠中随意打开“合成麻痹”，使我们能够对其生理学和神经元电路组织进行详细分析。几乎所有动物的细胞和生理过程都有昼夜节律，分子振荡器的同步协调对健康很重要。在仓鼠身上有证据表明，冬眠会导致这些生物钟暂停。目前还不清楚小鼠的麻痹是否会发生类似的现象-如果确实发生，这可能会导致大脑主时钟和身体局部时钟的不同步（就像时差反应一样），这对动物有害。我们将测试这些时钟在休眠期间和休眠之后是否保持同步（控制温度），以及如何实现这一点。我们将在大鼠身上采取类似的回路解剖方法，看看我们是否能在非冬眠物种中产生“合成麻痹”。这将开始确定大鼠下丘脑中是否存在相同的调节回路，以及是什么阻止它们触发麻痹。通过这样做，我们将了解麻木的调节和触发，并进一步确定这种用于保护生物体的显着的细胞和生理适应是否有一天可以用于人类，这可能具有从太空旅行到医疗保健的广泛应用。

Torpor can be thought of as a short term hibernation. It is a protective physiological strategy adopted by many different species (including mice) to conserve energy during environmental challenges, such as exposure to low ambient temperature and/or food shortage and/or illness. Torpid animals actively and profoundly decrease their metabolic rate (by up to 90%) and temperature (to just above ambient temperature). Remarkably, animals emerge uneventfully from this state without incurring harm to themselves or their organ systems. In addition to creating resilience to decreased tissue delivery of oxygen and nutrients, torpor also modulates the immune system, enables tolerance of infection, promotes resistance to radiation and halts tumour growth. Because of these extraordinary characteristics, torpor has been studied for several decades, and even though some progress has been made in its understanding, the complex physiology triggering and regulating this state has been largely unknown. Since natural torpor is widespread across mammalian species (including some primates), it is reasonable to hypothesize that there are common brain circuits, present in all animals but active only in few of them. This suggests that the same neural circuit might be artificially activated in animals that do not show torpor (like rats or humans), allowing them to be induced to decrease their body temperature below the normal tightly regulated 37 degrees C. Recent advances have begun to identify the brain circuit responsible for torpor in the mouse hypothalamus in an area that is known to be involved in temperature regulation. Activation of particular neurons in this region can trigger Torpor without the need for an external motivation (like food shortage or cold ambient temperature). These neurons can be selectively targeted using genetic strategies to express engineered receptors for specific drugs or light sensitive proteins allowing 'synthetic torpor' to be switched on in mice at will, allowing us to undertake a detailed analysis of its physiology and neuronal circuit organisation. Almost all animals have day-night rhythms in their cellular and physiological processes whose synchronised co-ordination by molecular oscillators is important for health. There is evidence in hamsters that hibernation can cause these clocks to pause. It is not clear whether a similar phenomenon happens with torpor in mice - if it does happen then this could lead to de-synchronisation of the brain master clock and the body's local clocks (like happens with jet lag) which would be detrimental to the animal. We will test whether these clocks remain in synchrony during and after torpor (controlling for temperature) and how this is achieved. We will take a similar circuit dissection approach in rats to see whether we can produce 'synthetic torpor' in a non-hibernator species. This will start to define whether the same regulatory circuits are present in the rat hypothalamus and what prevents them from triggering torpor. In so doing we will learn about regulation and triggering of torpor and further identify whether this remarkable set of cellular and physiological adaptations which serve to protect the organism could one day be used in humans which could have a broad range of applications from space travel to healthcare.