Targeting torpor circuits across species: towards translation

麻木可以被认为是一种短期的冬眠。这是许多不同物种(包括老鼠)在面临环境挑战时采取的一种保护性策略，例如暴露在环境温度低和/或食物短缺或疾病中。迟钝的动物积极而深刻地降低它们的耗氧量(高达90%)和体温(略高于环境温度)。值得注意的是，动物在这种状态下平安无事地出现，而不会对自己或他们的器官系统造成伤害。除了对组织中氧气和营养物质输送的减少产生弹性外，昏迷还调节免疫系统，使人能够耐受感染，提高对辐射的抵抗力，并阻止肿瘤生长。由于这些非同寻常的特性，Torpor在临床应用和未来可能的长途太空旅行方面都很有兴趣。最近取得了重大进展，开始识别引发小鼠麻木的大脑关键区域。我们和其他人独立地聚集在下丘脑的同一区域，在一个已知参与温度调节的区域。我们知道，在昏迷期间，大脑的这一区域是活跃的，使用遗传策略在这一区域表达工程受体或光敏蛋白，使我们能够启动神经元，并观察这如何影响小鼠的行为。当我们打开小鼠大脑的这一部分时，我们看到温度下降，其他组也观察到心率减慢，但我们不知道这一区域是否单独控制麻木的所有方面。由于自然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大脑回路，这种回路存在于所有动物中，但只在少数动物中活跃。事实上，我们最近发现，激活大鼠大脑的相应区域可以使大鼠降温，减少其氧气消耗，并减缓心脏的速度。这些都是麻木的基本特征，这一发现令人震惊，因为老鼠不会自然进入麻木状态。因此，我们在一个物种中激活了一种合成的麻木状态，对这种物种来说，这不是一种自然行为。该项目将在这项工作的基础上发展。我们将更详细地探索导致小鼠麻木的大脑回路。我们渴望确切地知道是哪种类型的神经元负责，以及它们在哪里发送信号来产生我们在麻木中看到的所有变化。我们还将比较小鼠的麻木状态和我们在大鼠身上产生的合成麻木状态，以了解两者的相似程度。我们还将更详细地探索在大鼠大脑中产生合成麻木的回路，将它们与小鼠进行比较，并确定它们在大鼠中的正常作用。最后，我们将测试大鼠的合成麻木状态在急性肺损伤模型中是否具有保护性。在急性肺损伤期间，肺吸收氧气的能力会降低。我们已经知道，在合成麻木期间，大鼠的耗氧量减少了大约40%。因此，合成麻木可能会让大鼠更好地耐受受损的肺功能，因为身体需要的氧气更少。该项目将进一步加深我们对麻木神经控制的理解，开始探索合成麻木的翻译潜力，并为减少重症监护患者的代谢需求是否可能使他们更好地耐受疾病和保护器官免受损害提供概念证据。

Torpor can be thought of as a short-term hibernation. It is a protective 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, or illness. Torpid animals actively and profoundly decrease their oxygen consumption (by up to 90%) and body 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 is of interest both for clinical applications and for possible long-distance space travel in the future. Recently significant progress has been made so that are beginning to identify the key regions of the brain that trigger torpor in mice. We and others have independently converged on the same region of the hypothalamus, in an area that is known to be involved in temperature regulation. We know that this region of the brain is active during torpor, and using genetic strategies to express engineered receptors, or light sensitive proteins, in this region allows us to switch the neurons on and observe how this affects the behaviour of mice. When we switch this part of the mouse brain on, we see a drop in temperature and other groups have observed reduced heart rate, but we do not know whether this region alone controls all aspects of torpor. 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. Indeed, we have recently found that activating the corresponding region of the rat brain makes the rat cool down, reduce its oxygen consumption, and slows down the heart. These are cardinal features of torpor, and this finding is striking because rats do not naturally enter torpor. Hence, we have activated a synthetic torpor-like state in a species for which it is not a natural behaviour. The project will develop on this work. We will explore in more detail the brain circuits responsible for triggering torpor in the mouse. We are keen to know exactly what type of neuron is responsible, and where they send their signals to generate all the changes that we see in torpor. We will also compare the characteristics of torpor in the mouse with the synthetic torpor state we have generated in the rat in order to understand the degree of similarity. We will also explore in more detail the circuits within the brain that generate synthetic torpor in the rat, comparing them with the mouse, and identifying what is their normal role in the rat. Finally, we will test whether the synthetic torpor state in the rat is protective in a model of acute lung injury. During acute lung injury there is a reduction in the ability of the lungs to absorb oxygen. We already know that oxygen consumption in the rat is reduced by approximately 40% during synthetic torpor. Hence, synthetic torpor might allow the rat to better tolerate impaired lung function, as less oxygen is required by the body. This project will further our understanding of the neural control of torpor, begin to explore the translational potential of synthetic torpor, and provide proof of concept evidence for whether reducing the metabolic demand in intensive care patients might allow them to better tolerate illness and protect against organ damage.