Targeting torpor circuits across species: towards translation

针对跨物种的麻木回路：走向翻译

• 批准号: MR/W029138/1
• 负责人: Anthony Pickering
• 金额: $ 56.29万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW029138%2F1
• 关键词: Targeting; torpor; circuits; across; species

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.

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）采取的一种保护策略，以在环境挑战期间保存能量，例如暴露于低环境温度和/或食物短缺或疾病。迟钝的动物会主动地大幅降低耗氧量（高达90%）和体温（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。由于这些非凡的特性，麻痹在临床应用和未来可能的长距离太空旅行中都很有意义。最近已经取得了重大进展，因此开始确定大脑中触发小鼠麻痹的关键区域。我们和其他人已经分别集中在下丘脑的同一区域，这是一个已知参与温度调节的区域。我们知道大脑的这一区域在麻木期间是活跃的，使用遗传策略在这一区域表达工程受体或光敏蛋白，使我们能够打开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下降，但我们不知道这一区域是否单独控制了麻木的所有方面。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。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，减少其耗氧量，并减慢心脏跳动。这些都是昏睡的基本特征，这一发现是惊人的，因为大鼠不会自然进入昏睡状态。因此，我们在一个物种中激活了一种合成的类似torpor-like的状态，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负责触发小鼠麻痹的大脑回路。我们渴望知道究竟是哪种神经元负责，以及它们将信号发送到哪里，以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痹特征与我们在大鼠中产生的合成麻痹状态，以了解相似程度。我们还将更详细地探索大鼠大脑中产生合成性麻痹的回路，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痹状态是否在急性肺损伤模型中具有保护作用。在急性肺损伤期间，肺部吸收氧气的能力下降。我们已经知道，大鼠在合成麻痹期间的耗氧量减少了大约40%。因此，合成的麻痹可能使大鼠更好地耐受受损的肺功能，因为身体需要更少的氧气。该项目将进一步加深我们对麻痹的神经控制的理解，开始探索合成麻痹的转化潜力，并为减少重症监护患者的代谢需求是否可以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。