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.

蛰伏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/或食物短缺或疾病）期间节省能量的保护策略。迟钝的动物会积极而深刻地降低其耗氧量（高达 90%）和体温（略高于环境温度）。值得注意的是，动物能够平安地摆脱这种状态，而不会对其自身或器官系统造成伤害。除了增强组织对氧气和营养物质输送减少的抵抗力外，休眠还可以调节免疫系统，增强感染耐受性，增强对辐射的抵抗力，并阻止肿瘤生长。由于这些非凡的特性，麻木状态在临床应用和未来可能的长距离太空旅行中都引起了人们的兴趣。最近取得了重大进展，开始确定引发小鼠麻木状态的大脑关键区域。我们和其他人独立地聚集在下丘脑的同一区域，该区域已知与温度调节有关。我们知道大脑的这个区域在麻木状态下是活跃的，并且使用遗传策略来表达该区域的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，我们会看到温度下降，其他组也观察到心率降低，但我们不知道该区域是否单独控制了麻木的所有方面。由于自然麻木现象在哺乳动物物种（包括一些灵长类动物）中普遍存在，因此可以合理地假设，所有动物中都存在共同的大脑回路，但仅在少数动物中活跃。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，减少耗氧量，并减慢心率。这些是麻木状态的主要特征，这一发现是惊人的，因为老鼠不会自然地进入麻木状态。因此，我们在一个物种中激活了一种合成的类似麻木的状态，但这并不是一种自然行为。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木状态的大脑回路。我们渴望确切地知道什么类型的神经元负责，以及它们在哪里发送信号以产生我们在麻木状态下看到的所有变化。我们还将比较小鼠的麻木状态与我们在大鼠中产生的合成麻木状态，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麻木状态的回路，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作用。在急性肺损伤期间，肺部吸收氧气的能力会降低。我们已经知道，在人工休眠期间，大鼠的耗氧量减少了约 40%。因此，合成麻木可能使大鼠能够更好地忍受受损的肺功能，因为身体需要的氧气较少。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转化潜力，并为减少重症监护患者的代谢需求是否可以让他们更好地耐受疾病和保护器官提供概念证据。损害。