Can social buffering pheromones be used to reduce stress?

压力是影响圈养动物健康和福利的一个主要因素。除了围绕动物福利的伦理问题外，压力还降低了使用实验动物（如小鼠）获得的数据的质量，由于变异性增加和可靠性降低，使用的动物数量增加。众所周知，同一物种的其他动物的存在对减轻压力有有益的福利作用。此外，其他个体的这种社会缓冲作用在很大程度上是由嗅觉检测到的化学信号介导的。这三种化学物质的混合物最近被证明可以激活一种特定类型的嗅觉受体，称为OR37受体。此外，这种社会缓冲化学物质的混合显著降低了小鼠在新环境中的激素应激反应的激活。这是通过激活直接的大脑通路来实现的，该通路抑制了控制应激激素释放的细胞。该项目的总体目标是确定这些社会缓冲化学物质是否对小鼠具有一般的减压作用，可以用来减少实验室环境中经历的压力。我们将首先确定三种化学物质的最佳比例和浓度，以减少新奇诱导的应激。我们将继续确定这种混合物是否会减少对其他压力情况的压力，包括习得性焦虑反应和社会隔离。该项目的一个主要重点将是利用我们已建立的实验方案来确定这些化学信号是否能减轻小鼠对二氧化碳暴露的压力和焦虑。这一点尤其重要，因为每年有数百万只实验室老鼠被二氧化碳安乐死杀死。在缺乏更人道的二氧化碳替代品的情况下，发现一种可以减少与二氧化碳相关的压力的药物安乐死将对福利产生重大影响。我们还将研究化学物质的社会缓冲混合是否有效对抗暴露于小鼠报警信息素的压力促进效应，这是在二氧化碳安乐死过程中释放的。在本研究的最后一部分，我们的目标是将这些知识应用于开发一种压力较小的二氧化碳安乐死程序，以及改进饲养程序，以减少实验室小鼠在其他实验环境中所经历的压力。除了测量与压力相关的大脑区域的激活和压力激素水平外，还将记录一系列焦虑的行为测量。这不仅能让我们更全面地了解压力反应，还能让我们确定化学物质的社会缓冲混合是否对压力反应的不同行为/激素成分有不同的影响。最令人兴奋的是，在大多数其他哺乳动物物种中都发现了对这些应激激素减少化学物质做出反应的同类OR37嗅觉受体。因此，如果我们能证明这些化学物质在老鼠身上有普遍的减轻压力的作用，它将开辟一个新的研究领域，寻找在包括人类在内的其他哺乳动物身上具有减轻压力作用的类似化学物质。这将产生巨大的潜在影响，不仅会改善农场、动物园和伴侣动物的福利，而且还会有多种潜在的医疗应用，可以提高动物和人类的健康和福祉。

Stress is a major factor affecting the health and welfare of captive animals. In addition to the ethical issues surrounding animal welfare, stress also decreases the quality of data obtained by the use of laboratory animals such as mice, increasing the number of animals used due to increased variability and decreased reliability. It is well established that the presence of other animals of the same species has beneficial welfare effects to reduce stress. Moreover, this social buffering effect of other individuals is largely mediated by chemical signals that are detected by the sense of smell. A mixture of three such chemicals has recently been shown to activate a specific type of smell receptor, known as OR37 receptors. Moreover, this mix of social buffering chemicals dramatically reduces activation of the hormonal stress response of mice placed in a novel environment. This occurs via activation of a direct brain pathway that inhibits cells that control the release of stress hormones. The overall aim of this project is to determine whether these social buffering chemicals have a general stress reducing effect in mice that could be utilized to reduce the stress experienced in the laboratory environment. We will firstly determine the optimum ratio and concentration of the three chemicals to reduce novelty-induced stress. We will go on to determine whether the mixture reduces the stress to other stressful situations, including learned anxiety responses and social isolation.A major focus of the project will be to use our established experimental protocols to determine whether these chemical signals reduce the stress and anxiety observed in mice in response to carbon dioxide exposure. This is particularly important, as millions of laboratory mice are killed each year by means of carbon dioxide euthanasia. In the absence of a more humane alternative to carbon dioxide, the discovery of an agent that could reduce stress associated with carbon dioxide euthanasia would have a major welfare impact. We will also study whether the social buffering mix of chemicals are effective against the stress-promoting effects of exposure to a mouse alarm pheromone, which is released during carbon dioxide euthanasia. In the last part of this study we aim to apply this knowledge to develop a less stressful carbon dioxide euthanasia procedure, as well as improvements to husbandry procedures to reduce the stress experienced by laboratory mice in other experimental contexts. A range of behavioural measures of anxiety will be recorded, in addition to measuring activation of stress-related brain regions and stress hormone levels. This will not only give us a more complete picture of the stress response, but will enable us to determine whether the social buffering mix of chemicals has differential affects on the different behavioural/hormonal components of the stress response.Most excitingly, the same class of OR37 smell receptors that respond to these stress hormone-reducing chemicals are found across most other mammalian species. Therefore, if we can show that these chemicals have a general stress reducing effect in mice, it will open up a new field of research to look for similar chemicals that have stress reducing effects in other mammals including humans. This would have enormous potential impact, to not only improve the welfare, of farmed, zoo and companion animals, but would also have multiple potential medical applications that could enhance both animal and human health and wellbeing.