Validating inactivity in the home-cage as a depression-like state indicator in mice

非人类动物（以下简称动物）在它们的围栏里会变得奇怪地不活跃，一动不动（尽管醒着），不与它们的环境互动。然而，与这种清醒的不活动相关的情感状态仍然没有得到很好的理解。令人信服的是，活动减少和缺乏与环境的接触是支持人类临床抑郁症诊断的一种现象。此外，人类抑郁症的病因学强调，令人厌恶的生活事件和慢性压力是这种疾病的常见诱因，而表现出清醒时不活动的动物通常经历了一系列的压力源，比如生活在社交和/或空间受限的环境中。因此，我们提出，在动物中，清醒时不活动的特定形式，其特征是一动不动，睁着眼睛，代表了类似抑郁症的症状。这个项目建立在我们的研究基础上，我们已经在老鼠身上描绘了一种特定形式的清醒不活动（在家里的笼子里清醒但不动），由相对贫瘠的实验室笼子引发，并与人类疾病的一种类似抑郁症的关键症状有关：面对挑战时倾向于放弃。我们的目标是进一步验证这一假设，即清醒时不活动是小鼠自发的类似抑郁的症状，这将是一个容易测量的动物福利的家庭笼子指标，可以跨物种翻译。为了实现这一目标，我们将采用一种“从人类到动物”的转化方法，用抑郁的人作为不活跃的老鼠的“模型”。因此，动物类抑郁症的潜在标志可能与动物中与人类抑郁症相似的一系列症状共同变化。此外，如果一种动物的状态被认为与人类的疾病是同源的，那么动物和人类陷入这种状态以及从这种状态中解脱出来的过程必须有相似之处。如果清醒时不活动反映了小鼠的抑郁样状态，那么其风险和治疗因素应该与人类疾病相似。因此，我们的研究将广泛针对共同的病因学[清醒时不活动是由多种危险因素共同引发的人类临床抑郁症吗？，症状相似性[清醒时不活动是否与一系列类似于人类临床抑郁症的症状共同变化？和常见的治疗因素[是否通过临床有效的人类治疗来减轻清醒不活动？]。认知症状是人类抑郁症的常见部分。然而，在动物身上需要一种快速而简单的抑郁状态认知测量方法，因此我们将首先在小鼠身上验证这种测量方法，然后用它来评估小鼠清醒时不活动与人类抑郁之间的症状相似性。如果得到证实，我们的结果将证实笼中清醒不活动是小鼠抑郁样状况的标志。这对动物福利有明确的影响，因为如果我们要在现场发现福利问题，评估改进的有效性，并最大限度地提高实验动物的福利，首先需要识别精神痛苦状态的有效方法。从研究的角度来看，检测类似抑郁状态的能力也具有至关重要的意义，因为处于消极情感状态的老鼠可能代表了人类抑郁的改进模型，同时可能使压力和抑郁不感兴趣的研究无效。因此，一种新的、非侵入性的测量情感状态的工具将引起动物福利科学家、神经科学家和对动物情感评估感兴趣的精神药理学家的兴趣；生物医学科学家的研究可能受到自发发生的抑郁样状态在他们的实验动物的影响；以及实验室管理人员和科学家寻求改善他们的研究动物的福利。

Non-human animals (hereafter animals) can become strangely inactive in their home pens, being motionless (although awake) and not interacting with their environment. The affective states associated with this waking inactivity are, however, still not well understood. Compellingly, reduced activity and lack of engagement with the environment is one phenomenon supporting clinical depression diagnosis in humans. Moreover, the aetiology of human depression emphasizes aversive life events and chronic stress as common triggers of the disorder, and animals showing waking inactivity have often experienced an array of stressors, such as living in socially and/or spatially restricted environments. We therefore propose that,in animals, specific forms of waking inactivity characterised by being immobile with eyes open represent a marker of depression-like conditions.This project builds upon our research that has already delineated in mice Mus musculus a specific form of waking inactivity [being awake but motionless within the home cage], triggered by relatively barren lab cages and associated with a key depression-like symptom of the human illness: the tendency to give up when faced with challenge. Our goal is to further test the hypothesis that waking inactivity is a spontaneous depression-like symptom in mice, which would be an easily measured home-cage indicator of animal welfare that could be translated across species. To achieve this goal, we will adopt a translational 'from humans to animals' approach, using depressed people as a 'model' for inactive mice. As such, potential markers of animal depression-like conditions are expected to co-vary with a range of symptoms in animals similar to those described in human depression. Moreover, for an animal condition to be deemed homologous to a human illness, the processes by which both animal and humans fall into, and are released from, this state must share similarities. If waking inactivity reflects depression-like states in mice, its risk and curative factors should thus be similar to those of the human disease. Our investigations will thus broadly target shared aetiology [is waking inactivity triggered by a combination of risk factors triggering clinical depression in humans?], symptomatic similarities [does waking inactivity co-vary with a range of symptoms similar to those of clinical depression in humans?], and common curative factors [is waking inactivity alleviated by treatments clinically efficient in humans?]. Cognitive symptoms are a frequent part of depression in humans. A quick and easy cognitive measure of depression-like states is however needed in animals, and we will thus first validate such a measure of in mice, and then use this later to assess the symptomatic similarities between waking inactivity in mice and depression in humans.If confirmed, our results will validate in-cage waking inactivity as a marker of a depression-like condition in mice. This has clear implications for animal welfare, as validated methods of identifying states of mental suffering are first required if we are to detect welfare problems in situ, assess the effectiveness of refinements, and maximise the welfare of lab animals. The ability to detect depression-like states also has crucial implications from a research perspective, since mice in negative affective states may for instance represent improved models of human depression, while potentially invalidating research where stress and depression are not of interest. A new, non-invasive tool to measure affective states will thus be of interest to animal welfare scientists, neuroscientists & psychopharmacologists interested in the assessment of animal affect; biomedical scientists whose research may be impacted by spontaneous occurrence of depression-like states in their subject animals; and laboratory managers & scientists seeking to improve welfare of their research animals.