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

非人类的动物（以下简称动物）在它们的围栏里会变得奇怪的不活跃，一动不动（尽管是醒着的），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，减少活动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该疾病的常见触发因素，并且表现出清醒不活动的动物通常经历了一系列压力源，例如生活在社交和/或空间受限的环境中。因此，我们提出，在动物中，特定形式的清醒不活动，其特征是睁着眼睛不动，代表了抑郁样条件的标志。这个项目建立在我们已经在小鼠Mus musculus中描述了一种特定形式的清醒不活动[醒着但在笼子里不动]的研究基础上，由相对贫瘠的实验室笼子引发，并与人类疾病的一个关键抑郁症样症状有关：面对挑战时放弃的倾向。我们的目标是进一步验证这一假设，即清醒时的不活动是小鼠的一种自发性抑郁样症状，这将是一个容易测量的动物福利指标，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”的方法，将抑郁的人作为不活跃小鼠的“模型”。因此，预期动物抑郁样病症的潜在标志物与动物中类似于人类抑郁症中描述的一系列症状共变。此外，动物的状况要被认为与人类的疾病同源，动物和人类陷入这种状态和从这种状态中解脱出来的过程必须具有相似性。如果清醒的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[清醒时的不活动是由引发人类临床抑郁症的风险因素组合引发的吗？]，症状相似性[清醒时的不活动是否与人类临床抑郁症的一系列症状相似？]，和常见的治疗因素[清醒时的不活动是否通过临床有效的治疗而减轻？]。认知症状是人类抑郁症的常见部分。然而，在动物中需要一种快速而简单的抑郁样状态的认知测量，因此我们将首先在小鼠中验证这种测量，然后使用它来评估小鼠清醒时不活动和人类抑郁症之间的症状相似性。如果得到证实，我们的结果将验证笼内清醒时不活动作为小鼠抑郁样状态的标志。这对动物福利有明显的影响，因为如果我们要在原位检测福利问题，评估改进的有效性，并最大限度地提高实验室动物的福利，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，检测抑郁样状态的能力也具有重要意义，因为处于负面情感状态的小鼠可能代表了人类抑郁症的改进模型，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，非侵入性的工具来测量情感状态将感兴趣的动物福利科学家，神经科学家和精神药理学家感兴趣的动物影响的评估;生物医学科学家的研究可能会受到自发发生的抑郁样状态在他们的主题动物;和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.