Romanò Nicola, Menzies John
Centre for Discovery Brain Sciences, Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Edinburgh, UK.
University of Edinburgh-Zhejiang University Joint Institute, Zhejiang University School of Medicine, Zhejiang University, Haining, China.
J Neuroendocrinol. 2025 Jun 11:e70051. doi: 10.1111/jne.70051.
Chronic variable stress (CVS) procedures are widely used to model depression in laboratory mice and rats. In order to explore how study design might impact experimental outcomes, we systematically documented characteristics of study design in a series of published rodent CVS studies and, in a subset of studies, measured effect sizes in the behavioural tests used to evaluate the effects of CVS. We hypothesised that CVS procedures that were longer or involved more stressors would be associated with larger effect sizes in five commonly used behavioural tests: the sucrose preference test (SPT), the tail suspension test (TST), the forced swim test (FST), the open field test (OFT) and the elevated plus maze (EPM). We also hypothesised that effect sizes would positively correlate between the behavioural tests that are believed to measure the same consequences of CVS. We searched PubMed for articles using CVS procedures with mice or rats and systematically documented the duration (the length of the CVS procedure), burden (the total number of stressors experienced by the animal) and diversity (the total number of different types of stressors used) of the CVS procedures used. We also systematically documented the design of the behavioural tests used to evaluate the effects of CVS in each study and calculated the effect sizes obtained in these tests. To ask whether effect sizes in these tests correlated with characteristics of the CVS procedure used, we used a linear model of the effect of duration, burden, and diversity on the effect size, then calculated the Euclidean distance between studies' characteristics and correlated those with the differences in effect size between studies. To explore whether effect sizes correlated between different behavioural tests, we calculated a pairwise Pearson correlation. We observed that most studies used a unique CVS procedure. In contrast to our hypothesis, the most evident impact of CVS procedure design was on FST effect sizes, where longer-duration CVS procedures with more diverse types of stressors were associated with a smaller effect size in behavioural tests. When exploring correlations between behavioural test effect sizes, we found a positive correlation between effect sizes in the TST and FST, and in the OFT and EPM, but the strongest positive correlations were between the EPM and TST, and between the EPM and FST. These data uncover complex relationships that are not necessarily in concordance with current understanding of what these tests measure. Accordingly, our data raise scientific questions around the design of CVS procedures used and the behavioural tests used to evaluate them.
慢性可变应激（CVS）程序被广泛用于在实验室小鼠和大鼠中模拟抑郁症。为了探究研究设计如何可能影响实验结果，我们系统地记录了一系列已发表的啮齿动物CVS研究中的研究设计特征，并在一部分研究中，测量了用于评估CVS效果的行为测试中的效应大小。我们假设，更长或涉及更多应激源的CVS程序在五个常用的行为测试中会与更大的效应大小相关：蔗糖偏好测试（SPT）、悬尾测试（TST）、强迫游泳测试（FST）、旷场测试（OFT）和高架十字迷宫（EPM）。我们还假设，在被认为测量CVS相同后果的行为测试之间，效应大小会呈正相关。我们在PubMed上搜索使用CVS程序对小鼠或大鼠进行研究的文章，并系统地记录所使用的CVS程序的持续时间（CVS程序的长度）、负担（动物经历的应激源总数）和多样性（使用的不同类型应激源的总数）。我们还系统地记录了每项研究中用于评估CVS效果的行为测试的设计，并计算了这些测试中获得的效应大小。为了询问这些测试中的效应大小是否与所使用的CVS程序的特征相关，我们使用了一个关于持续时间、负担和多样性对效应大小影响的线性模型，然后计算研究特征之间的欧几里得距离，并将其与研究之间效应大小的差异相关联。为了探究不同行为测试之间的效应大小是否相关，我们计算了成对的皮尔逊相关性。我们观察到大多数研究使用了独特的CVS程序。与我们的假设相反，CVS程序设计最明显的影响是对FST效应大小，在行为测试中，具有更多不同类型应激源的较长持续时间的CVS程序与较小的效应大小相关。在探究行为测试效应大小之间的相关性时，我们发现TST和FST的效应大小之间，以及OFT和EPM的效应大小之间存在正相关，但最强的正相关是在EPM和TST之间，以及EPM和FST之间。这些数据揭示了复杂的关系，这些关系不一定与目前对这些测试所测量内容的理解一致。因此，我们的数据围绕所使用的CVS程序的设计以及用于评估它们的行为测试提出了科学问题。
