“The wrong tools for the right job”: a critical meta-analysis of traditional tests to assess behavioural impacts of early life stress

Abstract Rationale: Unconditioned tasks in rodents have been the mainstay of behavioural assessment for decades, but their validity and sensitivity to detect the behavioural consequences of early life stress (ELS) remains contentious and highly variable. Objectives: In the present study, we carried out a meta-analysis to investigate whether persistent behavioural effects, as assessed using unconditioned procedures in rats, are a reliable consequence of early repeated maternal separation, a commonly used procedure in rodents to study ELS. Methods: A literature search identified 100 studies involving maternally separated rats and the following unconditioned procedures: the elevated plus maze (EPM); open field test (OFT); sucrose preference test (SPT) and forced swim task (FST). Studies were included for analysis if the separation of offspring from the dam was at least 60 min every day during the pre-weaning period prior to the start of adolescence. Results: Our findings show that unconditioned tasks are generally poor at consistently demonstrating differences between control and separated groups with pooled effect sizes that were either small or non-existent (EPM: Hedge’s g= -0.35, p=0.01, OFT: Hedge’s g= -0.32, p=0.05, SPT: Hedge’s g=-0.33, p=0.21, FST: Hedge’s g=0.99, p=0.0001). Despite considerable procedural variability between studies, heterogeneity statistics were low; indicating the lack of standardization in the maternal separation protocol was the not the cause of these inconsistent effects. Conclusions: Our findings indicate that unconditioned tests of depression and anxiety are unreliable for measuring the behavioural sequelae of ELS. We argue that more objective tasks that sensitively detect specific cognitive processes are better suited for translational research on stress-related disorders such as depression.