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Repeated behavioral testing and the use of summary measures reveal trait anxiety in preclinical rodent models

ABSTRACT: The reliability and validity of preclinical anxiety testing is essential for translating animal research into clinical use. However, the commonly used anxiety tests lack inter-test correlations and face challenges with repeatability. While translational animal research should be able to capture stable individual anxiety traits - the core feature of anxiety disorders - the conventional approach employs a single type of test at a single time, which primarily reflects transient states of animals that are heavily influenced by experimental conditions. Here, we propose a validated, optimized test battery capable of reliably capturing trait anxiety in rats and mice of both sexes. Instead of developing novel tests, we combined widely used tests (elevated plus-maze, open field and light-dark test) to provide instantly applicable adjustments for better predictive validity. We repeated these tests three times to capture behavior across multiple challenges, which we combined to generate summary measures (SuMs). Our approach resolved inter-test correlation issues and provided better predictions for subsequent outcomes under more anxiogenic conditions or fear conditioning. SuMs were also shown to be more sensitive markers of stress-induced anxiety following social isolation. Finally, we tested our method's efficacy in discovering anxiety-related molecular pathways through RNA sequencing of the medial prefrontal cortex. SuMs revealed four-times more molecular correlates of trait anxiety than transient states, highlighting novel gene clusters. Furthermore, 16% of these correlates were also found in the amygdala. In summary, we provide a novel approach to capture trait anxiety in rodents, offering improved predictions for potential therapeutic targets for personalized medicine. We also provide recommendations to enhance feasibility without compromising validity or animal ethics, tailored to various scientific goals.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE240493 | GEO | 2025/11/05

REPOSITORIES: GEO

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Project description:Aggression among group housed male mice continues to challenge laboratory animal researchers because mitigation strategies are generally applied at the cage level without a good understanding of how it affects the dominance hierarchy. Aggression is typically displayed by the dominant mouse, targeting lower ranking subordinates, thus strategies may be more successful if applied specifically to the dominant mouse. Unfortunately, dominance rank is often not assessed because of time intensive observations or tests. Several dominance measures have been developed, but none directly compared to home cage behavior in standard housing. This study assessed the convergent validity of three dominance measures (urinary darcin, tube test score, preputial gland to body length ratio) with wound severity and rankings based on home cage behavior, using factor analysis. Discriminant validity with open field measures was assessed to determine if tube test scores are independent from anxiety. Cages were equally split between SJL and albino C57BL/6 strains and group sizes of 3 or 5 (N=24). During the first week, home cage behavior was observed, and the dominance measures were recorded over the second week. After controlling for strain and group size, darcin and preputial ratio had strong loadings on the same factor as home cage ranking and were significant predictors of home cage ranking showing strong convergent validity. Tube test scores were not significantly impacted by open field data, showing discriminant validity. Social network analysis was also done to reveal that despotic power structures were prevalent, aggressors were typically more active and rested away from cage mates, and the amount of social investigation and aggression performed by an individual were highly correlated. Data from this study show that darcin and preputial ratio are representative of home cage aggression and provide further insight on individual behavior patterns in group housed male mice.

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Repeated behavioral testing and the use of summary measures reveal trait anxiety in preclinical rodent models

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