Integrated behavioral z-scoring increases the sensitivity and reliability of behavioral phenotyping in mice: Relevance to emotionality and sex

Abstract

Defining anxiety- and depressive-like states in mice (“emotionality”) is best characterized by the use of complementary tests, leading sometimes to puzzling discrepancies and lack of correlation between similar paradigms. To address this issue, we hypothesized that integrating measures along the same behavioral dimensions in different tests would reduce the intrinsic variability of single tests and provide a robust characterization of the underlying “emotionality” of individual mouse, similarly as mood and related syndromes are defined in humans through various related symptoms over time. We describe the use of simple mathematical and integrative tools to help phenotype animals across related behavioral tests (syndrome diagnosis) and experiments (meta-analysis). We applied z-normalization across complementary measures of emotionality in different behavioral tests after unpredictable chronic mild stress (UCMS) or prolonged corticosterone exposure - two approaches to induce anxious-/depressive-like states in mice. Combining z-normalized test values, lowered the variance of emotionality measurement, enhanced the reliability of behavioral phenotyping, and increased analytical opportunities. Comparing integrated emotionality scores across studies revealed a robust sexual dimorphism in the vulnerability to develop high emotionality, manifested as higher UCMS-induced emotionality z-scores, but lower corticosterone-induced scores in females compared to males. Interestingly, the distribution of individual z-scores revealed a pattern of increased baseline emotionality in female mice, reminiscent of what is observed in humans. Together, we show that the z-scoring method yields robust measures of emotionality across complementary tests for individual mice and experimental groups, hence facilitating the comparison across studies and refining the translational applicability of these models.

Behavioral abnormalities in APPSwe/PS1dE9 mouse model of AD-like pathology: comparative analysis across multiple behavioral domains

“…In summary, we conclude that is possible to use a global index behavioral profile for mouse models of AD-like amyloidosis as a reliable diagnostic index reflecting compromised function in multiple behavioral domains. Such analytical approach of developing composite indices of performance was successfully applied in studies investigating the emotional behavior in mice (Guilloux et al, 2011), and in studies comparing complex home cage behavior between multiple mice strains (Vannoni et al, 2014). Our evaluation of the APP/PS1 indicates that this model displays abnormalities in both mnemonic and non-mnemonic behavioral systems at the age of robust brain amyloid pathology.…”

The Modified Hole Board - Measuring Behavior, Cognition and Social Interaction in Mice and Rats

“…In some cases this may lead to inconclusive results. Guilloux et al (2011) introduced integrated behavioral z-scores to the behavioral phenotyping in mice 24 . With the use of integrated behavioral z-scores the multiple parameters can be combined to a single z-score describing a particular motivational system.…”

Perinatal vs Genetic Programming of Serotonin States Associated with Anxiety

“…Prior to factor analysis, behavior data for each variable were normalized to same-sex/same-age/ treatment or genotype control groups. Standard score normalization was applied using the equation z ¼ (x À m)/ s, where x is the individual score, m is the mean for the appropriate control group, and s is the control group SD (Guilloux et al, 2011). Saline-treated SERT þ / þ mice were controls for postnatal SSRI-treated groups.…”

“…For global behavior analysis, standard score normalization was applied with respect to age and sex for each variable to combine data with different dynamic ranges and directions of change (Guilloux et al, 2011). Standard scores were weighted by coefficients proportional to their loadings in the factor analysis (Supplementary Table S3 The open field anxiety-like parameters, center time, and ratio of center to total distance traveled loaded on a separate factor ('Anxiety OFT').…”