Social Factors Influence Behavior in the Novel Object Recognition Task in a Mouse Model of Down Syndrome.

Cesar Sierra,Lorenzo Lo Cascio,Mara Dierssen,Esteban Vegas,Ilario De Toma

doi:10.3389/fnbeh.2021.772734

Abstract

The use of mouse models has revolutionized the field of Down syndrome (DS), increasing our knowledge about neuropathology and helping to propose new therapies for cognitive impairment. However, concerns about the reproducibility of results in mice and their translatability to humans have become a major issue, and controlling for moderators of behavior is essential. Social and environmental factors, the experience of the researcher, and the sex and strain of the animals can all have effects on behavior, and their impact on DS mouse models has not been explored. Here we analyzed the influence of a number of social and environmental factors, usually not taken into consideration, on the behavior of male and female wild-type and trisomic mice (the Ts65Dn model) in one of the most used tests for proving drug effects on memory, the novel object recognition (NOR) test. Using principal component analysis and correlation matrices, we show that the ratio of trisomic mice in the cage, the experience of the experimenter, and the timing of the test have a differential impact on male and female and on wild-type and trisomic behavior. We conclude that although the NOR test is quite robust and less susceptible to environmental influences than expected, to obtain useful results, the phenotype expression must be contrasted against the influences of social and environmental factors.

Highlights

Behavioral testing is critical in rodent models of brain disorders, but there are numerous influences on behavioral measures, of which we are unaware
In the novel object recognition (NOR) paradigm, we detected slight hyperactivity in female Ts65Dn (TS) mice in the familiarization session that was not detected in the habituation or the test (Figure 1B, top left panel, Supplementary Table 2 and Supplementary Figure 1A)
Our work indicates that social factors, such as the litter composition, the ratio of trisomics, or animal density in the home cage, differentially affect the phenotype expression in trisomic and wild-type mice

Summary

Introduction

Behavioral testing is critical in rodent models of brain disorders, but there are numerous influences on behavioral measures, of which we are unaware. This leads to experimental variability from unknown sources reducing reproducibility and may be one of the reasons that preclinical studies in rodents are often not corroborated in humans. This is especially important for Down syndrome (DS), the most common genetic cause of intellectual disability. Even though specific guidelines, such as the ARRIVE or PREPARE guidelines, have addressed the design and conduct of in vivo animal experiments, and recently, the Trisomy 21 Research Society has adapted such guidelines to DS models (Roper et al, 2020), the use of thoroughly planned and well-reported protocols does not automatically guarantee the reproducibility of the study

Methods

Results

Discussion

Conclusion