Conclusions from a behavioral aging study on male and female F2 hybrid mice on age-related behavior, buoyancy in water-based tests, and an ethical method to assess lifespan

Julia Adelöf,Jaime M Ross,John Wiseman,Stanley E Lazic,Madeleine Zetterberg,Malin Hernebring

doi:10.18632/aging.102242

Abstract

Due to strain-specific behavioral idiosyncrasies, inbred mouse strains are suboptimal research models for behavioral aging studies. The aim of this study is to determine age-related behavioral changes of F2 hybrid C57BL/6NxBALB/c male and female mice. Lifespan was followed (nmales=48, nfemales=51) and cohorts of mature adult (7 months), middle-aged (15 months), and old mice (22 months of age; n=7-12 per group) were assessed regarding open-field activity, exploration, passive avoidance learning/memory, and depressive-like behavior. We found that both males and females demonstrated decreased exploratory behavior with age, while memory and depressive-like behavior were maintained. Females exhibited enhanced depressive-like behavior compared to males; however, a correlation between fat mass and swimming activity in the test directly accounted for 30-46% of this behavioral sex difference. In addition, we suggest a method to qualitatively estimate natural lifespan from survival analyses in which animals with signs of pain or severe disease are euthanized. This is, to our knowledge, the first behavioral study to consider both sex and aging in hybrid mice. We here define decreased exploratory behavior as a conserved hallmark of aging independent of sex, highlight the effect of buoyancy in water tests, and provide a method to assay lifespan with reduced animal suffering.

Highlights

Mice are the leading mammalian model system for studying genetic effects on cognitive function and are well-suited model organisms for gerontological research with their relatively short lifespan and economic husbandry
C57BL/6N×BALB/c F2 female and male hybrid mice were followed in a lifespan study, strictly following Swedish animal ethics regulations; if an animal displayed signs of pain or severe disease the animal was euthanized
Since animals of severe disease are likely to live longer than the onset of disease, but not as long as healthy littermates, Survival Curve A is an underestimation of natural lifespan and Survival Curve B is an overestimation

Summary

Introduction

Mice are the leading mammalian model system for studying genetic effects on cognitive function and are well-suited model organisms for gerontological research with their relatively short lifespan and economic husbandry. Inbred strains can be problematic for aging research since they develop strain-specific maladies with advancing age and www.aging-us.com studies that intend to determine anti-aging effects might only pick up processes targeting these conditions. Inbred strains demonstrate age-related behavioral idiosyncrasies, e.g. coordination, learning capacity, and anxiety-like behavior, which can limit findings to the specific strain used [2, 3]. To ensure that these factors do not affect the results, it is considered favorable to use hybrid mice [4,5,6]. F2 hybrids are genetically similar but never uniformly homozygous, which reflects heterogenetic populations better than inbred mice and improves the extrapolation from mice to humans [5, 7]

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