C57BL/6 mice as a preclinical model to study age-related cognitive deficits: Executive functions impairment and inter-individual differences

Objectives: The aim of this study was to characterize age-related deficits of mice using different behavioral endpoints, with a focus on executive function and performance heterogeneity. Methods: 2 month-old and 18 month-old C57BL/6J mice were tested in the novelty-based spatial preference Y-maze test and in sequential tasks in the Morris water maze test (reference memory, reversal learning and working memory), before being evaluated for motor skills in the activity meter and accelerating rotarod tests. Results: Aged mice displayed an almost normal acquisition in the water maze test, however, difficulties were observed in ability to perform reversal learning and working memory tasks. A marked heterogeneity characterized the performances of aged mice in both Morris water maze and Y-maze tests. Good and poor performers were observed in aged mice although the number of these mice varied depending on the cognitive parameter considered. Conclusion: Aged mice display deficits in executive function and working memory, with varying severity between individual subjects, something that is also observed in other older animals and humans. Taking into account the heterogeneity in aged subjects within the experimental design of studies evaluating pharmacological treatments represents a promising way to improve the translational value of preclinical studies. In future studies, preselection of poor performers administered with cognitive enhancers and use of good performers as controls is suggested so that all cohorts of aged mice show similar physical and motor characteristics.