QTL analysis identifies multiple behavioral dimensions in ethological tests of anxiety in laboratory mice

Background: Ethological tests of anxiety-related behaviors, such as the ope n field arena and elevated plus maze, are often carried out on transgenic a nimals in the attempt to correlate gene function with a behavioral phenotyp e. However, the interpretation of such tests is problematic, as it is proba ble that different tests measure different aspects of behavior; indeed, anx iety may not be a unitary phenomenon. Here, we address these questions by a sking whether behaviors in five ethological tests of anxiety are under the influence of a common set of genes. Results: Using over 1600 F2 intercross animals, we demonstrate that separat e, but overlapping, genetic effects can be detected that influence differen t behavioral dimensions in the open field, elevated plus maze, square maze, light-dark box, and mirror chamber. We find quantitative trait loci (QTLs) on chromosomes 1, 4, and 15 that operate in four tests of anxiety but can be differentiated by their action on behavior in threatening and nonthreate ning environments and by whether habituation of the animals to an aversive environment alters their influence. QTLs on chromosomes 7, 12, 14, 18, and X influenced a subset of behavioral measures. Conclusions: The chromosome 15 QTL acts primarily on avoidance behavior, th e chromosome 1 QTL influences exploration, and the QTL on chromosome 4 infl uences activity. However, the effects of loci on other chromosomes are not so readily reconciled with our current understanding of the psychology of a nxiety. Genetic effects on behaviors in these tests are more complex than e xpected and may not reflect an influence on anxiety.