A Quantitative Trait Locus Influencing Anxiety in the Laboratory Rat

Abstract

A critical test for a gene that influences susceptibility to fear in animals is that it should have a consistent pattern of effects across a broad range of conditioned and unconditioned models of anxiety. Despite many years of research, definitive evidence that genetic effects operate in this way is lacking. The limited behavioral test regimes so far used in genetic mapping experiments and the lack of suitable multivariate methodologies have made it impossible to determine whether the quantitative trait loci (QTL) detected to date specifically influence fear-related traits. Here we report the first multivariate analysis to explore the genetic architecture of rodent behavior in a battery of animal models of anxiety. We have mapped QTLs in an F2 intercross of two rat strains, the Roman high and low avoidance rats, that have been selectively bred for differential response to fear. Multivariate analyses show that one locus, on rat chromosome 5, influences behavior in different models of anxiety. The QTL influences two-way active avoidance, conditioned fear, elevated plus maze, and open field activity but not acoustic startle response or defecation in a novel environment. The direction of effects of the QTL alleles and a coincidence between the behavioral profiles of anxiolytic drug and genetic action are consistent with the QTL containing at least one gene with a pleiotropic action on fear responses. As the neural basis of fear is conserved across species, we suggest that the QTL may have relevance to trait anxiety in humans.

Proteomic-based genotyping in a mouse model of trait anxiety exposes disease-relevant pathways

“…To test this hypothesis, an F2 panel, where both genotypes and phenotypes can freely segregate, was used as a means to identify functional associations between genetic and phenotypic features. 6,[32][33][34][35] In this study, we were able to show that the two SNPs in the EP gene quite likely contribute to both enzymatic activity and phenotype. Indeed, AA and TT mice spent significantly more time on the open arms of the EPM than did their GG and CC counterparts, thus confirming the hypothesized association between the SNPs, the EP isoform enzymatic activity, the metabolic consequences and their functional contribution to the phenotype.…”

Depressive-like behavior and stress reactivity are independent traits in a Wistar Kyoto × Fisher 344 cross

“…For example, while open arm entries in the elevated plus maze had low estimated heritabilities in a segregating F2 population between Lewis and SHR rats, 48 a significant quantitative trait locus has recently been found for this trait in an F2 intercross of Roman high and low avoidance rats. 65 Small phenotypic differences between the parent strains, and large variability in the phenotypic measures, can have undue influence over the heritability estimates. This point is illustrated for our traits with small estimated heritabilities (eg, female immobility and basal CORT), where the heritability standard errors were larger than the heritability estimates, suggesting the unreliability of these values.…”

The molecular genetic architecture of human personality: beyond self-report questionnaires

“…85,87,88 Further evidence for a putative involvement of chromosome 1p in anxiety-related personality traits is the identification of a syntenic rat locus on chromosome 5 that influences rodent emotionality. 89 …”