Abstract
Impulsivity describes the tendency to act prematurely without appropriate foresight and is symptomatic of a number of neuropsychiatric disorders. Although a number of genes for impulsivity have been identified, no study to date has carried out an unbiased, genome-wide approach to identify genetic markers associated with impulsivity in experimental animals. Herein we report a linkage study of a six-generational pedigree of adult rats phenotyped for one dimension of impulsivity, namely premature responding on the five-choice serial reaction time task, combined with genome wide sequencing and transcriptome analysis to identify candidate genes associated with the expression of the impulsivity trait. Premature responding was found to be heritable (h2 = 13–16%), with significant linkage (LOD 5.2) identified on chromosome 1. Fine mapping of this locus identified a number of polymorphic candidate genes, however only one, beta haemoglobin, was differentially expressed in both the founder strain and F6 generation. These findings provide novel insights into the genetic substrates and putative neurobiological mechanisms of impulsivity with broader translational relevance for impulsivity-related disorders in humans.
Highlights
Impulsivity describes the tendency to act prematurely without appropriate foresight and is symptomatic of a number of neuropsychiatric disorders
The proportion of high impulsive (HI) rats produced in each litter was significantly greater in litters selectively bred for HI than low impulsive (LI) (Fig. 2B; main effect of breeding F(1,39) = 11.26,p < 0.01) and while there was a trend for a change in this proportion over successive generations, this was not significant (F(4,39) = 2.466, p = 0.07)
The average quantitative magnitude of the impulsivity phenotype was found to be significantly greater in HI offspring of parents bred selectively bred for HI compared to LI, while no difference was observed for LI offspring of either lineage (main effect of breeding F(1,69) = 11.087, p
Summary
Impulsivity describes the tendency to act prematurely without appropriate foresight and is symptomatic of a number of neuropsychiatric disorders. We report a linkage study of a six-generational pedigree of adult rats phenotyped for one dimension of impulsivity, namely premature responding on the five-choice serial reaction time task, combined with genome wide sequencing and transcriptome analysis to identify candidate genes associated with the expression of the impulsivity trait. Premature responding was found to be heritable (h2 = 13–16%), with significant linkage (LOD 5.2) identified on chromosome 1 Fine mapping of this locus identified a number of polymorphic candidate genes, only one, beta haemoglobin, was differentially expressed in both the founder strain and F6 generation. To investigate further the genetic mechanisms of impulsivity we assessed the heritability of a single quantitative measure of impulsivity in male and female rats, premature responding on the 5-choice serial reaction time task (5CSRTT). Microarray- based gene expression profiling of brain regions previously implicated in impulsive behavior on the 5CSRTT (i.e. NAcbC, NAcbS, PFC) was subsequently carried out to reveal differentially-expressed genes with underlying sequence variation within the linkage region
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