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Abstract
Impulsivity is associated with a spectrum of psychiatric disorders including drug addiction. To investigate genetic associations with impulsivity and initiation of drug taking, we took a two-step approach. First, we identified genes whose expression level in prefrontal cortex, striatum and accumbens were associated with impulsive behavior in the 5-choice serial reaction time task across 10 BXD recombinant inbred (BXD RI) mouse strains and their progenitor C57BL/6J and DBA2/J strains. Behavioral data were correlated with regional gene expression using GeneNetwork (www.genenetwork.org), to identify 44 genes whose probability of association with impulsivity exceeded a false discovery rate of < 0.05. We then interrogated the IMAGEN database of 1423 adolescents for potential associations of SNPs in human homologs of those genes identified in the mouse study, with brain activation during impulsive performance in the Monetary Incentive Delay task, and with novelty seeking scores from the Temperament and Character Inventory, as well as alcohol experience. There was a significant overall association between the human homologs of impulsivity-related genes and percentage of premature responses in the MID task and with fMRI BOLD-response in ventral striatum (VS) during reward anticipation. In contrast, no significant association was found between the polygenic scores and anterior cingulate cortex activation. Univariate association analyses revealed that the G allele (major) of the intronic SNP rs6438839 in the KALRN gene was significantly associated with increased VS activation. Additionally, the A-allele (minor) of KALRN intronic SNP rs4634050, belonging to the same haplotype block, was associated with increased frequency of binge drinking.
Highlights
MATERIALS AND METHODSThe ability to inhibit inappropriate or undesirable responses plays a fundamental role in successful human behavior
No differences in impulsivity were found between B6 and D2 mice during baseline conditions, upon the introduction of the long inter-trial interval (ITI) sessions, in which all strains increased premature responding, we found B6 mice to display higher levels of premature responding than D2 mice, which showed the lowest value of all the strains tested; B6 mice showed intermediate values of impulsivity in comparison with other strains
Using a two-stage translational approach, we first identified 42 genes whose expression level in prefrontal cortex across mouse strains correlated with impulsive behavior, and studied their association with human adolescent impulsivity
Summary
MATERIALS AND METHODSThe ability to inhibit inappropriate or undesirable responses plays a fundamental role in successful human behavior. Recent advances in neuropsychological testing, which include neuroimaging as well as psychometric characterizations, allow more objective and precise assessments of those separate aspects of impulsivity Such assessments suggest distinct behavioral endophenotypes for impulsive behaviors (Robbins et al, 2012) and provide the opportunity for integration of data obtained from putatively homologous measures in animal and human subjects (Sanchez-Roige et al, 2014a). We examined potential associations of these candidate genes with a related measure of impulsivity, as well as with risk taking and alcohol use in human adolescence, a time when limited experience of drug or alcohol abuse was unlikely to have contributed to the development of loss of control by impairing fronto-striatal function. We hoped to identify potential genetic factors that contribute to experimentation with, and abuse of, alcohol at an early stage
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