This application is responsive to PAR-15-120 (Identification of Genetic and Genomic Variants by Next-Gen Sequencing in Non-Human Animal Models). Substance use disorders are often characterized by heightened preference for small, immediate over larger, delayed rewards (?delay discounting?). Research has successfully related this type of impulsive decision- making bias with etiological factors predictive of drug use, with the progression to regular use, and with the likelihood of succeeding in cessation efforts. Research has also begun to identify the neural and genetic correlates of delay discounting. However, research identifying the specific genes associated with this phenotype remains ambiguous. Accordingly, the primary objective of the proposed work is to increase our understanding of the genetic basis of delay discounting, thereby providing a better understanding of impulsivity.
Four aims are proposed to accomplish this objective.
Aim 1 will phenotype 600 heterogeneous stock (HS) rats for delay discounting using the adjusting amount procedure (Richards et al. 1997; Wilhelm and Mitchell 2009) so that Genotyping-By-Sequencing (GBS) can detect behavioral quantitative trait loci (bQTLs).
Aim 2 will use bi-directional short-term selective breeding on a subset of these HS rats to form high (HD) and low (LD) delay discounting selected lines based on relative preference for the small, immediate reward over the larger later reward. Rats from the 4th generation of selection will be used to identify changes in allele frequency due to selection by genotyping the LD and HD selected lines using GBS and gene dropping.
Aim 3 will sequence the brain transcriptome in 200 phenotyped HS rats to characterize the gene expression signatures for delay discounting in three brain regions of interest: nucleus accumbens core, the prelimbic cortex and the basolateral amygdala. The sufficiency of these signatures to predict selection targets will be evaluated by analyzing the transcriptomes (RNA-Seq) from HD and LD selected lines at the 4th generation of selection collected under Aim 2.
Aim 4 will examine HD and LD rats' performance on other measures of impulsivity, including performance on a within sessions measure of delay discounting, the stop signal task and the 5-choice serial reaction time task. This will permit us to examine genetic correlates of delay discounting, and lay a foundation for research examining the shared genetic bases of these other behavioral phenotypes of impulsivity. Identifying the genotype and functional genetics for expression of high or low levels of delay discounting will facilitate identification of individuals at risk for developing substance use disorders and other psychopathologies. It will provide information about the transcriptomics of impulsive choice, and encourage future explorations of the neurogenetics of this type of decision-making bias.
High levels of impulsivity have been clearly associated with numerous psychopathologies, including substance use disorders (SUDs). Both preclinical and clinical data provide convincing evidence that impulsivity is heritable. By identifying the critical genes, we will be able to detect individuals genetically-predisposed to extreme levels of impulsivity early in their life, possibly preventing them developing a SUD, gaining information about the mechanisms that cause individuals to behave impulsively, and pointing the way to novel SUD treatment strategies.
