A Functional 3′UTR Polymorphism (rs2235749) of Prodynorphin Alters microRNA-365 Binding in Ventral Striatonigral Neurons to Influence Novelty Seeking and Positive Reward Traits

Abstract

Genetic factors impact behavioral traits relevant to numerous psychiatric disorders and risk-taking behaviors, and different lines of evidence have indicated that discrete neurobiological systems contribute to such individual differences. In this study, we explored the relationship of genetic variants of the prodynorphin (PDYN) gene, which is enriched in the striatonigral/striatomesencephalic pathway, a key neuronal circuit implicated in positive 'Go' behavioral choice and action. Our multidisciplinary approach revealed that the single nucleotide polymorphism (SNP) rs2235749 (in high linkage disequilibrium with rs910080) modifies striatal PDYN expression via impaired binding of miR-365, a microRNA that targets the PDYN 3′-untranslated region (3′UTR), and is significantly associated to novelty-and reward-related behavioral traits in humans and translational animal models. Carriers of the rs2235749G allele exhibited increased levels of PDYN 3′UTR in vitro and had elevated mRNA expression in the medial nucleus accumbens shell (NAcSh) and caudate nucleus in postmortem human brains. There was an association of rs2235749 with novelty-seeking trait and a strong genotype-dose association with positive reinforcement behavior in control subjects, which differed in cannabis-dependent individuals. Using lentiviral miRZip-365 constructs selectively expressed in Pdyn-neurons of the NAcSh, we demonstrated that the Pdyn-miR365 interaction in the NAcSh directly influences novelty-seeking exploratory behavior and facilitates self-administration of natural reward. Overall, this translational study suggests that genetically determined miR-365-mediated epigenetic regulation of PDYN expression in mesolimbic striatonigral/striatomesencephalic circuits possibly contributes to novelty seeking and positive reinforcement traits.

Sex differences in neural mechanisms mediating reward and addiction

“…Organizational influences: epigenetics. Although there is strong evidence for epigenetic regulation of Pdyn via DNA methylation and miRNAs within limbic brain regions [197,198], and Oprk1 via histone acetylation (acetylated histone H3 Lysine9) in the spinal cord [199], there is no direct evidence (to our knowledge) of sex differences in epigenetic regulation of either Pdyn or Oprk1.…”

Gender-specific association of functional <em>prodynorphin</em> 68 bp repeats with cannabis exposure in an African American cohort

“…This study therefore provides the first data on genetic associations of the functional 68 bp PDYN genotype, suggesting that this genotype influences the early stages of cannabis use in males and, potentially, the progression to heavy exposure. 41 – 43 …”

Molecular windows into the human brain for psychiatric disorders

“…Emphasizing this potential, a recent meta-analysis of over 1000 microarray profiles from several independent studies determined that many of the genes that were most robustly affected across studies were not previously underscored in ASD literature 78 . In addition to highlighting genes such as PDYN that have been shown to be relevant to other neuropsychiatric vulnerability, 43, 79 but never really emphasized previously in ASD despite validation in replication cohorts 80 , the meta-analysis revealed several novel genes suggesting a strong contribution of mitochondrial dysfunction to ASD 78 . These previously unreported genes are of significant interest since they emphasize a common transcriptome ASD signature that can be further explored mechanistically and that could offer potential future therapy development.…”