Publications by Author: David Potter

Anxiety disorders disproportionately affect women compared to men, which may arise from sex differences in stress responses. MiRNAs are small non-coding RNAs known to regulate gene expression through actions on mRNAs. MiRNAs are regulated, in part, by factors such as stress and gonadal sex, and they have been implicated in the pathophysiology of multiple psychiatric disorders. Here, we assessed putative sex differences in miRNA expression in the bed nucleus of the stria terminalis (BNST) - a sexually dimorphic brain region implicated in anxiety - of adult male and female rats that had been exposed to social isolation (SI) stress throughout adolescence. To assess the translational utility of our results, we assessed if childhood trauma in humans resulted in changes in blood miRNA expression that are similar to those observed in rats. Male and female Sprague-Dawley rats underwent SI during adolescence or remained group housed (GH) and were tested for anxiety-like behavior in the elevated plus maze as adults. Small RNA sequencing was performed on tissue extracted from the BNST. Furthermore, we re-analyzed an already available small RNA sequencing data set from the Grady Trauma Project (GTP) from men and women to identify circulating miRNAs that are associated with childhood trauma exposure. Our results indicated that there were greater anxiogenic-like effects and changes in BNST miRNA expression in SI versus GH females compared to SI versus GH males. In addition, we found nine miRNAs that were regulated in both the BNST from SI compared to GH rats and in blood samples from humans exposed to childhood trauma. These studies emphasize the utility of rodent models in studying neurobiological mechanisms underlying psychiatric disorders and suggest that rodent models could be used to identify novel sex-specific pharmacotherapies for anxiety disorders.

BACKGROUND: There is an urgent need to identify factors that increase vulnerability to opioid addiction to help stem the opioid epidemic and develop more efficient pharmacotherapeutics. MicroRNAs are small non-coding RNAs that regulate gene expression at a posttranscriptional level and have been implicated in chronic drug-taking in humans and in rodent models. Recent evidence has shown that chronic opioid treatment regulates the microRNA miR-9. The present study was designed to test the hypothesis that miR-9 in the nucleus accumbens potentiates oxycodone addictive-like behavior.

METHODS: We utilized adeno-associated virus (AAV) to overexpress miR-9 in the nucleus accumbens of male rats and tested the effects on intravenous self-administration of the highly abused prescription opioid, oxycodone, in 1-hour short-access followed by 6-h long-access sessions, the latter of which leads to escalation of drug intake. In separate rats, we assessed the effects of nucleus accumbens miR-9 overexpression on mRNA targets including RE1-silencing transcription factor (REST) and dopamine D2 receptor (DRD2), which have been shown to be regulated by drugs of abuse.

RESULTS: Overexpression of miR-9 in the nucleus accumbens significantly increased oxycodone self-administration compared with rats expressing a control, scrambled microRNA. Analysis of the pattern of oxycodone intake revealed that miR-9 overexpression increased "burst" episodes of intake and decreased the inter-infusion interval. Furthermore, miR-9 overexpression decreased the expression of REST and increased DRD2 in the nucleus accumbens at time points that coincided with behavioral effects.

CONCLUSIONS: These results suggest that nucleus accumbens miR-9 regulates oxycodone addictive-like behavior as well as the expression of genes that are involved in drug addiction.