miR-10a-5p as a critical molecular regulator of dopaminergic impulsivity in the nucleus accumbens

Abstract

Impulsive-compulsive disorders (ICDs), including pathological gambling, hypersexuality, and compulsive buying, are frequently precipitated by dopamine D2/3 receptor agonists such as pramipexole (PPX), yet the molecular mechanisms that confer individual vulnerability remain poorly understood. Impulsive choice, a core dimension of ICDs, is modulated by dopaminergic signaling within corticostriatal circuits, but the microRNAs (miRs) that potentially translate this signaling into persistent behavioral change have not been identified. Here, we combined a delay discounting task (DDT) with high-throughput miR sequencing in the dorsal striatum and nucleus accumbens (NAcc) of rats stratified by baseline impulsivity and subchronic PPX treatment. PPX increased impulsive choice selectively in low- and mid-impulsive rats, whereas high-impulsive rats remained unaffected, consistent with a ceiling effect. Among the differentially expressed miRs, miR-10a-5p emerged as the strongest candidate: it was constitutively elevated in high-impulsive rats and upregulated by PPX in low- and mid-impulsive animals in both regions, thereby paralleling the trait-dependent behavioral effect of the drug. In vivo viral-mediated overexpression of miR-10a-5p confirmed its predicted downregulation of the PI3K-AKT-mTOR and BDNF pathways in the striatum, and, critically, overexpression restricted to the NAcc, but not the dorsal striatum, was sufficient to increase impulsive choice, recapitulating the pro-impulsive effect of PPX. These findings identify miR-10a-5p as a critical molecular regulator of impulsivity through its activity in the NAcc, providing a mechanistic link between dopaminergic perturbation, trait vulnerability, and ICDs, and opening new avenues for the development of miR-directed therapeutic strategies for these disorders.