Cell-type specific transcriptional adaptations of nucleus accumbens interneurons to amphetamine

Parvalbumin-expressing (PV+) interneurons of the nucleus accumbens (NAc) play an essential role in the addictive-like behaviors induced by psychostimulant exposure. To identify molecular mechanisms of PV+ neuron plasticity, we isolated interneuron nuclei from the NAc of male and female mice following acute or repeated exposure to amphetamine (AMPH) and sequenced for cell type-specific RNA expression and chromatin accessibility. AMPH regulated the transcription of hundreds of genes in PV+ interneurons, and this program was largely distinct from that regulated in other NAc GABAergic neurons. Chromatin accessibility at enhancers predicted cell-type specific gene regulation, identifying transcriptional mechanisms of differential AMPH responses. Finally, we assessed expression of PV-enriched, AMPH-regulated genes in an Mecp2 mutant mouse strain that shows heightened behavioral sensitivity to psychostimulants to explore the functional importance of this transcriptional program. Together these data provide novel insight into the cell-type specific programs of transcriptional plasticity in NAc neurons that underlie addictive-like behaviors.

Automated summary

This study found that amphetamine regulates the transcription of PV+ interneurons in the NAc and the regulation program is distinct from that of other GABAergic neurons in the NAc. Chromatin accessibility at enhancers predicts cell-type specific gene regulation, providing insight into transcriptional mechanisms. The functional importance of this transcriptional program was explored through expression assessment in a mouse strain with heightened behavioral sensitivity.