Single-Nucleus Transcriptomics Identifies Neuroblast Migration Programs Sensitive to Reelin and Cannabis in the Adolescent Nucleus Accumbens

The interplay between cannabis exposure during adolescence and genetic predisposition has been linked to increased vulnerability to psychiatric disorders. To investigate the molecular underpinnings of this interaction, we performed single-nucleus RNA sequencing of the nucleus accumbens (NAc) in a mouse model of Reln haploinsufficiency, a genetic risk factor for psychiatric disorders, following adolescent exposure to tetrahydrocannabinol (THC), the primary psychoactive component of cannabis. We identified a gene co-expression network influenced by both Reln genotype and THC, enriched in genes associated with human psychiatric disorders and predominantly expressed in a GABAergic neuroblast subpopulation. We showed that neuroblasts actively migrated in the adolescent NAc, but declined with age. Cell-to-cell communication analysis further revealed that these neuroblasts receive migratory cues from cholecystokinin interneurons, which express high levels of cannabinoid receptors. Together, these findings provide mechanistic insights into how adolescent THC exposure and genetic risk factors may impair GABAergic circuit maturation.