Single-nucleus transcriptomics reveals convergent effects of THC exposure and Reelin signaling on nucleus accumbens maturation in adolescence

Abstract

The nucleus accumbens undergoes extensive maturation during adolescence, but how drug exposure and genetic vulnerability interact to shape this process remains poorly understood. Here, we used single-nucleus RNA sequencing to examine the effects of chronic adolescent tetrahydrocannabinol (THC) exposure and reduced Reelin signaling in mice. THC produced broader transcriptional changes than Reelin haploinsufficiency, particularly in medium spiny neurons (MSNs). Analysis of cell-cell communication identified a THC-sensitive signaling program in which inhibitory interneurons were the principal receivers of MSN-derived signals related to axon-guidance and synaptic maturation. Despite the dominant effect of THC, both perturbations converged on shared gene networks linked to human genetic risk for substance use and psychiatric disorders. These effects were strongest in a population of immature neurons that we confirmed are generated in the adolescent nucleus accumbens and decline in adulthood. These findings show that adolescent THC exposure and Reelin signaling converge on transcriptional programs that regulate late neuronal maturation in striatal circuits.