Prenatal THC exposure disrupts mitochondrial respiratory gene programs and delays medium spiny neuron maturation in the nucleus accumbens

Prenatal cannabis exposure (PCE) is increasingly prevalent and has been associated with adverse neurodevelopment outcomes, yet its molecular impact on brain reward circuitry remains poorly defined. Here, we investigated transcriptional and epigenomic alterations in the nucleus accumbens (NAc) following prenatal Δ ⁹ -tetrahydrocannabinol (THC) exposure in a rat model using snRNA-seq and snATAC-seq analyses. PCE markedly suppressed the expression of genes involved in mitochondrial oxidative phosphorylation in the NAc on postnatal day 24 (P24), consistent with impaired mitochondrial respiration capacity. This mitochondrial dysfunction was accompanied by coordinated alterations in ribosomal and proteasomal pathways regulating protein homeostasis in NAc medium spiny neurons (MSNs), indicating coupled disruption of cellular metabolism and neuronal maturation. snATAC-seq analysis revealed altered chromatin accessibility at promoter regions enriched with NRF1 and YY2 binding motifs, highlighting the importance of transcriptional regulation of mitochondrial gene in MSNs after PCE. Moreover, an acute THC challenge in PCE offspring at P24 further exacerbated mitochondrial dysfunction and delayed MSN maturation. Together, these findings define a transcriptional and epigenetic framework through which PCE perturbs mitochondrial function and impairs MSN maturation in the NAc, providing mechanistic insights into how PCE may alter the development of reward circuity.