Prenatal THC exposure disrupts mitochondrial respiratory gene programs and medium spiny neuron maturation trajectories in the nucleus accumbens.
Zhong Chen, Wanqiu Chen, Yun Seok Lee, Wendell Jones, Laura Goetzl, Jennifer Dawn Thomas, Yan Dong, Charles Wang
bioRxiv June 19, 2026 preprint DOI: 10.64898/2026.04.26.720961 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study |
|---|---|
| Population | Rats prenatally exposed to Δ9-tetrahydrocannabinol |
| Topics | Cannabis |
| Key findings | Prenatal THC exposure in rats suppressed mitochondrial oxidative phosphorylation genes and disrupted protein-homeostasis pathways in nucleus accumbens medium spiny neurons at postnatal day 24, with altered chromatin accessibility at Nrf1- and Yy2-enriched promoter regions. An acute THC challenge further exacerbated these effects, suggesting a transcriptional and epigenetic mechanism by which prenatal cannabis exposure may impair reward-circuitry development. |
Abstract
Prenatal cannabis exposure (PCE) is increasingly prevalent and has been associated with adverse neurodevelopmental 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 Δ9-tetrahydrocannabinol exposure in a rat model using snRNA-seq and snATAC-seq analyses. PCE markedly suppressed the expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) in the NAc on postnatal day 24 (P24), indicating reduced mitochondrial respiration capacity. This disrupted mitochondrial respiratory gene programming was accompanied by coordinated alterations in ribosomal and proteasomal pathways regulating protein homeostasis in NAc medium spiny neurons (MSNs), suggesting coupled disruption of cellular metabolism and neuronal maturation. snATAC-seq analysis revealed altered chromatin accessibility at promoter regions enriched for Nrf1 and Yy2 binding motifs, implicating Hrf1- and Yy2-associated transcriptional regulation of mitochondrial genes in MSNs following PCE. Moreover, an acute THC challenge in PCE offspring at P24 further exacerbated the suppression of genes involved in mitochondrial OXPHOS and MSN maturation. Together, these findings define a transcriptional and epigenetic framework through which PCE may perturb mitochondrial function and impair MSN maturation trajectories in the NAc, providing mechanistic insights into how PCE may alter the development of reward circuitry.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cites 3
- Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone Nature Neuroscience September 11, 2019
- Selective effects of Δ9-tetrahydrocannabinol on medium spiny neurons in the striatum. PLoS One 2018
- Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users. Journal of Neuroscience April 16, 2014