Dysregulated Gene Regulatory Networks in Substance Use Disorder and HIV Infection: Insights from Single-Cell Genomics

Abstract Opioid use disorders (OUD) exacerbate the complexity of neurocognitive impairments and neurodevelopmental disorders, with poorly understood molecular mechanisms at the gene regulatory level. This study utilized single-nuclei RNA sequencing (snRNA-seq) data from the SCORCH (Single-Cell Opioid Responses in the Context of HIV) program, examining brain samples from 95 donors, including individuals with and without a history of opioid abuse, to explore the gene regulatory networks within the ventral tegmental area (VTA). While traditional differential gene expression analysis identified some significantly altered genes, including downregulation of FOS (p = 1.105e-3) in astrocytes from opioid users, our network-based approach revealed more profound disruptions in regulatory relationships. Most notably, correlation network analysis identified substantial alteration in FOS-centered regulatory networks, including complete loss of the FOS-NR4A1 connection despite unchanged NR4A1 expression levels. These findings suggest opioid-induced selective alterations in intracellular gene regulation, potentially contributing to addiction pathology and offering new insights into the molecular underpinnings of opioid-related neurocognitive dysfunction. This work expands our understanding of the mechanisms through which substance use disorders and HIV may synergistically impact brain function through altered gene regulatory networks, potentially revealing novel targets for therapeutic intervention. Competing Interest Statement The authors have declared no competing interest.