Transcriptomic signatures in tetrapartite brain region identifies shared and unique gene signatures for substance-use.

Introduction: Chronic substance use is a neuropsychiatric disorder marked by persistent craving, reward seeking, and progression to addiction. The midbrain governs hunger, reward, and pleasure; the DLPFC modulates craving, decision making, and tolerance; the NAc influences feeding, reward, stress, and drug self-administration; and the amygdala regulates emotion and memory. Methods: To understand these complex and dynamic events in the context of substance use disorders, we profiled transcriptomes from these four regions and integrated clustering, biclustering, WGCNA, and pathway enrichment analyses. Results: Upregulation of gene expression was dominant in all four brain regions of cases versus controls. Distinct differential transcriptomic signatures were both unique to individual regions and shared across regions, identifying 186 genes exclusive to midbrain, 29 to DLPFC, 160 to NAc, and 442 in amygdala. Network analysis revealed DEGs across all regions interconnected via a neuropeptide-neurotransmitter axis, suggesting substances disrupt the equilibrium between neurotransmitters and neuropeptides. Significant upregulation of CSF3, GADD45B, SOCS3, and NPAS4 across all four regions enriched the CREB Signaling in Neurons pathway, supporting their involvement in long-lasting maladaptations of neurocircuitry due to chronic substance use. Discussion: By unraveling unique and shared transcriptomic signatures, our study advances understanding of crosstalk among key players in each brain region in substance use, implying that induction and exclusion signals drive distinct pathway signaling and sustain addiction behavior. Alongside known genes in substance biology and addiction, we also identified several novel biomarkers that could confer susceptibility for addiction risk.