Marianne L Seney1, Sam-Moon Kim2, Jill R Glausier3, Mariah A Hildebrand3, Xiangning Xue4, Wei Zong4, Jiebiao Wang4, Micah A Shelton3, BaDoi N Phan5, Chaitanya Srinivasan5, Andreas R Pfenning6, George C Tseng4, David A Lewis3, Zachary Freyberg7, Ryan W Logan8. 1. Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Center for Adolescent Reward, Rhythms, and Sleep, University of Pittsburgh, Pittsburgh, Pennsylvania. 2. Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Center for Adolescent Reward, Rhythms, and Sleep, University of Pittsburgh, Pittsburgh, Pennsylvania; Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, Bar Harbor, Maine. 3. Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 4. Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania. 5. Department of Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania. 6. Department of Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania; Neuroscience Institute, Carnegie Mellon University, Pittsburgh, Pennsylvania. 7. Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania. 8. Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, Bar Harbor, Maine; Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts; Center for Systems Neuroscience, Boston University, Boston, Massachusetts. Electronic address: rwlogan@bu.edu.
Abstract
BACKGROUND: Prevalence rates of opioid use disorder (OUD) have increased dramatically, accompanied by a surge of overdose deaths. While opioid dependence has been extensively studied in preclinical models, an understanding of the biological alterations that occur in the brains of people who chronically use opioids and who are diagnosed with OUD remains limited. To address this limitation, RNA sequencing was conducted on the dorsolateral prefrontal cortex and nucleus accumbens, regions heavily implicated in OUD, from postmortem brains in subjects with OUD. METHODS: We performed RNA sequencing on the dorsolateral prefrontal cortex and nucleus accumbens from unaffected comparison subjects (n = 20) and subjects diagnosed with OUD (n = 20). Our transcriptomic analyses identified differentially expressed transcripts and investigated the transcriptional coherence between brain regions using rank-rank hypergeometric orderlap. Weighted gene coexpression analyses identified OUD-specific modules and gene networks. Integrative analyses between differentially expressed transcripts and genome-wide association study datasets using linkage disequilibrium scores assessed the genetic liability of psychiatric-related phenotypes in OUD. RESULTS: Rank-rank hypergeometric overlap analyses revealed extensive overlap in transcripts between the dorsolateral prefrontal cortex and nucleus accumbens in OUD, related to synaptic remodeling and neuroinflammation. Identified transcripts were enriched for factors that control proinflammatory cytokine, chondroitin sulfate, and extracellular matrix signaling. Cell-type deconvolution implicated a role for microglia as a potential driver for opioid-induced neuroplasticity. Linkage disequilibrium score analysis suggested genetic liabilities for risky behavior, attention-deficit/hyperactivity disorder, and depression in subjects with OUD. CONCLUSIONS: Overall, our findings suggest connections between the brain's immune system and opioid dependence in the human brain.
BACKGROUND: Prevalence rates of opioid use disorder (OUD) have increased dramatically, accompanied by a surge of overdose deaths. While opioid dependence has been extensively studied in preclinical models, an understanding of the biological alterations that occur in the brains of people who chronically use opioids and who are diagnosed with OUD remains limited. To address this limitation, RNA sequencing was conducted on the dorsolateral prefrontal cortex and nucleus accumbens, regions heavily implicated in OUD, from postmortem brains in subjects with OUD. METHODS: We performed RNA sequencing on the dorsolateral prefrontal cortex and nucleus accumbens from unaffected comparison subjects (n = 20) and subjects diagnosed with OUD (n = 20). Our transcriptomic analyses identified differentially expressed transcripts and investigated the transcriptional coherence between brain regions using rank-rank hypergeometric orderlap. Weighted gene coexpression analyses identified OUD-specific modules and gene networks. Integrative analyses between differentially expressed transcripts and genome-wide association study datasets using linkage disequilibrium scores assessed the genetic liability of psychiatric-related phenotypes in OUD. RESULTS: Rank-rank hypergeometric overlap analyses revealed extensive overlap in transcripts between the dorsolateral prefrontal cortex and nucleus accumbens in OUD, related to synaptic remodeling and neuroinflammation. Identified transcripts were enriched for factors that control proinflammatory cytokine, chondroitin sulfate, and extracellular matrix signaling. Cell-type deconvolution implicated a role for microglia as a potential driver for opioid-induced neuroplasticity. Linkage disequilibrium score analysis suggested genetic liabilities for risky behavior, attention-deficit/hyperactivity disorder, and depression in subjects with OUD. CONCLUSIONS: Overall, our findings suggest connections between the brain's immune system and opioid dependence in the human brain.
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