MicroRNA–mRNA networks are dysregulated in opioid use disorder postmortem brain: Further evidence for opioid-induced neurovascular alterations

Abstract

IntroductionTo understand mechanisms and identify potential targets for intervention in the current crisis of opioid use disorder (OUD), postmortem brains represent an under-utilized resource. To refine previously reported gene signatures of neurobiological alterations in OUD from the dorsolateral prefrontal cortex (Brodmann Area 9, BA9), we explored the role of microRNAs (miRNA) as powerful epigenetic regulators of gene function.MethodsBuilding on the growing appreciation that miRNAs can cross the blood-brain barrier, we carried out miRNA profiling in same-subject postmortem samples from BA9 and blood tissues.ResultsmiRNA–mRNA network analysis showed that even though miRNAs identified in BA9 and blood were fairly distinct, their target genes and corresponding enriched pathways overlapped strongly. Among the dominant enriched biological processes were tissue development and morphogenesis, and MAPK signaling pathways. These findings point to robust, redundant, and systemic opioid-induced miRNA dysregulation with a potential functional impact on transcriptomic changes. Further, using correlation network analysis, we identified cell-type specific miRNA targets, specifically in astrocytes, neurons, and endothelial cells, associated with OUD transcriptomic dysregulation. Finally, leveraging a collection of control brain transcriptomes from the Genotype-Tissue Expression (GTEx) project, we identified a correlation of OUD miRNA targets with TGF beta, hypoxia, angiogenesis, coagulation, immune system, and inflammatory pathways.DiscussionThese findings support previous reports of neurovascular and immune system alterations as a consequence of opioid abuse and shed new light on miRNA network regulators of cellular response to opioid drugs.

Opioid Modulation of Differential Gene Expression and Neuronal Differentiation in the Ventricular-Subventricular Zone of Adult Male Zebra Finches

“…Our findings suggest that the levels of miR-124-3p, transiently upregulated during exposure to naloxone, favoured a shift towards the neuroblast stage from the neuronal precursor cells in the V-SVZ. These findings are supported by an earlier study which has demonstrated that miRNAs regulate mu-opioid receptors in rodents and humans [25]. Taken together, our findings underline the intimate involvement of mature miRNAs in modulating the effects of the endogenous opioid system on neurogenesis.…”

MicroRNA-mediated translational pathways are regulated in the orbitofrontal cortex and peripheral blood samples during acute abstinence from heroin self-administration

“…Only one such study has been performed with human samples, and this is likely due to the challenges of collecting blood and postmortem samples in a timely manner. Grimm et al reported the correspondence of frontal cortex brain and blood miRNA levels in postmortem human samples from OUD subjects and observed a large overlap in miRNA expression [ 65 ]. Of the miRNA profile measured in the BA9 region, the authors observed differential expression of hsa-miR-10b-5p, hsa-miR-337-3p, has-miR-340-5, hsa-miR-376a-3p, hsa-miR-376b-3p, hsa-miR-379-5p, hsa-miR-486-3p, hsa-miR-495-3p, and hsa-miR-758-3p [ 65 ], which were all dysregulated in the OFC of heroin-exposed rats in the current study.…”

“…Grimm et al reported the correspondence of frontal cortex brain and blood miRNA levels in postmortem human samples from OUD subjects and observed a large overlap in miRNA expression [ 65 ]. Of the miRNA profile measured in the BA9 region, the authors observed differential expression of hsa-miR-10b-5p, hsa-miR-337-3p, has-miR-340-5, hsa-miR-376a-3p, hsa-miR-376b-3p, hsa-miR-379-5p, hsa-miR-486-3p, hsa-miR-495-3p, and hsa-miR-758-3p [ 65 ], which were all dysregulated in the OFC of heroin-exposed rats in the current study. Investigation into the relationship between drug exposure and regulation of brain miRNAs that can also be detected in the periphery can be accomplished easily with rodent models of self-administration but has yet to be done.…”

Circadian rhythm disruptions associated with opioid use disorder in synaptic proteomes of human dorsolateral prefrontal cortex and nucleus accumbens

“…Recent work in postmortem brains of subjects with OUD from us [ 2 , 3 ] and others [ 4 , 6 , 9 , 10 ] have primarily focused on the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), key brain regions involved in cognition and reward, which are significantly impacted in OUD [ 11 – 13 ]. An interplay between inflammation and synaptic remodeling associated with OUD in both DLPFC and NAc has been a consistent finding across human postmortem brain studies [ 3 , 9 , 10 ]. Most recently, our work linked alterations in neuroinflammatory, dopaminergic, and GABAergic signaling in DLPFC and NAc of OUD subjects with significant disruptions in circadian rhythms of transcript expression [ 2 ].…”