Differentially expressed gene networks, biomarkers, long noncoding RNAs, and shared responses with cocaine identified in the midbrains of human opioid abusers

Saad, Manal H.; Rumschlag, Matthew; Guerra, Michael H.; Savonen, Candace; Jaster, Alaina M; Olson, Philip D.; Alazizi, Adnan; Luca, Francesca; Piqué-Regi, Roger; Schmidt, Carl J.; Bannon, Michael J.

doi:10.1038/s41598-018-38209-8

Cited by 37 publications

(53 citation statements)

References 52 publications

(68 reference statements)

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“…YBX3 regulates the expression of the large neutral amino acid transporter 1 (LAT1)(90), which is necessary for the uptake of catecholamine precursor, L-DOPA in dopaminergic cells (91). Interestingly, changes in the expression of YBX3 in human midbrain has previously been implicated in opioid dependence (92). Together, our data provides further evidence that there are direct associations between neuroinflammation and OUD.…”

Section: Increased Connectivity Of Neuroinflammatory and Ecm Signalinmentioning

confidence: 61%

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

Seney

Moon-Kim

Glausier

et al. 2020

Preprint

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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, we still have a very limited understanding of the biological changes that occur in the brains of people who chronically use opioids and who are diagnosed with OUD. To address this, we conducted the largest transcriptomics study to date using postmortem brains from subjects with OUD. We focused on the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), two regions heavily implicated in OUD. We discovered a high degree of overlap in transcripts between DLPFC and NAc in OUD, primarily associated with neuroinflammation. Moreover, additional transcripts were enriched for factors that control pro-inflammatory cytokine-mediated signaling and remodeling of the extracellular matrix (ECM). Our results also implicate a role for microglia as a critical driver for opioid-induced neuroplasticity. Overall, our findings reveal new connections between the brain’s immune system and opioid dependence in the human brain.

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Section: Increased Connectivity Of Neuroinflammatory and Ecm Signalinmentioning

confidence: 61%

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

Seney

Moon-Kim

Glausier

et al. 2020

Preprint

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“…In light of the current study, we suggest various directions for future 432 research. Relatively large post-mortem human brain samples are publically 433 available for alcohol 39 and opiates 40 and could be integrated with a multitude of 434 traits from model systems. Animal models of compulsive drug use (e.g., escalated 435 use, aversion resistant users etc.)…”

Section: Discussion 343mentioning

confidence: 99%

Meso-limbic Gene Expression Findings from Mouse Cocaine Self-Administration Recapitulate Human Cocaine Use Disorder

Huggett

Bubier

Chesler

et al. 2020

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Animal models of drug use have been employed for over 100 years to facilitate the 10 identification of mechanisms governing human substance use and addiction. Most 11 cross-species research on drug use/addiction examines behavioral overlap, but 12 studies assessing neuro-molecular correspondence are lacking. Our study utilized 13 transcriptome-wide data from the hippocampus and ventral tegmental area 14 (VTA)/midbrain from a total of 35 human males with cocaine use disorder/controls 15 and 49 male C57BL/6J cocaine/saline administering/exposed mice. We 16hypothesized that individual genes (differential expression) and systems of co-17 expressed genes (gene networks) would demonstrate appreciable overlap across 18 mouse cocaine self-administration and human cocaine use disorder. We found 19modest, but significant associations between differentially expressed genes 20 associated with cocaine self-administration (short access) and cocaine use disorder 21 within meso-limbic circuitry, but non-robust associations with mouse models of 22 acute cocaine exposure, (cocaine) context re-exposure and cocaine + context re-23 exposure. Investigating systems of co-expressed genes, we also found several 24 validated gene networks with weak to moderate conservation between 25 cocaine/saline self-administering mice and disordered cocaine users/controls. The 26 most conserved hippocampal and VTA gene networks demonstrated substantial 27 overlap (2,029 common genes) and included novel and previously implicated 28 targets of cocaine use/addiction. Lastly, we conducted expression-based phenome-29 wide association studies of the nine common hub genes across conserved gene 30 networks and found that they were associated with dopamine/serotonin function, 31cocaine self-administration and other relevant mouse traits. Overall, our study 32 identified and characterized homologous transcriptional effects between mouse 33 models of cocaine self-administration and human cocaine use disorder that may 34 serve as a benchmark for future research. 35 36

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“…In an attempt to validate prior findings, we compared the effect sizes (i.e., log2 fold change) of the top genes identified by Saad et al (13) to the effect sizes of those same genes in the present analysis. Among the 545 genes differentially expressed in their study, 55 genes were not sequenced in our analysis and 15 did not survive our quality control, leading to 490 genes that overlapped across studies.…”

Section: Replication Of Prior Ewasmentioning

confidence: 80%

“…First, this analysis focuses on gene expression in the dlPFC. Although gene expression has been studied in the midbrain (13), and both the midbrain and dlPFC are implicated in addiction, evidence suggests that gene expression varies across brain regions (14). Second, the present analysis contains data on cell composition and comorbid psychiatric diagnosis, accounting for primary sources of confounding.…”

Section: Introductionmentioning

confidence: 99%

Differential Expression of NPAS4 in the Dorsolateral Prefrontal Cortex Following Acute Opioid Intoxication

Sosnowski

Jaffe

Tao

et al. 2020

Preprint

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Background and AimsThe physical, emotional, and social impacts of opioid abuse are well known; although preclinical models reveal the neurobiological pathways altered through opioid abuse, comprehensive assessments of gene expression in human brain samples are lacking. The goals of the present study were to compare gene expression in the prefrontal cortex between brain samples of individuals who died of acute opioid intoxication and group-matched controls, and to test if differential gene expression was enriched in gene sets related to opioid use.DesignCross-sectional study using human brains donated to the Lieber Institute for Brain Development. Study groups included 72 brain samples from individuals who died of acute opioid intoxication, 53 group-matched psychiatric control samples, and 28 group-matched normal control samples.SettingMaryland, USA.ParticipantsPostmortem tissue samples of the dorsolateral prefrontal cortex from 153 deceased individuals (Mage = 35.42, SD = 9.43 years; 62% male; 77% White).MeasurementsWhole transcriptome RNA sequencing was used to generate exon counts, and differential expression was tested using limma-voom. Analyses controlled for relevant sociodemographic characteristics, technical covariates, and cryptic relatedness and batch effects using quality surrogate variable analysis. Gene set enrichment analyses (GSEA) also were conducted.FindingsSixteen genes were differentially expressed (i.e., FDR-corrected p < .10) in opioid samples compared to control samples. The top differentially expressed gene, NPAS4 (FDR adjusted p = .005), was downregulated in opioid samples and has previously been implicated in cocaine use. Enrichment analyses did not provide evidence for enrichment in pathways obviously related to opioid use.ConclusionsNPAS4 is differentially expressed in the prefrontal cortex of subjects that died of an opioid overdose, providing evidence for another gene with functional relevance to opioid use and overdose.

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Differentially expressed gene networks, biomarkers, long noncoding RNAs, and shared responses with cocaine identified in the midbrains of human opioid abusers

Cited by 37 publications

References 52 publications

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

Meso-limbic Gene Expression Findings from Mouse Cocaine Self-Administration Recapitulate Human Cocaine Use Disorder

Differential Expression of NPAS4 in the Dorsolateral Prefrontal Cortex Following Acute Opioid Intoxication

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