Single nucleus transcriptomics of ventral midbrain identifies glial activation associated with chronic opioid use disorder

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Sept. 12, 2023

Abstract Dynamic interactions of neurons and glia in the ventral midbrain mediate reward addiction behavior. We studied gene expression 212,713 single nuclei from 95 individuals with history opioid misuse, without drug exposure. Chronic exposure to opioids was not associated change proportions glial neuronal subtypes, however transcriptomes were broadly altered, involving 9.5 − 6.2% expressed genes within microglia, oligodendrocytes, astrocytes. Genes activation immune response including interferon, NFkB signaling, cell motility pathways upregulated, contrasting down-regulated synaptic signaling plasticity non-dopaminergic neurons. Ventral transcriptomic reprogramming context chronic included 325 that previous genome-wide studies had linked risk substance use traits broader population, thereby pointing heritable architectures genomic organization brain’s circuitry.

Language: Английский

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Extracellular matrix abnormalities in the hippocampus of subjects with substance use disorder

Translational Psychiatry, Journal Year: 2024, Volume and Issue: 14(1)

Published: Feb. 24, 2024

Contextual triggers are significant factors contributing to relapse in substance use disorders (SUD). Emerging evidence points a critical role of extracellular matrix (ECM) molecules as mediators reward memories. Chondroitin sulfate proteoglycans (CSPGs) subset ECM that form perineuronal nets (PNN) around inhibitory neurons. PNNs restrict synaptic connections and help maintain synapses. Rodent models suggest modulation may strengthen contextual memories SUD. However, there is currently lack information regarding the hippocampus people with SUD well how comorbidity major depressive disorder (MDD) affect PNNs. We used postmortem hippocampal tissues from cohorts human nonhuman primates or without chronic alcohol test hypothesis increased subjects histochemical labeling quantitative microscopy examine PNNs, qRT-PCR gene expression for molecules, markers related markers. identified densities CSPG-labeled glial cells SUD, coinciding decreased protease metalloproteinase 9 (Mmp9), excitatory marker vesicle associated membrane protein 2 (Vamp2). Similar increases were observed monkeys self-administration. Subjects MDD displayed changes opposite comorbid had minimal any outcome measures examined. Our findings demonstrate possibly stabilizing suggested by preclinical studies. results also point previously unsuspected CSPG Evidence suggests targeting weaken promising therapeutic approach however consideration.

Language: Английский

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Angiogenic gene networks are dysregulated in opioid use disorder: evidence from multi-omics and imaging of postmortem human brain

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 26(12), P. 7803 - 7812

Published: Aug. 12, 2021

Language: Английский

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Inflammatory Biomarkers in Addictive Disorders

Biomolecules, Journal Year: 2021, Volume and Issue: 11(12), P. 1824 - 1824

Published: Dec. 3, 2021

Substance use disorders are a group of diseases that associated with social, professional, and family impairment represent high socio-economic impact on the health systems countries around world. These present very complex diagnosis treatment regimen due to lack suitable biomarkers supporting correct classification difficulty selecting effective therapies. Over last few years, several studies have pointed out these addictive systemic central nervous system inflammation, which could play relevant role in onset progression diseases. Therefore, identifying different immune components as such be crucial step promote appropriate treatment. Thus, this work aims provide an overview alterations may various disorders.

Language: Английский

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Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder

Translational Psychiatry, Journal Year: 2022, Volume and Issue: 12(1)

Published: March 26, 2022

Abstract Severe and persistent disruptions to sleep circadian rhythms are common in people with opioid use disorder (OUD). Preclinical evidence suggests altered molecular the brain modulate reward relapse. However, whether disrupted brains of OUD remained an open question, critical understanding role addiction. Using subjects’ times death as a marker time day, we investigated transcriptional subjects compared unaffected comparison subjects. We discovered rhythmic transcripts both dorsolateral prefrontal cortex (DLPFC) nucleus accumbens (NAc), key areas involved OUD, that were largely distinct between Fewer identified DLPFC subjects, whereas NAc, nearly double number was OUD. In NAc peaked either evening or near sunrise, associated opioid, dopamine, GABAergic neurotransmission. Associations neurotransmission further supported by co-expression network analysis which OUD-specific modules enriched for GABA, glutamatergic synaptic functions. Additionally, genomic loci sleep-related GWAS traits, including duration insomnia. Collectively, our findings connect rhythm changes opioidergic, dopaminergic, signaling human traits

Language: Английский

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Adaptations in Nucleus Accumbens Neuron Subtypes Mediate Negative Affective Behaviors in Fentanyl Abstinence

Biological Psychiatry, Journal Year: 2022, Volume and Issue: 93(6), P. 489 - 501

Published: Aug. 30, 2022

Language: Английский

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

Frontiers in Psychiatry, Journal Year: 2023, Volume and Issue: 13

Published: Jan. 12, 2023

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

Language: Английский

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Identifying novel gene dysregulation associated with opioid overdose death: A meta-analysis of differential gene expression in human prefrontal cortex

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 13, 2024

Abstract Only recently have human postmortem brain studies of differential gene expression (DGE) associated with opioid overdose death (OOD) been published; sample sizes from these modest (N = 40-153). To increase statistical power to identify OOD-associated genes, we leveraged prefrontal cortex RNAseq data four independent OOD and conducted a transcriptome-wide DGE meta-analysis 285). Using unified processing analysis framework across studies, meta-analyzed 20LJ098 genes found 335 significant differentially expressed (DEGs) by status (false discovery rate < 0.05). Of these, 66 DEGs were among the list 303 reported as in prior molecular including genes/gene families (e.g., OPRK1, NPAS4 , DUSP, EGR ). The remaining 269 not previously NR4A2, SYT1, HCRTR2, BDNF There was little evidence genetic drivers for observed differences between addiction cases controls. Enrichment analyses pathway biological process databases highlight an interconnected set pathways orexin tyrosine kinase receptors through MEK/ERK/MAPK signaling affect neuronal plasticity.

Language: Английский

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Transcriptional impacts of substance use disorder and HIV on human ventral midbrain neurons and microglia

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

Abstract For people with HIV (PWH), substance use disorders (SUDs) are a prominent neurological risk factor, and the impacts of both on dopaminergic pathways potential point deleterious convergence. Here, we profile, at single nucleus resolution, substantia nigra (SN) transcriptomes 90 postmortem donors in context chronic opioid/cocaine SUD, including 67 prospectively characterized PWH. We report altered microglial expression for hundreds pro- anti-inflammatory regulators attributable to HIV, separately, SUD. Stepwise, progressive dysregulation, coupled SN GABAergic signaling, was associated SUD/HIV dual diagnosis further lack viral suppression blood. In virologically suppressed donors, SUD comorbidity transcriptional changes permissive infection. HIV-related downregulation monoamine reuptake transporters specifically neurons regardless status or load, additional signatures consistent selective vulnerability dopamine neurons.

Language: Английский

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Integrative genomics approach identifies glial transcriptomic dysregulation and risk in the cortex of individuals with Alcohol Use Disorder

Biological Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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