A Glitch in the Matrix: The Role of Extracellular Matrix Remodeling in Opioid Use Disorder

Ray, Madelyn H.; Williams, Benjamin R.; Kuppe, Madeline K.; Bryant, Camron D.; Logan, Ryan W.

doi:10.3389/fnint.2022.899637

Cited by 21 publications

(15 citation statements)

References 96 publications

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“…Considering that the AI is heavily weighted to prior behavior (i.e., before withdrawal), these results may indicate that the strongest ECM changes are state dependent and more specific to ongoing opioid use. These findings are consistent with previous reports that suggest that opioids induce various changes to ECM biology [reviewed in (35)], specifically, recent reports from human OUD patient that identified a key role for heroin-induced changes to ECM biology in promoting opioid use (15). Although ECM changes were most apparent from the AI and H24 conditions in this study, it is plausible that the processes affected by this remodeling may drive functional changes supporting relapse (37).…”

Section: Discussionsupporting

confidence: 93%

“…One major theme uncovered by these studies was heroininduced dysfunction in processes supporting ECM function throughout the reward circuit, which has been hypothesized to be a key component of substance use disorders (33)(34)(35)(36). The ECM of the brain is a complex milieu of proteins, proteoglycans, and polysaccharides that support various processes including cell-cell adhesion, blood-brain barrier integrity, and synaptic plasticity (20).…”

Section: Discussionmentioning

confidence: 99%

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Transcriptional signatures of heroin intake and relapse throughout the brain reward circuitry in male mice

et al. 2023

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Opioid use disorder (OUD) looms as one of the most severe medical crises facing society. More effective therapeutics will require a deeper understanding of molecular changes supporting drug-taking and relapse. Here, we develop a brain reward circuit-wide atlas of opioid-induced transcriptional regulation by combining RNA sequencing (RNA-seq) and heroin self-administration in male mice modeling multiple OUD-relevant conditions: acute heroin exposure, chronic heroin intake, context-induced drug-seeking following abstinence, and relapse. Bioinformatics analysis of this rich dataset identified numerous patterns of transcriptional regulation, with both region-specific and pan-circuit biological domains affected by heroin. Integration of RNA-seq data with OUD-relevant behavioral outcomes uncovered region-specific molecular changes and biological processes that predispose to OUD vulnerability. Comparisons with human OUD RNA-seq and genome-wide association study data revealed convergent molecular abnormalities and gene candidates with high therapeutic potential. These studies outline molecular reprogramming underlying OUD and provide a foundational resource for future investigations into mechanisms and treatment strategies.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Transcriptional signatures of heroin intake and relapse throughout the brain reward circuitry in male mice

et al. 2023

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“…Using gene ontology analysis, we found that this hub gene cluster enriched for biological processes related to extracellular matrix (ECM) maintenance and associated collagen biology. This finding was particularly interesting given our recent work profiling transcriptional regulation in a mouse model of OUD, as well as recent findings in postmortem NAc from patients with OUD, both of which implicate an important role for ECM dysregulation in supporting opioid addiction pathology (11,12,30). Nearly all genes in this cluster were associated with module 3 (see sunburst plots in Figure 2), a large gene network containing nearly 5700 genes (Supp Fig 2B).…”

Section: Resultsmentioning

confidence: 70%

Shared and divergent transcriptomic regulation in nucleus accumbens D1 and D2 medium spiny neurons by cocaine and morphine

Browne,

Mews,

Zhou

et al. 2023

Preprint

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Substance use disorders (SUDs) induce widespread molecular dysregulation in the nucleus accumbens (NAc), a brain region pivotal for coordinating motivation and reward. These molecular changes are thought to support lasting neural and behavioral disturbances that promote drug-seeking in addiction. However, different drug classes exert unique influences on neural circuits, cell types, physiology, and gene expression despite the overlapping symptomatology of SUDs. To better understand common and divergent molecular mechanisms governing SUD pathology, our goal was to survey cell-type-specific restructuring of the NAc transcriptional landscape in after psychostimulant or opioid exposure. We combined fluorescence-activated nuclei sorting and RNA sequencing to profile NAc D1 and D2 medium spiny neurons (MSNs) across cocaine and morphine exposure paradigms, including initial exposure, prolonged withdrawal after repeated exposure, and re-exposure post-withdrawal. Our analyses reveal that D1 MSNs display many convergent transcriptional responses across drug classes during exposure, whereas D2 MSNs manifest mostly divergent responses between cocaine and morphine, with morphine causing more adaptations in this cell type. Utilizing multiscale embedded gene co-expression network analysis (MEGENA), we discerned transcriptional regulatory networks subserving biological functions shared between cocaine and morphine. We observed largely integrative engagement of overlapping gene networks across drug classes in D1 MSNs, but opposite regulation of key D2 networks, highlighting potential therapeutic gene network targets within MSNs. These studies establish a landmark, cell-type-specific atlas of transcriptional regulation induced by cocaine and by morphine that can serve as a foundation for future studies towards mechanistic understanding of SUDs. Our findings, and future work leveraging this dataset, will pave the way for the development of targeted therapeutic interventions, addressing the urgent need for more effective treatments for cocaine use disorder and enhancing the existing strategies for opioid use disorder.

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“…The top upregulated genes in dopamine neurons was the extracellular matrix protein Ecel1 , and the actin polymerization regulator Diaph3 , both of which are implicated in synaptic function and structural remodeling. These will be interesting gene targets to explore, as chronic morphine is known to induce structural plasticity of VTA dopamine neurons 12,38,39 , and extracellular matrix proteins are an area of interest in the opioid use disorder field 40 . We found increased expression of Insulin receptor substrate Irs1 and Irs2 , opposite of the decreased Irs proteins after chronic morphine in rat VTA 41 .…”

Section: Discussionmentioning

confidence: 99%

Transcriptional signatures of fentanyl use in the mouse ventral tegmental area

Fox,

Montemarano,

Ostman

et al. 2023

Preprint

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Synthetic opioids such as fentanyl contribute to the vast majority of opioid-related overdose deaths, but fentanyl use remains broadly understudied. Like other substances with misuse potential, opioids cause lasting molecular adaptations to brain reward circuits, including neurons in the ventral tegmental area (VTA). The VTA contains numerous cell types that play diverse roles in opioid use and relapse, however it is unknown how fentanyl experience alters the transcriptional landscape in specific subtypes. Here, we performed single nuclei RNA sequencing to study transcriptional programs in fentanyl experienced mice. Male and female C57/BL6 mice self-administered intravenous fentanyl (1.5 µg/kg/infusion) or saline for 10 days. After 24 hr abstinence, VTA nuclei were isolated and prepared for sequencing on the 10X platform. We identified different patterns of gene expression across cell types. In dopamine neurons, we found enrichment of genes involved in growth hormone signaling. In dopamine-glutamate-GABA combinatorial neurons, and some GABA neurons, we found enrichment of genes involved in Pi3k-Akt signaling. In glutamate neurons, we found enrichment of genes involved in cholinergic signaling. We identified transcriptional regulators for the differentially expressed genes in each neuron cluster, including downregulation of transcriptional repressor Bcl6, and upregulation of Wnt signaling partner Tcf4. We also compared the fentanyl-induced gene expression changes identified in mouse VTA with a published rat dataset in bulk VTA, and found overlap in genes related to GABAergic signaling and extracellular matrix interaction. Together, we provide a comprehensive picture of how fentanyl self-administration alters the transcriptional landscape of the mouse VTA, that serves for the foundation for future mechanistic studies.

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A Glitch in the Matrix: The Role of Extracellular Matrix Remodeling in Opioid Use Disorder

Cited by 21 publications

References 96 publications

Transcriptional signatures of heroin intake and relapse throughout the brain reward circuitry in male mice

Transcriptional signatures of heroin intake and relapse throughout the brain reward circuitry in male mice

Shared and divergent transcriptomic regulation in nucleus accumbens D1 and D2 medium spiny neurons by cocaine and morphine

Transcriptional signatures of fentanyl use in the mouse ventral tegmental area

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