Profiling neuronal methylome and hydroxymethylome of opioid use disorder in the human orbitofrontal cortex

Rompala, Gregory; Nagamatsu, Sheila T.; Martínez-Magaña, José Jaime; Nuñez-Ríos, Diana L.; Wang, Jiawei; Girgenti, Matthew J.; Krystal, John H.; Gelernter, Joel; ,; Alvarez, Victor E.; Benedek, David; Che, Alicia; Cruz, Dianne A.; Davis, David A.; Girgenti, Matthew J.; Hoffman, Ellen; Holtzheimer, Paul E.; Huber, Bertrand R.; Kaye, Alfred; Krystal, John H.; Labadorf, Adam T.; Keane, Terence M.; Logue, Mark W.; McKee, Ann; Marx, Brian; Miller, Mark W.; Noller, Crystal; Montalvo-Ortiz, Janitza; Scott, William K.; Schnurr, Paula; Stein, Thor; Ursano, Robert; Williamson, Douglas E.; Wolf, Erika J.; Young, Keith A.; Hurd, Yasmin L.; Montalvo-Ortiz, Janitza L.

doi:10.1038/s41467-023-40285-y

Cited by 13 publications

(7 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Efforts to develop new treatment strategies and to bolster avenues of existing treatments for opioid addiction require a deeper understanding of the changes that occur in the human brain with chronic opioid use. To date, few studies have investigated the molecular changes associated with OUD at the cellular level in human brain 2 – 8 . Recently, we and others have reported alterations in inflammatory signaling 5 , 9 , along with pathways involved in neurodegeneration 2 , 6 , 7 , oxidative stress 10 , and DNA damage 11 in the brains of individuals with OUD.…”

Section: Introductionmentioning

confidence: 99%

Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder

Phan,

Ray,

Xue

et al. 2024

Nat Commun

View full text Add to dashboard Cite

In brain, the striatum is a heterogenous region involved in reward and goal-directed behaviors. Striatal dysfunction is linked to psychiatric disorders, including opioid use disorder (OUD). Striatal subregions are divided based on neuroanatomy, each with unique roles in OUD. In OUD, the dorsal striatum is involved in altered reward processing, formation of habits, and development of negative affect during withdrawal. Using single nuclei RNA-sequencing, we identified both canonical (e.g., dopamine receptor subtype) and less abundant cell populations (e.g., interneurons) in human dorsal striatum. Pathways related to neurodegeneration, interferon response, and DNA damage were significantly enriched in striatal neurons of individuals with OUD. DNA damage markers were also elevated in striatal neurons of opioid-exposed rhesus macaques. Sex-specific molecular differences in glial cell subtypes associated with chronic stress were found in OUD, particularly female individuals. Together, we describe different cell types in human dorsal striatum and identify cell type-specific alterations in OUD.

show abstract

Section: Introductionmentioning

confidence: 99%

Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder

Phan,

Ray,

Xue

et al. 2024

Nat Commun

View full text Add to dashboard Cite

show abstract

“…The orbitofrontal cortex (OFC) plays a vital role in cognitive and behavioral regulation. OFC alterations have been associated with neuropsychiatric disorders including depression, schizophrenia, and addictive behaviors, as well as cognitive-motivational impairments ( Olausson et al, 2007 ; Huang et al, 2023 ; Rompala et al, 2023 ; Wang et al, 2023 ). Furthermore, gut microbiota dysbiosis can increase gut permeability, thereby influencing hypothalamic–pituitary–adrenal (HPA) axis function and activity ( Cussotto et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Causal associations between gut microbiota and regional cortical structure: a Mendelian randomization study

Zhou,

Chen,

Chen

et al. 2023

Front. Neurosci.

View full text Add to dashboard Cite

IntroductionObservational studies have reported associations between gut microbiota composition and central nervous system diseases. However, the potential causal relationships and underlying mechanisms remain unclear. Here, we applied Mendelian randomization (MR) to investigate the causal effects of gut microbiota on cortical surface area (SA) and thickness (TH) in the brain.MethodsWe used genome-wide association study summary statistics of gut microbiota abundance in 18,340 individuals from the MiBioGen Consortium to identify genetic instruments for 196 gut microbial taxa. We then analyzed data from 56,761 individuals from the ENIGMA Consortium to examine associations of genetically predicted gut microbiota with alterations in cortical SA and TH globally and across 34 functional brain regions. Inverse-variance weighted analysis was used as the primary MR method, with MR Egger regression, MR-PRESSO, Cochran’s Q test, and leave-one-out analysis to assess heterogeneity and pleiotropy.ResultsAt the functional region level, genetically predicted higher abundance of class Mollicutes was associated with greater SA of the medial orbitofrontal cortex (β = 8.39 mm2, 95% CI: 3.08–13.70 mm2, p = 0.002), as was higher abundance of phylum Tenericutes (β = 8.39 mm2, 95% CI: 3.08–13.70 mm2, p = 0.002). Additionally, higher abundance of phylum Tenericutes was associated with greater SA of the lateral orbitofrontal cortex (β = 10.51 mm2, 95% CI: 3.24–17.79 mm2, p = 0.0046). No evidence of heterogeneity or pleiotropy was detected.ConclusionSpecific gut microbiota may causally influence cortical structure in brain regions involved in neuropsychiatric disorders. The findings provide evidence for a gut-brain axis influencing cortical development, particularly in the orbitofrontal cortex during adolescence.

show abstract

“…While the first RNA-seq study was published in 2014 [ 36 ], this technique has since progressively replaced microarrays, reflecting well-recognized advantages (higher sensitivity and throughput, gene discovery). For epigenomic profiling, 3 studies used DNA methylation arrays [ 71 , 73 , 74 ], 2 bisulfite sequencing [ 70 , 72 ], and 1 ATACseq (Assay for Transposase-Accessible Chromatin with sequencing) [ 85 ].…”

Section: Qualitative Analysis ( N = 73 Studies)mentioning

confidence: 99%

“…While aforementioned studies focused on bulk tissue, 3 others used Fluorescence-Activated Nuclei Sorting (FANS) to achieve cell-type specific analysis of the neuronal methylome, in the orbitofrontal cortex [ 70 – 72 ]. One used 450 K arrays and, comparing 37 heroin users who died from heroin overdose with 28 controls, identified 1298 differentially methylated CG sites, which were more frequently annotated to genes expressed by glutamatergic than GABAergic neurons [ 71 ].…”

Section: Non-coding and Epigenomic Mechanismsmentioning

confidence: 99%

“…Differential methylation events were found to be more frequent in the non-CG ( n = 2352) than in the reference CG context ( n = 397), with enrichments in GO terms and gene sets (from Genome-Wide Association Studies, GWAS) related to neuronal function and psychiatric diseases [ 70 ]. Similarly, hmCG levels were found more frequently modified ( n = 1740) than mCG, at least in genomic regions covered by RRoxBS, and enriched in GO terms and co-methylation modules relevant to neuronal physiology [ 72 ]. Together, these 2 studies suggest that OUD pathophysiology may be strongly dependent on atypical, brain-enriched forms of methylomic plasticity.…”

Section: Non-coding and Epigenomic Mechanismsmentioning

confidence: 99%

See 1 more Smart Citation

Functional genomic mechanisms of opioid action and opioid use disorder: a systematic review of animal models and human studies

Falconnier,

Caparros-Roissard,

Decraene

et al. 2023

Mol Psychiatry

View full text Add to dashboard Cite

In the past two decades, over-prescription of opioids for pain management has driven a steep increase in opioid use disorder (OUD) and death by overdose, exerting a dramatic toll on western countries. OUD is a chronic relapsing disease associated with a lifetime struggle to control drug consumption, suggesting that opioids trigger long-lasting brain adaptations, notably through functional genomic and epigenomic mechanisms. Current understanding of these processes, however, remain scarce, and have not been previously reviewed systematically. To do so, the goal of the present work was to synthesize current knowledge on genome-wide transcriptomic and epigenetic mechanisms of opioid action, in primate and rodent species. Using a prospectively registered methodology, comprehensive literature searches were completed in PubMed, Embase, and Web of Science. Of the 2709 articles identified, 73 met our inclusion criteria and were considered for qualitative analysis. Focusing on the 5 most studied nervous system structures (nucleus accumbens, frontal cortex, whole striatum, dorsal striatum, spinal cord; 44 articles), we also conducted a quantitative analysis of differentially expressed genes, in an effort to identify a putative core transcriptional signature of opioids. Only one gene, Cdkn1a, was consistently identified in eleven studies, and globally, our results unveil surprisingly low consistency across published work, even when considering most recent single-cell approaches. Analysis of sources of variability detected significant contributions from species, brain structure, duration of opioid exposure, strain, time-point of analysis, and batch effects, but not type of opioid. To go beyond those limitations, we leveraged threshold-free methods to illustrate how genome-wide comparisons may generate new findings and hypotheses. Finally, we discuss current methodological development in the field, and their implication for future research and, ultimately, better care.

show abstract

Profiling neuronal methylome and hydroxymethylome of opioid use disorder in the human orbitofrontal cortex

Cited by 13 publications

References 74 publications

Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder

Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder

Causal associations between gut microbiota and regional cortical structure: a Mendelian randomization study

Functional genomic mechanisms of opioid action and opioid use disorder: a systematic review of animal models and human studies

Contact Info

Product

Resources

About