scholarly journals Alcohol use disorder causes global changes in splicing in the human brain

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Derek Van Booven ◽  
Mengying Li ◽  
J. Sunil Rao ◽  
Ilya O. Blokhin ◽  
R. Dayne Mayfield ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Human Brain ◽  
Alcohol Use Disorder ◽  
Brain Regions ◽  
Gene Set Enrichment Analysis ◽  
Splicing Factor ◽  
Central Nucleus ◽  
Global Changes ◽  
Aberrant Expression ◽  
Altered Expression

AbstractAlcohol use disorder (AUD) is a widespread disease leading to the deterioration of cognitive and other functions. Mechanisms by which alcohol affects the brain are not fully elucidated. Splicing constitutes a nuclear process of RNA maturation, which results in the formation of the transcriptome. We tested the hypothesis as to whether AUD impairs splicing in the superior frontal cortex (SFC), nucleus accumbens (NA), basolateral amygdala (BLA), and central nucleus of the amygdala (CNA). To evaluate splicing, bam files from STAR alignments were indexed with samtools for use by rMATS software. Computational analysis of affected pathways was performed using Gene Ontology Consortium, Gene Set Enrichment Analysis, and LncRNA Ontology databases. Surprisingly, AUD was associated with limited changes in the transcriptome: expression of 23 genes was altered in SFC, 14 in NA, 102 in BLA, and 57 in CNA. However, strikingly, mis-splicing in AUD was profound: 1421 mis-splicing events were detected in SFC, 394 in NA, 1317 in BLA, and 469 in CNA. To determine the mechanism of mis-splicing, we analyzed the elements of the spliceosome: small nuclear RNAs (snRNAs) and splicing factors. While snRNAs were not affected by alcohol, expression of splicing factor heat shock protein family A (Hsp70) member 6 (HSPA6) was drastically increased in SFC, BLA, and CNA. Also, AUD was accompanied by aberrant expression of long noncoding RNAs (lncRNAs) related to splicing. In summary, alcohol is associated with genome-wide changes in splicing in multiple human brain regions, likely due to dysregulation of splicing factor(s) and/or altered expression of splicing-related lncRNAs.

scholarly journals Family history of alcohol use disorder is associated with brain structural and functional changes in healthy first-degree relatives

2019 ◽  
Vol 62 ◽  
pp. 107-115 ◽  
Author(s):  
Irina Filippi ◽  
Nicolas Hoertel ◽  
Eric Artiges ◽  
Guillaume Airagnes ◽  
Christophe Guérin-Langlois ◽  
...  
Keyword(s):  
Family History ◽  
Alcohol Use ◽  
Childhood Maltreatment ◽  
Alcohol Use Disorder ◽  
Grey Matter ◽  
Brain Regions ◽  
Whole Brain ◽  
Childhood Trauma Questionnaire ◽  
Functional Changes ◽  
History Of

Abstract Background: Neuroimaging studies of vulnerability to Alcohol Use Disorder (AUD) have identified structural and functional variations which might reflect inheritable features in alcohol-naïve relatives of AUD individuals (FH+) compared to controls having no such family history (FH-). However, prior research did not simultaneously account for childhood maltreatment, any clinically significant disorder and maternal AUD. Therefore, we mainly aimed to investigate the brain structure and reward-related neural activations (fMRI), using whole-brain analysis in FH+ young adults with no prevalent confounders. Methods: 46 FH+ and 45 FH- male and female participants had no severe childhood maltreatment exposure, neither any psychiatric disorder or AUD, nor a prenatal exposure to maternal AUD. We used a 3 T MRI coupled with a whole brain voxel-based method to compare between groups the grey matter volumes and activations in response to big versus small wins during a Monetary Incentive Delay task. The Childhood Trauma Questionnaire score was used as confounding variable in the analyses to account for the remaining variance between groups. Results: Compared to FH- controls, FH+ participants had smaller grey matter volumes in the frontal and cingulate regions as well as in the bilateral nucleus accumbens and right insula. The FH+ participants’ fMRI datasets denoted a blunted activation in the middle cingulum with respect to FH- controls’ during the processing of reward magnitude, and a greater activation in the anterior cingulum in response to anticipation of a small win. Conclusions: Family history of alcohol use disorder is linked to structural and functional variations including brain regions involved in reward processes.

Effect of alcohol use disorder on oxytocin peptide and receptor mRNA expression in human brain: A post-mortem case-control study

2017 ◽  
Vol 85 ◽  
pp. 14-19 ◽  
Author(s):  
Mary R. Lee ◽  
Melanie L. Schwandt ◽  
Vignesh Sankar ◽  
Petra Suchankova ◽  
Hui Sun ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Human Brain ◽  
Mrna Expression ◽  
Alcohol Use Disorder ◽  
Case Control Study ◽  
Case Control ◽  
Post Mortem ◽  
Receptor Mrna ◽  
Control Study

scholarly journals Epigenome-wide Association Study of Alcohol Use Disorder in Five Brain Regions

2021 ◽  
Author(s):  
Lea Zillich ◽  
Josef Frank ◽  
Fabian Streit ◽  
Marion M Friske ◽  
Jerome C Foo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Alcohol Use ◽  
Brain Region ◽  
Alcohol Use Disorder ◽  
Brain Regions ◽  
Anterior Cingulate ◽  
Human Brain Tissue ◽  
Postmortem Human Brain ◽  
Association Analyses ◽  
Cpg Sites

Alcohol Use Disorder (AUD) is closely linked to the brain regions forming the neurocircuitry of addiction. Postmortem human brain tissue enables the direct study of the molecular pathomechanisms of AUD. This study aims to identify these mechanisms by examining differential DNA-methylation between cases with severe AUD (n=53) and controls (n=58) using a brain region-specific approach. Samples of the anterior cingulate cortex (ACC), Brodmann Area 9 (BA9), caudate nucleus (CN), ventral striatum (VS), and putamen (PUT) were investigated. DNA-methylation levels were determined using the Illumina HumanMethylationEPIC Beadchip. Epigenome-wide association analyses were carried out to identify differentially methylated CpG-sites and regions between cases and controls in each brain region. Weighted Correlation Network Analysis (WGCNA), gene-set and GWAS-enrichment analyses were performed. Two differentially methylated CpG-sites were associated with AUD in the CN, and 18 in VS (q < .05). No epigenome-wide significant CpG-sites were found in BA9, ACC, or PUT. Differentially methylated regions associated with AUD case-/control status (q < .05) were found in the CN (n=6), VS (n=18) and ACC (n=1). These findings were mapped to several genes including IREB2, SLC30A8, and DDAH2. In the VS, the WGCNA-module showing the strongest association with AUD was enriched for immune-related pathways. This study is the first to analyze methylation differences between AUD cases and controls in multiple brain regions and consists of the largest sample to date. Several novel CpG-sites and regions implicated in AUD were identified, providing a first basis to explore epigenetic correlates of AUD

scholarly journals Exploration of alcohol use disorder-associated brain miRNA–mRNA regulatory networks

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yolpanhchana Lim ◽  
Jennifer E. Beane-Ebel ◽  
Yoshiaki Tanaka ◽  
Boting Ning ◽  
Christopher R. Husted ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Regulatory Networks ◽  
Alcohol Use Disorder ◽  
Brain Regions ◽  
Fold Change ◽  
Differentially Expressed ◽  
Tissue Samples ◽  
Postmortem Brain Tissue ◽  
Cortical Interneurons ◽  
Transcriptomic Changes

AbstractTranscriptomic changes in specific brain regions can influence the risk of alcohol use disorder (AUD), but the underlying mechanism is not fully understood. We investigated AUD-associated miRNA–mRNA regulatory networks in multiple brain regions by analyzing transcriptomic changes in two sets of postmortem brain tissue samples and ethanol-exposed human embryonic stem cell (hESC)-derived cortical interneurons. miRNA and mRNA transcriptomes were profiled in 192 tissue samples (Set 1) from eight brain regions (amygdala, caudate nucleus, cerebellum, hippocampus, nucleus accumbens, prefrontal cortex, putamen, and ventral tegmental area) of 12 AUD and 12 control European Australians. Nineteen differentially expressed miRNAs (fold-change>2.0 & P < 0.05) and 97 differentially expressed mRNAs (fold-change>2.0 & P < 0.001) were identified in one or multiple brain regions of AUD subjects. AUD-associated miRNA–mRNA regulatory networks in each brain region were constructed using differentially expressed and negatively correlated miRNA–mRNA pairs. AUD-relevant pathways (including CREB Signaling, IL-8 Signaling, and Axonal Guidance Signaling) were potentially regulated by AUD-associated brain miRNA–mRNA pairs. Moreover, miRNA and mRNA transcriptomes were mapped in additional 96 tissue samples (Set 2) from six of the above eight brain regions of eight AUD and eight control European Australians. Some of the AUD-associated miRNA–mRNA regulatory networks were confirmed. In addition, miRNA and mRNA transcriptomes were analyzed in hESC-derived cortical interneurons with or without ethanol exposure, and ethanol-influenced miRNA–mRNA regulatory networks were constructed. This study provided evidence that alcohol could induce concerted miRNA and mRNA expression changes in reward-related or alcohol-responsive brain regions. We concluded that altered brain miRNA–mRNA regulatory networks might contribute to AUD development.

scholarly journals Multi-Omics Signatures of Alcohol Use Disorder in the Dorsal and Ventral Striatum

2021 ◽  
Author(s):  
Lea Zillich ◽  
Eric Poisel ◽  
Josef Frank ◽  
Jerome C. Foo ◽  
Marion M. Friske ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Molecular Mechanisms ◽  
Ventral Striatum ◽  
Cell Structure ◽  
Dorsal Striatum ◽  
Gene Set Enrichment Analysis ◽  
Integrated Analysis

Alcohol Use Disorder (AUD) is a major contributor to global mortality and morbidity. Postmortem human brain tissue enables the investigation of molecular mechanisms of AUD in the neurocircuitry of addiction. We aimed to identify differentially expressed (DE) genes in the ventral and dorsal striatum between individuals with AUD and controls, and to integrate the results with findings from genome- and epigenome-wide association studies (GWAS/EWAS) to identify functionally relevant molecular mechanisms of AUD. DNA-methylation and gene expression (RNA-seq) data was generated from postmortem brain samples of 48 individuals with AUD and 51 controls from the ventral striatum (VS) and the dorsal striatal regions caudate nucleus (CN) and putamen (PUT). We identified DE genes using DESeq2, performed gene-set enrichment analysis (GSEA), and tested enrichment of DE genes in results of GWASs using MAGMA. Weighted correlation network analysis (WGCNA) was performed for DNA-methylation and gene expression data and gene overlap was tested. In the dorsal striatum, we discovered differential expression (FDR<0.05) for a total of 50 genes. In the VS, DE genes at FDR<0.25 were overrepresented in a recent GWAS of problematic alcohol use. The ARHGEF15 gene was upregulated in all three brain regions. GSEA in CN and VS pointed towards cell-structure associated GO-terms and in PUT towards immune pathways. The WGCNA modules most strongly associated with AUD showed strong enrichment for immune response and inflammation pathways. Our integrated analysis of multi-omics data sets provides further evidence for the importance of immune-and inflammation-related processes in AUD.

scholarly journals Genome- and Transcriptome-wide Splicing Associations with Problematic Alcohol Use and Alcohol Use Disorder

2021 ◽  
Author(s):  
Spencer B. Huggett ◽  
Ami S. Ikeda ◽  
Qingyue Yuan ◽  
Chelsie E. Benca-Bachman ◽  
Rohan H.C. Palmer
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Association Studies ◽  
Brain Regions ◽  
Mrna Splicing ◽  
Sequencing Data ◽  
Problematic Alcohol ◽  
Alternative Mrna Splicing ◽  
Polygenic Scores ◽  
Problematic Alcohol Use

ABSTRACTGenetic mechanisms of alternative mRNA splicing have been shown in the brain for a variety of neuropsychiatric traits, but not substance use disorders. Our study used RNA-sequencing data on alcohol use disorder (AUD) in the brain’s reward circuitry (n=56; ages 40-73; 100% ‘Caucasian’; four brain regions) and genome-wide association data on problematic alcohol use (n=435,563, ages 22-90; 100% European-American) to investigate potential genetic links with alcohol-related alternative mRNA splicing. Polygenic scores of problematic alcohol use predicted alternative mRNA brain splicing associated with AUD, which depended on brain region. Across brain regions, we found 714 differentially spliced genes in various putative addiction genes and other novel gene targets. We found 6,463 splicing quantitative trait loci (sQTLs) that were associated with the AUD differentially spliced genes. sQTLs were enriched in loose chromatin genomic regions and downstream gene targets. Additionally, the heritability of problematic alcohol use was significantly enriched for DNA variants in and around differentially spliced genes associated with AUD. Our study also performed splicing transcriptome-wide association studies (TWASs) of problematic alcohol use and other drug use traits that unveiled individual genes for follow-up and robust splicing correlations across SUDs. Finally, we show that differentially spliced genes associated showed significant overlap in primate models of chronic alcohol consumption at the gene-level in similar brain regions. Altogether, our study illuminates substantial genetic contributions of alternative mRNA splicing in relation to problematic alcohol use and AUD.

scholarly journals Neural Mechanisms Underlying the Rewarding and Therapeutic Effects of Ketamine as a Treatment for Alcohol Use Disorder

2020 ◽  
Vol 14 ◽  
Author(s):  
Caroline E. Strong ◽  
Mohamed Kabbaj
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Treatment Options ◽  
Dorsal Striatum ◽  
Brain Regions ◽  
Repeated Treatment ◽  
Therapeutic Effects ◽  
Acute Administration ◽  
Treatment Regimens ◽  
Antidepressant Effects

Alcohol use disorder (AUD) is the most prevalent substance use disorder and causes a significant global burden. Relapse rates remain incredibly high after decades of attempting to develop novel treatment options that have failed to produce increased rates of sobriety. Ketamine has emerged as a potential treatment for AUD following its success as a therapeutic agent for depression, demonstrated by several preclinical studies showing that acute administration reduced alcohol intake in rodents. As such, ketamine’s therapeutic effects for AUD are now being investigated in clinical trials with the hope of it being efficacious in prolonging sobriety from alcohol in humans (ClinicalTrials.gov, Identifier: NCT01558063). Importantly, ketamine’s antidepressant effects only last for about 1-week and because AUD is a lifelong disorder, repeated treatment regimens would be necessary to maintain sobriety. This raises questions regarding its safety for AUD treatment since ketamine itself has the potential for addiction. Therefore, this review aims to summarize the neuroadaptations related to alcohol’s addictive properties as well as ketamine’s therapeutic and addictive properties. To do this, the focus will be on reward-related brain regions such as the nucleus accumbens (NAc), dorsal striatum, prefrontal cortex (PFC), hippocampus, and ventral tegmental area (VTA) to understand how acute vs. chronic exposure will alter reward signaling over time. Additionally, evidence from these studies will be summarized in both male and female subjects. Accordingly, this review aims to address the safety of repeated ketamine infusions for the treatment of AUD. Although more work about the safety of ketamine to treat AUD is warranted, we hope this review sheds light on some answers about the safety of repeated ketamine infusions.

scholarly journals Proteomics reveals profound metabolic changes in the alcohol use disorder brain

2018 ◽  
Author(s):  
Charmaine Enculescu ◽  
Edward D. Kerr ◽  
K. Y. Benjamin Yeo ◽  
Peter R. Dodd ◽  
Gerhard Schenk ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Brain Regions ◽  
Substantial Effect ◽  
Biochemical Processes ◽  
Data Independent Acquisition ◽  
Metabolic Adaptations ◽  
Brain Proteome ◽  
Acetate Utilization ◽  
The Brain

AbstractChanges in brain metabolism are a hallmark of Alcohol Use Disorder (AUD). Determining how AUD changes the brain proteome is critical for understanding the effects of alcohol consumption on biochemical processes in the brain. We used data-independent acquisition mass spectrometry proteomics to study differences in the abundance of proteins associated with AUD in pre-frontal lobe and motor cortex from autopsy brain. AUD had a substantial effect on the overall brain proteome exceeding the inherent differences between brain regions. Proteins associated with glycolysis, trafficking, the cytoskeleton, and excitotoxicity were altered in abundance in AUD. We observed extensive changes in the abundance of key metabolic enzymes, consistent with a switch from glucose to acetate utilization in the AUD brain. We propose that metabolic adaptations allowing efficient acetate utilization contribute to ethanol dependence in AUD.

scholarly journals Epigenome-wide association study of alcohol use disorder in five brain regions

2021 ◽  
Author(s):  
Lea Zillich ◽  
Josef Frank ◽  
Fabian Streit ◽  
Marion M. Friske ◽  
Jerome C. Foo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Alcohol Use ◽  
Brain Region ◽  
Alcohol Use Disorder ◽  
Brain Regions ◽  
Anterior Cingulate ◽  
Human Brain Tissue ◽  
Postmortem Human Brain ◽  
Association Analyses ◽  
Cpg Sites

AbstractAlcohol use disorder (AUD) is closely linked to the brain regions forming the neurocircuitry of addiction. Postmortem human brain tissue enables the direct study of the molecular pathomechanisms of AUD. This study aims to identify these mechanisms by examining differential DNA-methylation between cases with severe AUD (n = 53) and controls (n = 58) using a brain-region-specific approach, in which sample sizes ranged between 46 and 94. Samples of the anterior cingulate cortex (ACC), Brodmann Area 9 (BA9), caudate nucleus (CN), ventral striatum (VS), and putamen (PUT) were investigated. DNA-methylation levels were determined using the Illumina HumanMethylationEPIC Beadchip. Epigenome-wide association analyses were carried out to identify differentially methylated CpG-sites and regions between cases and controls in each brain region. Weighted correlation network analysis (WGCNA), gene-set, and GWAS-enrichment analyses were performed. Two differentially methylated CpG-sites were associated with AUD in the CN, and 18 in VS (q < 0.05). No epigenome-wide significant CpG-sites were found in BA9, ACC, or PUT. Differentially methylated regions associated with AUD case-/control status (q < 0.05) were found in the CN (n = 6), VS (n = 18), and ACC (n = 1). In the VS, the WGCNA-module showing the strongest association with AUD was enriched for immune-related pathways. This study is the first to analyze methylation differences between AUD cases and controls in multiple brain regions and consists of the largest sample to date. Several novel CpG-sites and regions implicated in AUD were identified, providing a first basis to explore epigenetic correlates of AUD.

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