The Neuroimmune Transcriptome and Alcohol Dependence: Potential for Targeted Therapies

Warden, Anna S.; Erickson, Emma K.; Robinson, Gizelle; Harris, R. Adron

doi:10.2217/pgs-2016-0062

Cited by 30 publications

(24 citation statements)

References 145 publications

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“…The neuroimmune system is critical for the pathogenesis of neurological diseases such as Alzheimer's disease and multiple sclerosis (25) , and is also involved in regulating alcohol abuse and dependence (26) . To date, however, single cell/nucleus RNA-seq studies have not specifically evaluated neuroimmune gene expression among cell types.…”

Section: Neuroinflammatory Signalingmentioning

confidence: 99%

Single cell transcriptome profiling of the human alcohol-dependent brain

Brenner

Tiwari

Liu

et al. 2019

Preprint

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BackgroundAlcoholism remains a prevalent health concern throughout the world. Previous studies have identified transcriptomic patterns in the brain associated with alcohol dependence in both humans and animal models.But none of these studies have systematically investigated expression within the unique cell types present in the brain. ResultsWe utilized single nucleus RNA sequencing (snRNA-seq) to examine the transcriptomes of over 16,000 nuclei isolated from prefrontal cortex of alcoholic and control individuals. Each nucleus was assigned to one of seven major cell types by unsupervised clustering. Cell type enrichment patterns varied greatly among neuroinflammatory-related genes, which are known to play roles in alcohol dependence and neurodegeneration. Differential expression analysis identified cell type-specific genes with altered expression in alcoholics. The largest number of differentially expressed genes (DEGs), including both protein-coding and non-coding, were detected in astrocytes, oligodendrocytes, and microglia. ConclusionsTo our knowledge, this is the first single cell transcriptome analysis of alcohol-associated gene expression in any species, and the first such analysis in humans for any addictive substance. These findings greatly advance understanding of transcriptomic changes in the brain of alcohol-dependent individuals.1 Background Alcohol abuse is involved in over 200 pathologies and health conditions (e.g. alcohol dependence, liver cirrhosis, cancers, and injuries) and creates substantial social and economic burdens (1,2) . To develop more effective therapeutic strategies, we must first understand how alcohol affects the body at the cellular and molecular level. Previous studies of transcriptomic responses in human alcoholics (3-6) relied on RNA extracted from brain regions using tissue homogenates comprised of multiple cell types. This approach likely masks differences in gene expression patterns among specific cells, as well as heterogeneity from cell-to-cell variation within a given cell type.Single cell RNA sequencing (scRNA-seq) has recently gained attention in cell and molecular biology research for its ability to profile novel cell types and measure cell-to-cell variation in gene expression. To our knowledge, transcriptomic responses to chronic alcohol exposure or any other abused drug have not been studied at the cellular level in the human brain. We hypothesized that cell type-specific gene expression patterns associated with alcoholism will identify novel alcohol targets that were previously missed by bulk analysis of tissue homogenates, as has been shown for other neuropathologies (7,8) . Using single nucleus RNA-seq (snRNA-seq), a popular scRNA-seq alternative for analyzing frozen brain tissue (9-18) , we profiled the transcriptomes of 16,305 nuclei extracted from frozen prefrontal cortex (PFC) samples of 4 control and 3 alcohol dependent individuals. The PFC is involved in executive function and is an important substrate in the reward circuitry associated with development of a...

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Section: Neuroinflammatory Signalingmentioning

confidence: 99%

Single cell transcriptome profiling of the human alcohol-dependent brain

Brenner

Tiwari

Liu

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Sequence data can be integrated with protein data, physiological function, phenotypic traits, and other factors such as the microbiome, to create a more cohesive picture of the disease state (Farris and Mayfield, 2014). This information, coupled with corresponding information from animal models (Truitt et al, 2016), aims to uncover improved treatment strategies for AUD (Warden et al, 2016), and may one day be used to target an individual’s transcriptome profile. Advances in “precision” and “personalized” medicine could lead to improved therapies that surpass those obtained by current in silico bioinformatics approaches (Shin et al, 2016; Sliwczynski and Orlewska, 2016).…”

Section: Summary and Future Directionsmentioning

confidence: 99%

Gene expression profiling in the human alcoholic brain

Warden

Mayfield

2017

Neuropharmacology

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Long-term alcohol use causes widespread changes in gene expression in the human brain. Aberrant gene expression changes likely contribute to the progression from occasional alcohol use to alcohol use disorder (including alcohol dependence). Transcriptome studies have identified individual gene candidates that are linked to alcohol-dependence phenotypes. The use of bioinformatics techniques to examine expression datasets has provided novel systems-level approaches to transcriptome profiling in human postmortem brain. These analytical advances, along with recent developments in next-generation sequencing technology, have been instrumental in detecting both known and novel coding and non-coding RNAs, alternative splicing events, and cell-type specific changes that may contribute to alcohol-related pathologies. This review offers an integrated perspective on alcohol-responsive transcriptional changes in the human brain underlying the regulatory gene networks that contribute to alcohol dependence.

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“…Preclinical studies provide emerging evidence that neuroimmune genes are promising targets for treating AUD [150]. Metaanalyses of gene expression studies in alcohol preferring strains of mice and postmortem tissue from human alcoholics revealed dysregulation of neuroimmune and neuroinflammatory signaling pathways [151].…”

Section: Neuroimmune Signalingmentioning

confidence: 99%

Promising Pharmacogenetic Targets for Treating Alcohol Use Disorder: Evidence from Preclinical Models

Rinker

Mulholland

2017

Pharmacogenomics

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Inherited genetic variants contribute to risk factors for developing an alcohol use disorder, and polymorphisms may inform precision medicine strategies for treating alcohol addiction. Targeting genetic mutations linked to alcohol phenotypes has provided promising initial evidence for reducing relapse rates in alcoholics. Although successful in some studies, there are conflicting findings and the reports of adverse effects may ultimately limit their clinical utility, suggesting that novel pharmacogenetic targets are necessary to advance precision medicine approaches. Here, we describe promising novel genetic variants derived from preclinical models of alcohol consumption and dependence that may uncover disease mechanisms that drive uncontrolled drinking and identify novel pharmacogenetic targets that facilitate therapeutic intervention for the treatment of alcohol use disorder. Alcohol use disorder (AUD) is a chronic neurological disorder characterized by an inability to regulate alcohol intake despite a host of serious and harmful health, soci etal and personal consequences [1]. The cur rent pharmacotherapies available for AUD treatment have been met with variable out comes that are modest at best and thus have not been widely embraced by the medical community. This gap in treatment options provides an opportunity to explore new avenues toward identifying novel pharmaco therapeutic targets. As with other addictive disorders, AUD is influenced, to a consid erable degree, by genetics, with heritability estimates upward of 60% [2,3]. Despite the comparatively large influence of genetics, the exact etiology of AUD is by no means simple or straightforward, which under scores the difficulty in effective treatment of this disorder. In this review, we provide an evaluation of our understanding of the genet ics of AUD in relation to current precision medicine approaches. Demonstrating the considerable heterogeneity that exists within the AUD population and understanding the contribution of genetic variation to treatment response provides a framework for promot ing a pharmacogenetic approach. Moreover, understanding the genetic variation among individuals with AUD in treatment response will provide valuable information that will allow for personalized treatment plans.A diagnosis of AUD is based strictly on a set of clinical diagnostic criteria, because as of yet, there are no reliable biomarkers to identify AUD or subpopulations that might be more or less responsive to certain medica tions. This means that, at best, we are treat ing AUD by trial and error on a, presumably, largely heterogeneous population. There are currently only three US FDA approved pharmaco therapies for treating AUD, nal trexone, acamprosate and disulfiram, all of

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The Neuroimmune Transcriptome and Alcohol Dependence: Potential for Targeted Therapies

Cited by 30 publications

References 145 publications

Single cell transcriptome profiling of the human alcohol-dependent brain

Single cell transcriptome profiling of the human alcohol-dependent brain

Gene expression profiling in the human alcoholic brain

Promising Pharmacogenetic Targets for Treating Alcohol Use Disorder: Evidence from Preclinical Models

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