Michael F Miles

Virginia Commonwealth University | VCU · Department of Pharmacology and Toxicology and Department of Neurology

Background The phenomenon of alcohol analgesia and tolerance can facilitate misuse and lead to the development of alcohol use disorder (AUD). Numerous alcohol-induced behaviors are genetically influenced; however, it is unknown if alcohol analgesia has a genetic contribution. Rodent studies have shown that alcohol responses differ vastly between tw...

Background Chloride intracellular channel 4 (CLIC4) is a multifunctional metamorphic protein with a growing body of evidence supporting a major role in the brain’s molecular and behavioral response to ethanol. Although key to understanding the functional biology underlying this role, little is known about the cellular and subcellular expression pat...

The cover image is based on the Original Article Identifying a novel biological mechanism for alcohol addiction associated with circRNA networks acting as potential miRNA sponges by Eric Vornholt et al., https://doi.org/10.1111/adb.13071.

Chloride intracellular channels (CLICs) are a unique family of evolutionarily conserved metamorphic proteins, switching between stable conformations based on redox conditions. CLICs have been implicated in a wide variety biological processes including ion channel activity, apoptosis, membrane trafficking, and enzymatic oxidoreductase activity. Unde...

Our lab and others have shown that chronic alcohol use leads to gene and miRNA expression changes across the mesocorticolimbic (MCL) system. Circular RNAs (circRNAs) are noncoding RNAs that form closed-loop structures and are reported to alter gene expression through miRNA sequestration, thus providing a potentially novel neurobiological mechanism...

The National Institute on Drug Abuse and Joint Institute for Biological Sciences at the Oak Ridge National Laboratory hosted a meeting attended by a diverse group of scientists with expertise in substance use disorders (SUDs), computational biology, and FAIR (Findability, Accessibility, Interoperability, and Reusability) data sharing. The meeting’s...

Background Despite the increasing use of RNAseq for transcriptome analysis, microarrays remain a widely-used methodology for genomic studies. The latest generation of Affymetrix/Thermo-Fisher microarrays, the ClariomD/XTA and ClariomS array, provide a sensitive and facile method for complex transcriptome expression analysis. However, existing metho...

Chloride intracellular channels (CLICs) are a unique family of evolutionarily conserved metamorphic proteins, switching between stable conformations based on redox conditions. CLICs have been implicated in a wide variety biological processes including ion channel activity, apoptosis, membrane trafficking, and enzymatic oxidoreductase activity. Unde...

Chronic alcohol abuse has been linked to the disruption of executive function and allostatic conditioning of reward response dysregulation in the mesocorticolimbic pathway (MCL). Here, we analyzed genome-wide mRNA and miRNA expression from matched cases with alcohol dependence (AD) and controls (n = 35) via gene network analysis to identify unique...

Background Long noncoding RNA (lncRNA) have been implicated in the etiology of alcohol use. Since lncRNA provide another layer of complexity to the transcriptome, assessing their expression in the brain is the first critical step toward understanding lncRNA functions in alcohol use and addiction. Thus, we sought to profile lncRNA expression in the...

Progressive increases in ethanol consumption is a hallmark of alcohol use disorder (AUD). Persistent changes in brain gene expression are hypothesized to underlie the altered neural signaling producing abusive consumption in AUD. To identify brain regional gene expression networks contributing to progressive ethanol consumption, we performed microa...

Background Excessive alcohol consumption has become a growing public health concern worldwide due to the potential development of alcohol dependence (AD). Prolonged alcohol abuse leads to dysregulation of the mesocorticolimbic pathway (MCL), effectively disrupting executive functioning and the allostatic conditioning of reward response. Methods We...

Background: Trauma related psychiatric disorders, such as posttraumatic stress disorder (PTSD), and alcohol use disorder (AUD) are highly comorbid illnesses that separately present an opposing, sex-specific pattern, with increased prevalence of PTSD in females and increased prevalence of AUD diagnoses in males. Likewise, PTSD is a risk factor in t...

Adolescence is characterized by high levels of playful social interaction, cognitive development, and increased risk-taking behavior. Juvenile exposure to social isolation or social stress can reduce myelin content in the frontal cortex, alter neuronal excitability, and disrupt hypothalamic pituitary adrenal (HPA) axis function. As compared to grou...

Alcohol use and chronic pain are highly comorbid. Acute alcohol use typically produces an analgesic effect. However, chronic use can worsen the progression of chronic pain. In rodent models, acute models of pain have primarily been used to investigate the relationship between alcohol and pain analgesia. Here, we use two models of chronic pain, chro...

Despite recent extensive genomic and genetic studies on behavioral responses to ethanol, relatively few new therapeutic targets for the treatment of alcohol use disorder have been validated. Here, we describe a cross-species genomic approach focused on identifying gene networks associated with chronic ethanol consumption. To identify brain mechanis...

Introduction FTND (Fagerstrӧm test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. Methods Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted f...

Progressive increases in ethanol consumption is a hallmark of alcohol use disorder (AUD). Persistent changes in brain gene expression are hypothesized to underlie the altered neural signaling producing abusive consumption in AUD. To identify brain regional gene expression networks contributing to progressive ethanol consumption, we performed microa...

Background: Alcohol use disorder is a serious illness marked by uncontrollable drinking and a negative withdrawal state when not using. Alcohol is one of the most commonly used drugs among adolescent populations. Given that adolescence is a unique developmental stage during which alcohol has long-term effects on future drug-taking behavior; it is...

Background Trauma related psychiatric disorders, such as posttraumatic stress disorder (PTSD), and alcohol use disorder (AUD) are highly comorbid illnesses that separately present an opposing, sex-specific pattern, with increased prevalence of PTSD in females and increased prevalence of AUD diagnoses in males. Likewise, PTSD is a risk factor in the...

[This corrects the article DOI: 10.1371/journal.pone.0146257.].

Genome-wide association studies on alcohol dependence, by themselves, have yet to account for the estimated heritability of the disorder and provide incomplete mechanistic understanding of this complex trait. Integrating brain ethanol-responsive gene expression networks from model organisms with human genetic data on alcohol dependence could aid in...

Brain region-specific S-score values. One table per brain region, containing each of the following values: RMA values and S-scores from the maximally expressed probeset per gene, for each BXD strain; the associated probeset IDs, human gene symbols, and mouse gene symbols; and the Fisher’s combined False Discovery Rate (q-value) for each probeset. (...

Mega module gene ontology enrichment. One table for each ALSPAC-overrepresented Mega Module, containing ToppFun output for gene ontology enrichment groups with p<0.01 and minimum group size of 3 genes and maximum size of 1,000 genes, for the following categories: Biological Process, Cellular Component, Molecular Function, Human Phenotype, Mouse Phe...

Analytical pipeline of steps following EW-dmGWAS. Empirical p-values were calculated from standardized module scores based on a Z-distribution. The original EW-dmGWAS module score, permutation, and score standardization algorithms were used to calculate the respective Mega Modules parameters. Modules were considered to have >80% overlap if >80% of...

Mega module characteristics. One table per brain region, containing each of the following characteristics, for all significant Mega Modules: name; constituent genes; ALPSAC and IASPSAD p-values for each gene; Mega Module score (Sn), p-value (Sn_p), and False Discovery Rate (Sn_qFDR); and intramodular eigencentrality and connectivity. Significance v...

Recently, long noncoding RNA (lncRNA) were implicated in the etiology of alcohol dependence (AD). As lncRNA provide another layer of complexity to the transcriptome, assessing their expression in the brain is the first critical step towards understanding lncRNA functions in AD. To that end, we profiled the expression of lncRNA and protein coding ge...

Following the publication of this article Figs. 3b, c were published incorrectly. Also in sub-panel c of Fig. 4, ‘Chronic cloza ine’ should read ‘Chronic clozapine’.

Background Serotonin 5-HT2A and metabotropic glutamate 2 (mGlu2) are neurotransmitter G protein-coupled receptors (GPCRs) involved in the signaling mechanisms underlying psychosis and schizophrenia treatment. Previous findings in mGlu2 knockout (KO) mice suggested that mGlu2 is necessary for head-twitch behavior, a rodent phenotype characteristic o...

Background Recent reviews have highlighted the potential use of blood‐based methylation biomarkers as diagnostic and prognostic tools of current and future alcohol use and addiction. Due to the substantial overlap that often exists between methylation patterns across different tissues, including blood and brain, blood‐based methylation may track me...

Alcoholism is a complex behavioral disorder characterized by loss of control in limiting intake, and progressive compulsion to seek and consume ethanol. Prior studies have suggested that the characteristic behaviors associated with escalation of drug use are caused, at least in part, by ethanol-evoked changes in gene expression affecting synaptic p...

EES_SSS or SES_SSS regulated genes (RNA-Seq, edgeR, FDR = 0.1), ToppFun functional enrichment analysis summary.

EEP_SSP or SEP_SSP regulated exon genes (RNA-Seq, DEXSeq, padj < 0.01), ToppFun functional enrichment analysis summary.

EES_SSS or SES_SSS regulated exon genes (RNA-Seq, DEXSeq, padj < 0.01), ToppFun functional enrichment analysis summary.

MEME motif count matrices.

EdgeR CPM data (gene level).

RNAseq results for control genes.

Antibody specifications. (b) qRT-PCR primer specifications.

Synapse-specific differential exon usage.

Characterization of the synaptoneurosome preparation. (A) Schematic depicting synaptoneurosome preparation. Whole homogenate (WH) processed from pooled frontal pole tissue of four mice was used in the centrifugation/filtration scheme depicted here. The initial pellet (P1) contained cellular debris and nuclei. The supernatant from the initial centri...

EdgeR differential expression results (unfiltered data).

P2 enriched and S2 enriched genes and ToppGene analysis.

EEP_SSP or SEP_SSP regulated genes (RNA-Seq, edgeR, FDR = 0.1), ToppFun functional enrichment analysis summary.

DEXSeq differential exon usage results (unfiltered data).

Understanding how ethanol actions on brain signal transduction and gene expression lead to excessive consumption and addiction could identify new treatments for alcohol dependence. We previously identified glycogen synthase kinase 3-beta (Gsk3b) as a member of a highly ethanol-responsive gene network in mouse medial prefrontal cortex (mPFC). Gsk3b...

Genome-wide association studies on alcohol dependence, by themselves, have yet to account for the estimated heritability of the disorder and provide incomplete mechanistic understanding of this complex trait. Integrating brain ethanol-responsive gene expression networks from model organisms with human genetic data on alcohol dependence could aid in...

Preclinical findings in rodent models pointed toward activation of metabotropic glutamate 2/3 (mGlu2/3) receptors as a new pharmacological approach to treat psychosis. However, more recent studies failed to show clinical efficacy of mGlu2/3 receptor agonism in schizophrenia patients. We previously proposed that long-term antipsychotic medication re...

Evidence suggests that there is an association between polymorphisms in the α5 nicotinic acetylcholine receptor (nAChR) subunit and risk of developing alcohol dependence in humans. The α5 nAChR subunit has also recently been shown to modulate some of the acute response to ethanol in mice. The aim of the current study was to further characterize the...

Alcohol use disorder (AUD) is a heritable complex behavior. Due to the highly polygenic nature of AUD, identifying genetic variants that comprise this heritable variation has proved to be challenging. With the exception of functional variants in alcohol metabolizing genes (e.g. ADH1B and ALDH2), few other candidate loci have been confidently linked...

Complex behavioral traits, such as alcohol abuse, are caused by an interplay of genetic and environmental factors, producing deleterious functional adaptations in the central nervous system. The long-term behavioral consequences of such changes are of substantial cost to both the individual and society. Substantial progress has been made in the las...

Novel gene networks altered by binge ethanol in adolescent mice. Two novel gene networks generated by Ingenuity Pathway Analysis identified genes involved in histone methylation. The table reflects genes in the Gene Ontology analysis, GO: 0032454 histone demethylase activity (H3-K9 specific) or GO:0010452 histone H3-K36 methylation that were signif...

Novel gene network altered by binge ethanol and persistently altered in adulthood. A representative novel gene network generated by Ingenuity Pathway Analysis of genes persistently altered by adolescent binge ethanol. This network is enriched in genes involved in AMPA receptor signaling.

Adolescents primarily consume alcohol in binges, which can be particularly harmful to the developing frontal cortex and increase risk for an adult alcohol use disorder. We conducted a study investigating immediate and long lasting changes to the prefrontal cortex (PFC) transcriptome to determine the molecular mechanisms underlying adult ethanol beh...

Chronic tobacco use dramatically increases health burdens and financial costs. Limitations of current smoking cessation therapies indicate the need for improved molecular targets. The main addictive component of tobacco, nicotine, exerts its dependency effects via nicotinic acetylcholine receptors (nAChRs). Activation of the homomeric α7 nAChR redu...

Background: Alcohol Dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified. Methods: We conducted a genomewide association study in 706 related AD cases and 1748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms t...

The transition from acute to chronic ethanol exposure leads to lasting behavioral and physiological changes such as increased consumption, dependence, and withdrawal. Changes in brain gene expression are hypothesized to underlie these adaptive responses to ethanol. Previous studies on acute ethanol identified genetic variation in brain gene express...

Neuroactive steroids modulate alcohol’s impact on brain function and behavior. Ethanol exposure alters neuroactive steroid levels in rats, humans, and some mouse strains. We conducted an exploratoryanalysis of the neuroactive steroids (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP), (3α,5α)-3,21-dihydroxypregnan-20-one (3α,5α-THDOC), and pregnenolone a...

Genetic factors that influence the transition from initial drinking to dependence remain enigmatic. Recent studies have leveraged chronic intermittent ethanol (CIE) paradigms to measure changes in brain gene expression in a single strain at 0, 8, 72 h, and even 7 days following CIE. We extend these findings using LCM RNA-seq to profile expression i...

The BXD family of mice were generated by crossing and inbreeding ethanol-preferring C57BL/6J and ethanol-avoiding DBA/2J strains that differ greatly in genome sequence and other behaviors. This study evaluated variations in the level of voluntary ethanol intake in a cohort of 42 BXD strains and both progenitor strains using a model of alcohol depen...

Alcohol (ethanol) dependence is a chronic relapsing brain disorder partially influenced by genetics and characterized by an inability to regulate harmful levels of drinking. Emerging evidence has linked genes that encode KV7, KIR, and KCa2 K+ channels with variation in alcohol-related behaviors in rodents and humans. This led us to experimentally t...

Genetic differences in acute behavioral responses to ethanol contribute to the susceptibility to alcohol use disorder and the reduction of anxiety is a commonly reported motive underlying ethanol consumption among alcoholics. Therefore, we studied the genetic variance in anxiolytic-like responses to ethanol across the BXD recombinant inbred mouse p...

Long lasting abusive consumption, dependence, and withdrawal are characteristic features of alcohol use disorders (AUD). Mechanistically, persistent changes in gene expression are hypothesized to contribute to brain adaptations leading to ethanol toxicity and AUD. We employed repeated chronic intermittent ethanol (CIE) exposure by vapor chamber as...

Background: Ethanol (EtOH) and nicotine abuse are 2 leading causes of preventable mortality in the world, but little is known about the pharmacological mechanisms mediating co-abuse. Few studies have examined the interaction of the acute effects of EtOH and nicotine. Here, we examine the effects of nicotine administration on the duration of EtOH-i...