Biology subjects

Miles, M. F.

Publications and source records attributed to Miles, M. F..

16 recordsLinked to original sources

bioRxiv2025

Variation of Myelin-associated Gene Expression and Ndrg1 within the Prefrontal Cortex as Determinants for Initial Level of Response to Alcohol

BackgroundStudies in humans and animal models have documented relationships between initial sensitivity to alcohol and alcohol drinking behavior. Prior expression profiling studies of C57BL/6J and DBA/2J mice and rhesus macaques within the prefrontal cortex (PFC) have shown variation in myelin gene expression may be linked with alcohol sensitivity and consumption. MethodsCombining gene expression studies from human and mouse PFC, we identified a cross-species gene network enriched for myelin-associated genes. Since myelin expression is correlated to alcohol sensitivity and alcohol drinking behavior, we hypothesized basal levels of PFC myelin gene expression may be a genomic determinant for these behavioral responses. Using an animal model of CNS demyelination, and localized knock down of N-myc downstream regulated gene 1 (Ndrg1), we measured effects of cortical myelin reduction on initial alcohol sensitivity and drinking behavior. ResultsReducing myelin-related gene expression significantly altered sensitivity to alcohol and decreased alcohol consumption. Mouse genetic-based studies identified Ndrg1 as a putative quantitative trait gene for sedative-hypnotic responses to alcohol. Site-specific injections of shNdrg1 lentivirus into PFC led to a significant decrease in NDRG1 expression, causing increased alcohol behavioral sensitivity and reduced preference for high concentrations of alcohol. ConclusionMyelin is an important biological component underlying CNS disorders. Our studies demonstrate the role of a novel candidate gene (Ndrg1), and myelin-associated gene expression, as an important factor modulating initial sensitivity to alcohol and alcohol consumption. Differences in the expression of myelin-related genes, including Ndrg1, may serve as future therapeutic targets for the treatment of alcohol use disorders.

neuroscience↗

bioRxiv2025

Transcriptomic and network analyses of an alcohol-induced peripheral neuropathy model identify putative role for histone demethylase Jmjd1c

BackgroundAlcohol-induced peripheral neuropathy (AIPN) is a painful and prevalent condition associated with chronic alcohol use, yet its molecular underpinnings remain poorly understood. Because the analgesic effects of ethanol may reinforce alcohol consumption, elucidating the mechanisms driving AIPN is essential. This study aimed to identify ethanol-regulated gene expression patterns in the nervous system of a mouse model of AIPN. MethodsMale (n = 10) and female (n = 12) C57BL/6J mice were administered either an ethanol-containing Lieber-DeCarli liquid diet at 5% or an isocaloric control diet for four weeks. Ethanol consumption was recorded daily for the experimental group. After the drinking protocol, spinal cord and dorsal root ganglia tissues were collected for RNA sequencing. ResultsEthanol-regulated genes were identified for each sex-tissue group using DESeq2, and results were compared to known rodent neuropathic pain gene signatures. Weighted gene co-expression network analysis (WGCNA) identified modules of co-expressed genes associated with ethanol administration. Hub genes with high intramodular connectivity were identified for ethanol-correlated modules. Of the 14 identified hub genes, 10 have been previously implicated in pain or neuropathy, including Jmjd1c, Phf8, and Gas6, which emerged as particularly strong candidates for involvement in AIPN pathophysiology. ConclusionsThese findings provide novel insights into the gene networks underlying AIPN and nominate specific genes for future functional studies.

neuroscience↗

bioRxiv2025

Peripheral Neuropathy After Chronic Alcohol Exposure in Mice: Impact of sex, total intake and duration and alcohol metabolism.

Alcohol induced peripheral neuropathy (AIPN) is a neurodegenerative disease caused by chronic alcohol intake and is associated with peripheral nerve damage and somatosensory symptoms, such as allodynia. Current treatments lack efficacy and do not target underlying pathology emphasizing the need for preclinical models of AIPN to elucidate mechanisms and novel targets. Thus, we performed a detailed characterization of a mouse model of AIPN and candidate mechanistic associations including the role of neuroinflammation and acetaldehyde. Our studies showed chronic alcohol induced mechanical and cold hypersensitivity and deficits in spontaneous behaviors in EtOH concentration-, time- and sex-dependent manners. Female mice drank more alcohol and developed more rapid and severe hypersensitivity but less robust deficits of spontaneous behaviors. The grimace test demonstrated chronic alcohol promoted spontaneous pain independent of sex. Duration of intake impacted alcohol-induced deficits in peripheral nerve electrophysiology amplitude and intra-epidermal nerve fiber density. We characterized an extensive time-course of chronic alcohol-induced neuroinflammation in the DRG and spinal cord and found significant time, sex and tissue effects. Polymorphisms of ALDH2 have been associated with alcohol-induced neuroinflammation, alcohol-related pain, and alcohol-induced peripheral neuropathy. We investigated the role of acetaldehyde, via inhibition of ALDH2, in the development of AIPN and showed that ALDH2 inhibition accelerated and exacerbated development of chronic alcohol-induced hypersensitivity in male and female mice. Overall, our studies in a well-controlled model of AIPN strongly point to neuroinflammation and inflammatory modulators such as acetaldehyde as important mechanistic targets for possible intervention in AIPN.

pharmacology and toxicology↗

bioRxiv2025

Genetic Mapping in Diversity Outbred Mice Identifies Novel Loci and Candidate Genes for Anxiety-Like Behavior and Genetic Subgroups Predictive of Ethanol Consumption

Anxiety disorders are the most common class of psychiatric disorder. Risk for anxiety disorders is thought to be influenced by many genes, each contributing a small effect. The light-dark box behavioral assay was designed to measure anxiety-like behavior in rodents. Diversity Outbred (DO) mice were designed for high-resolution quantitative trait loci (QTL) mapping on a genetically-diverse background. Here, we studied a population of 518 male DO mice for anxiety-like and locomotor behaviors from a light-dark box assay. Multivariate analysis of behavioral data identified two major subgroups of animals differing in basal anxiety behavior and subsequent ethanol consumption patterns. Behavioral QTL analysis identified a significant locus on Chromosome 14 associated with 3 anxiety-like behavioral phenotypes. Haplotype analysis revealed an effect of C57BL/6J alleles at this locus, with mice carrying those alleles exhibiting more anxiety-like behavior. An additional 9 suggestive loci were identified. Genes located within the confidence intervals for the Chromosome 14 locus were analyzed for coding sequence polymorphisms, prefrontal cortex expression QTLs, human GWAS data, and additional data sets related to psychiatric conditions including substance use. Results prioritized two candidate genes, Tbc1d4 and Lmo7, for further study. These results represent the highest-resolution genetic mapping of light-dark box behaviors in mice to date, revealing insights into the complex biology of anxiety disorders. Additionally the studies identify striking subgroups of animals where basal anxiety-like behavior predicts eventual ethanol consumption phenotypes.

animal behavior and cognition↗

bioRxiv2025

RNA-sequencing Strain-specific Genome Alignment Increases Differential Expression Findings in Comparison of C57BL/6J and DBA/2J Nucleus Accumbens

Alcohol Use Disorder (AUD) is a polygenic disease defined by the inability to regulate alcohol consumption despite adverse consequences. C57BL/6J (B6) and DBA/2J (D2) mice, the progenitor strains to the BXD recombinant inbred strain, exhibit differences in voluntary ethanol consumption and other ethanol behaviors, making them frequently used models for studying genetic influences on ethanol responses. The B6 genome is the standard reference genome for the majority of mouse RNA-sequencing (RNAseq) studies, including studies on D2 mice. We hypothesized that aligning B6 and D2 RNAseq data to their strain specific genome would allow improved detection of differentially expressed genes (DEGs) in comparison of brain gene expression between these two strains. RNA samples obtained from B6 and D2 nucleus accumbens (NAc) tissue were analyzed using a standard RNAseq analysis pipeline except from genome alignment. Following quality control, samples were aligned to either the B6 reference genome (Release 108) or the D2 samples were aligned to a recent homologous genome assembly (GCA_921998315.2). Alignment of D2 samples to the D2 genome showed significantly higher alignment compared to the B6 reference genome (93.82% vs 92.02%, p = 0.0272), but also showed a decrease in the number of total reads assigned (72.30%% vs 74.36%, p <0.0001). When comparing B6 and D2 expression, using the D2 alignment resulted in large increases in the number of differentially expressed genes (DEGs) (10,777 vs 6,191) and differentially utilized exons (DUEs) (81,206 vs 21,223) with resulting changes in gene ontology functional analyses. The gene ontology identified substantial overlap between the two analyses while also adding novel categories. These studies highlight the importance of using strain-specific alignment in increasing the number of reads aligned and the number of DEGs and DUEs identified. The use of strain-specific alignment in RNA-seq studies may provide greater accuracy in investigating gene expression and pathways regulated by ethanol in model organism studies on molecular mechanisms of AUD.

genomics↗

bioRxiv2025

GSK3B inhibition partially reverses brain ethanol-induced transcriptomic changes in C57BL/6J mice: Expression network co-analysis with human genome-wide association studies

Alcohol use disorder (AUD) is a chronic behavioral disease with greater than 50% of its risk due to complex genetic contributions. Existing pharmacological and behavioral treatments for AUD are minimally effective and underutilized. Animal model behavioral genetics and human genome-wide association studies have begun to identify individual genes contributing to the progressive compulsive consumption of ethanol that occurs with AUD, promising possible new therapeutic targets. Our laboratory has previously identified Gsk3b as a central member in a network of ethanol-responsive genes in mouse prefrontal cortex, which altered ethanol consumption with genetic manipulation and was also significantly associated with risk for alcohol dependence in human genome-wide association studies. Here we perform detailed brain RNA sequencing transcriptomic studies to characterize a highly specific and clinically available GSK3B pharmacological inhibitor, tideglusib, as a possible therapeutic for clinical trials on treatment of AUD. A model of chronic intermittent ethanol consumption was used to study gene expression changes in prefrontal cortex and nucleus accumbens in the presence or absence of tideglusib treatment. Multivariate analysis of differentially expressed genes showed that tideglusib largely reversed ethanol- induced expression changes for two prominent clusters of genes in both prefrontal cortex and nucleus accumbens. Bioinformatic analysis showed these genes to have prominent roles in neuronal functioning and synaptic activity. Additionally, mouse brain differential gene expression data was analyzed together with human protein-protein interaction and genome-wide association studies on AUD to derive networks responding to tideglusib and relevant to human genetic risk for alcohol dependence. These studies identified discrete networks significantly enriched with genes provisionally associated with AUD, and provide key information on central hubs of such networks. Together these studies document tideglusib as a major modulator of chronic ethanol consumption-evoked brain gene expression signatures, and identify possible new targets for therapeutic modulation of AUD.

genomics↗

bioRxiv2024

Identification of ethanol analgesia quantitative trait loci and candidate genes in BXD recombinant inbred mouse lines

Alcohol consumption produces acute analgesic effects, and people experiencing pain conditions may drink alcohol to alleviate discomfort. However, tolerance to the analgesic properties of alcohol could prompt escalating consumption and dependence. Both nociception and alcohol-induced analgesia are under significant genetic control. Understanding the genetic architecture of these processes could inform better treatment options for people with pain conditions. This study aims to identify quantitative trait loci (QTL) driving variation in ethanol-induced analgesia across BXD recombinant inbred mouse lines. Male and female mice from 62 BXD strains received ethanol or saline oral gavage for five days and were tested for hot plate (HP) latency at baseline, Day 1, and Day 5. QTL mapping of HP phenotypes identified a significant provisional QTL on chromosome 17 for Day 1 HP latency in mice receiving ethanol. An additional highly suggestive QTL was present on chromosome 9 for the difference in pre- and post-ethanol thermal nociception. Candidate genes within QTL support intervals were provisionally identified using HP phenotypic correlations to transcriptomic database, expression QTL analysis, and other bioinformatics inquiries. The combined behavioral and bioinformatic analyses yielded strong ethanol analgesia candidate genes, specifically Myo6. Thus, the results of this genetic study of ethanol-induced analgesia in BXD mouse strains may contribute significantly to our understanding of the molecular basis for individual variation in the analgesic response to acute ethanol.

genetics↗

bioRxiv2024

Genomic and Transcriptomic Analysis of Ninein Alternative Splicing Between C57BL/6J and DBA/2J Mice

Ethanols anxiolytic actions contribute to increased consumption and the development of Alcohol Use Disorder (AUD). Our laboratory previously identified genetic loci contributing to the anxiolytic-like properties of ethanol in BXD recombinant inbred mice, derived from C57BL/6J (B6) and DBA/2J (D2) progenitor strains. That work identified Ninein (Nin) as a candidate gene underlying ethanols acute anxiolytic-like properties in BXD mice. Nin has a complex exonic content with known alternative splicing events that alter cellular distribution of the NIN protein. We hypothesize that strain-specific differences in Nin alternative splicing contribute to changes in Nin gene expression and B6/D2 strain differences in ethanol anxiolysis. Using quantitative reverse-transcriptase PCR to target Nin alternative splicing, we identified isoform-specific exon expression differences between B6 and D2 mice in prefrontal cortex, nucleus accumbens and amygdala. We extended this analysis using deep RNA sequencing in B6 and D2 nucleus accumbens samples and that Nin expression was significantly higher in D2 mice. Furthermore, exon utilization and alternative splicing analyses identified 8 differentially utilized exons and significant exon-skipping events between the strains, including 3 novel splicing events in the 3 end of the Nin gene that were specific to the D2 strain. Our studies provide the first in-depth analysis of Nin alternative splicing in brain and identify a potential genetic mechanism altering Nin expression between B6 and D2 mice, thus contributing to differences in the anxiolytic-like properties of ethanol between these strains. This work contributes to our understanding of genetic differences modulating ethanol actions on anxiety that may contribute to the risk for alcohol use disorder.

genetics↗

bioRxiv2024

A selective GSK3β inhibitor, tideglusib, decreases intermittent access and binge ethanol self-administration in C57BL/6J mice

Over 10% of the US population over 12 years old meets criteria for Alcohol Use Disorder (AUD), yet few effective, long-term treatments are currently available. Glycogen synthase kinase 3 beta (GSK3{beta}) has been implicated in ethanol behaviors and poses as a potential therapeutic target in the treatment of AUD. Here we investigate the role of tideglusib, a selective GSK3{beta} inhibitor, in ethanol consumption and other behaviors. We have shown tideglusib decreases ethanol consumption in both a model of daily, progressive ethanol intake (two-bottle choice, intermittent ethanol access) and binge-like drinking behavior (drinking-in-the-dark) without effecting water intake. Further, we have shown tideglusib to have no effect on ethanol pharmacokinetics, taste preference, or anxiety-like behavior, though there was a transient increase in total locomotion following treatment. Additionally, we assessed liver health following treatment via serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase and showed no effect on aminotransferase levels though there was a decrease in alkaline phosphatase. RNA sequencing studies revealed a role of GSK3{beta} inhibition via tideglusib on the canonical Wnt signaling pathway, suggesting tideglusib may carry out its effects on ethanol consumption through effects on {beta}-catenin binding to the transcription factors TCF3 and LEF1. The data presented here further implicate GSK3{beta} in alcohol consumption and support the use of tideglusib as a potential therapeutic in the treatment of AUD.

pharmacology and toxicology↗

bioRxiv2023

Identification of Genetic and Genomic Influences on Progressive Ethanol Consumption in Diversity Outbred Mice

Genetic factors play a significant role in the risk for development of alcohol use disorder (AUD). Using 3-bottle choice intermittent access ethanol (IEA), we have employed the Diversity Outbred (DO) mouse panel as a model of alcohol use disorder in a genetically diverse population. Through use of gene expression network analysis techniques, in combination with expression quantitative trait loci (eQTL) mapping, we have completed an extensive analysis of the influence of genetic background on gene expression changes in the prefrontal cortex (PFC). This approach revealed that, in DO mice, genes whose expression was significantly disrupted by intermittent ethanol in the PFC also tended to be those whose expression correlated to intake. This finding is in contrast to previous studies of both mice and nonhuman primates. Importantly, these analyses identified genes involved in myelination in the PFC as significantly disrupted by IEA, correlated to ethanol intake, and having significant eQTLs. Genes that code for canonical components of the myelin sheath, such as Mbp, also emerged as key drivers of the gene expression response to intermittent ethanol drinking. Several regulators of myelination were also key drivers of gene expression, and had significant QTLs, indicating that genetic background may play an important role in regulation of brain myelination. These findings underscore the importance of disruption of normal myelination in the PFC in response to prolonged ethanol exposure, that genetic variation plays an important role in this response, and that this interaction between genetics and myelin disruption in the presence of ethanol may underlie previously observed behavioral changes under intermittent access ethanol drinking such as escalation of consumption.

genomics↗

bioRxiv2022

Genetic Mapping of Progressive Ethanol Consumption in the Diversity Outbred Mouse

Traditional genetic mapping studies using inbred crosses are a powerful tool for identifying chromosomal regions associated with ethanol-related traits, but typically have very large confidence intervals which make identification of specific and potentially causal candidate genes difficult. Diversity Outbred (DO) mice offer the ability to map quantitative trait loci (QTLs) associated with ethanol-drinking behaviors at a high resolution that allows for easier identification of candidate genes. Here, we exposed a population of 636 male DO mice to four weeks of intermittent ethanol access via a three-bottle choice paradigm, identifying 3 significant (Chrs 3, 4, and 12) and 12 suggestive loci for ethanol-drinking behaviors. The confidence intervals for these loci were narrow (1-4 Mbp for significant QTLs). We then further analyzed positional candidate genes using transcriptomics data from prefrontal cortex samples taken from 220 of these animals, as well as human GWAS data and prior gene set data for ethanol or other drugs of abuse. These results represent the highest-resolution genetic mapping of ethanol consumption behaviors in mice to date, providing for the identification of novel loci and candidate genes for progressive ethanol consumption, including Car8 --the lone gene with a significant cis-eQTL in strong linkage disequilibrium with our QTL for last week ethanol consumption on Chr 4.

genetics↗

bioRxiv2021

Transcriptome Analysis of Chloride Intracellular Channel Knockdown in Drosophila Identifies Oxidation-Reduction Function as Possible Mechanism of Altered Sensitivity to Ethanol Sedation

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. Understanding the molecular mechanisms by which CLICs engage in these activities is an area of active research. Here, the sole Drosophila melanogaster ortholog, Clic, was targeted for RNAi knockdown to identify genes and biological processes associated with Clic expression. Clic knockdown had a substantial impact on global transcription, altering expression of over 9% of transcribed Drosophila genes. Overrepresentation analysis of differentially expressed genes identified enrichment of 23 Gene Ontology terms including Cytoplasmic Translation, Oxidation-Reduction Process, Heme Binding, Membrane, Cell Junction, and Nucleolus. The top term, Cytoplasmic Translation, was enriched almost exclusively with downregulated genes. Drosophila Clic and vertebrate ortholog Clic4 have previously been tied to ethanol sensitivity and ethanol-regulated expression. Clic knockdown-responsive genes from the present study were found to overlap significantly with gene sets from 4 independently published studies related to ethanol exposure and sensitivity in Drosophila. Bioinformatic analysis of genes shared between these studies revealed an enrichment of genes related to amino acid metabolism, protein processing, oxidation-reduction processes, and lipid particles among others. To determine whether the modulation of ethanol sensitivity by Clic may be related to co-regulated oxidation-reduction processes, we evaluated the effect of hyperoxia on ethanol sedation in Clic knockdown flies. Consistent with previous findings, Clic knockdown reduced acute ethanol sedation sensitivity in flies housed under nomoxia. However, this effect was reversed by exposure to hyperoxia, suggesting a common set of molecular-genetic mechanism may modulate each of these processes. This study suggests that Drosophila Clic has a major influence on regulation of oxidative stress signaling and that this function overlaps with the molecular mechanisms of acute ethanol sensitivity in the fly.

neuroscience↗

bioRxiv2020

Network Preservation Reveals Shared and Unique Biological Processes Associated with Chronic Alcohol Abuse in NAc and PFC.

BackgroundExcessive 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. MethodsWe utilized weighted gene co-expressed network analysis (WGCNA) and network preservation using a case/control study design (n=35) to identify unique and shared biological processes dysregulated in AD in the prefrontal cortex (PFC) and nucleus accumbens (NAc). We used correlation and regression analyses to identify mRNA/miRNA interactions and local expression quantitative trait loci (cis-eQTL) to identify genetic regulatory mechanisms for networks significantly associated with AD. ResultsNetwork analyses revealed 6 and 3 significant mRNA modules from the NAc and PFC, respectively. Network preservation revealed immune response upregulation in both regions, whereas cellular morphogenesis/localization and cilia-based cell projection processes were upregulated only in the NAc. We observed 4 significantly correlated module eigengenes (ME) between the significant mRNA and miRNA modules in PFC, and 6 significant miRNA/mRNA ME correlations in NAc, with the mir-449a/b cluster emerging as a potential regulator for cellular morphogenesis/localization dysregulation in this brain region. Finally, we identified cis-eQTLs (37 mRNA and 9 miRNA in NAc, and 17 mRNA and 16 miRNA in PFC) which potentially mediate alcohols effect in a brain region-specific manner. ConclusionIn agreement with previous reports, we observed a generalized upregulation of immune response processes in subjects with AD, that highlights alcohols neurotoxic properties, while simultaneously demonstrating distinct molecular changes in subcortical brain regions as a result of chronic alcohol abuse. Such changes further support previous neuroimaging and physiological studies that emphasize the distinct roles PFC and NAc play in the development of addictive behaviors.

genomics↗

bioRxiv2019

Brain Regional Gene Expression Network Analysis Identifies Unique Interactions Between Chronic Ethanol Exposure and Consumption

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 microarray and scale-free network analysis of expression responses in a C57BL/6J mouse model utilizing chronic intermittent ethanol by vapor chamber (CIE) in combination with limited access oral ethanol consumption. This model has previously been shown to produce long-lasting increased ethanol consumption, particularly when combining oral ethanol access with repeated cycles of intermittent vapor exposure. The interaction of CIE and oral consumption was studied by expression profiling and network analysis in medial prefrontal cortex, nucleus accumbens, hippocampus, bed nucleus of the stria terminalis, and central nucleus of the amygdala. Brain region expression networks were analyzed for ethanol-responsive gene expression, correlation with ethanol consumption and functional content using extensive bioinformatics studies. In all brain-regions studied the largest number of changes in gene expression were seen when comparing ethanol naive mice to those exposed to CIE and drinking. In the prefrontal cortex, however, unique patterns of gene expression were seen compared to other brain-regions. Network analysis identified modules of co-expressed genes in all brain regions. The prefrontal cortex and nucleus accumbens showed the greatest number of modules with significant correlation to drinking behavior. Across brain-regions, however, many modules with strong correlations to drinking, both baseline intake and amount consumed after CIE, showed functional enrichment for synaptic transmission and synaptic plasticity.

genomics↗

bioRxiv2019

A History of Chronic Repeated Predation Stress Reduces Aversion to Ethanol Adulteration in Male, but not Female, C57Bl/6J Mice

BackgroundTrauma 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 development of AUD, with conflicting data on the impact of sex in the comorbid development of both disorders. Because the likelihood of experiencing more than one traumatic event is high, we aim to utilize chronic repeated predatory stress (CRPS) to query the extent to which sex interacts with CRPS to influence alcohol consumption, or cessation of consumption. MethodsMale (n=16) and female (n=15) C57BL/6J mice underwent CRPS or daily handling for two weeks during adolescence (P35-P49) and two weeks during adulthood (P65-P79). Following the conclusion of two rounds of repeated stress, behavior was assessed in the open field. Mice subsequently underwent a two-bottle choice intermittent ethanol access (IEA) assessment (P90-131) with the options of 20% ethanol or water. After establishing drinking behavior, increasing concentrations of quinine were added to the ethanol to assess the drinking response to adulteration of the alcohol. ResultsCRPS increased fecal corticosterone concentrations and anxiety-like behaviors in the open field in both male and female mice as compared to control mice that had not been exposed to CRPS. Consistent with previous reports, we observed a sex difference in alcohol consumption such that females consumed more ethanol per gram of body mass than males. In addition, CRPS reduced alcohol aversion in male mice such that higher concentrations of quinine were necessary to reduce alcohol intake as compared to control mice. CRPS did not alter alcohol-related behaviors in female mice. ConclusionCollectively, we demonstrate that repeated CRPS can induce anxiety-like behavior in both sexes but selectively influences the response to ethanol adulteration in males.

neuroscience↗

bioRxiv2018

Cross-species alcohol dependence-associated gene networks: Co-analysis of mouse brain gene expression and human genome-wide association data

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 identifying dependence-associated genes and functional networks in which they are involved. This study used a modification of the Edge-Weighted Dense Module Searching for genome-wide association studies (EW-dmGWAS) approach to co-analyze whole-genome gene expression data from ethanol-exposed mouse brain tissue, human protein-protein interaction databases and alcohol dependence-related genome-wide association studies. Results revealed novel ethanol-regulated and alcohol dependence-associated gene networks in prefrontal cortex, nucleus accumbens, and ventral tegmental area. Three of these networks were overrepresented with genome-wide association signals from an independent dataset. These networks were significantly overrepresented for gene ontology categories involving several mechanisms, including actin filament-based activity, transcript regulation, Wnt and Syndecan-mediated signaling, and ubiquitination. Together, these studies provide novel insight for brain mechanisms contributing to alcohol dependence.

genetics↗