Ontology highlight
ABSTRACT:
PROVIDER: PRJNA634528 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11831400.fastq.gz | Fastqsanger.gz | |||
| SRR11831401.fastq.gz | Fastqsanger.gz | |||
| SRR11831402.fastq.gz | Fastqsanger.gz | |||
| SRR11831403.fastq.gz | Fastqsanger.gz | |||
| SRR11831404.fastq.gz | Fastqsanger.gz |
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Project description:Alcohol use disorder is marked by disrupted behavioral and emotional states which can persist into abstinence. The enduring synaptic alterations that remain despite the absence of alcohol are of interest for interventions to prevent relapse. 28 male rhesus macaques underwent over 20 months of alcohol drinking interspersed with three 30-day forced abstinence periods. After the last abstinence period, we paired ex vivo voltammetry in nucleus accumbens slices with RNA-sequencing of the ventral tegmental area. We found persistent augmentation of dopamine transporter function, kappa opioid receptor sensitivity, and dynorphin release – all inhibitory regulators which act to decrease extracellular dopamine. Surprisingly, though transcript expression was not altered, the relationship between gene expression and functional readouts of these encoded proteins was highly dynamic and altered by drinking history. Therefore, the long-lasting synaptic impact of alcohol use suggests that assessment of transcript-function relationships may provide avenues for precision therapeutics targeted to specific synaptic pathophysiologies.
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Project description:Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect. However, the role of the gut microbiome and its metabolites in modulating cocaine-seeking behavior after prolonged abstinence is unknown. Given that relapse prevention is the most clinically challenging issue in treating substance use disorders, studies examining the effects of microbiome manipulations in relapse-relevant models are critical. Here, Sprague-Dawley rats received either untreated water or antibiotics to deplete the gut microbiome and its metabolites. Rats were trained to self-administer cocaine and subjected to either within-session threshold testing to evaluate motivation for cocaine or 21 days of abstinence followed by a cue-induced cocaine-seeking task to model relapse behavior. Microbiome depletion did not affect cocaine acquisition on an FR1 schedule. However, microbiome-depleted subjects exhibited significantly enhanced motivation for low dose cocaine on a within-session threshold task. Similarly, microbiome depletion increased cue-induced cocaine-seeking following prolonged abstinence. In the absence of a normal microbiome, repletion of bacterially-derived SCFA metabolites reversed the behavioral and transcriptional changes associated with microbiome depletion. These findings suggest that gut bacteria, via their metabolites, are key regulators of drug-seeking behaviors, positioning the microbiome as a potential translational research target.
2024-05-01 | GSE227980 | GEO
Project description:Ethanol is the most common substance of abuse in the US, and abuse can lead to physical dependence, addiction, brain damage and premature death. The cycle of alcohol addiction has been described as a composite consisting of three stages: intoxication, withdrawal and craving/abstinence. As a complex brain disorder, there is evidence for both a genetic contribution to risk and sexually-dimorphic responses in alcoholism, but an overall understanding of the biological contributions and the neuroadaptive underpinnings of alcohol addiction is limited. Utilizing novel genetic animal models with highly divergent withdrawal severity, Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) selected lines of mice and by examining both sexes, the distinct or common contributions of response to alcohol genotype/phenotype and of sex to addiction stages over time were characterized. Transcriptional profiling was performed to identify neuroadaptive changes as a consequence of chronic intoxication in the medial prefrontal cortex (mPFC). Significant expression differences were identified for each line and tracked over a behaviorally-relevant time course that covered each stage of alcohol addiction; i.e., after chronic intoxication, during peak withdrawal, and after a defined period of abstinence. Females were more responsive to ethanol with higher fold expression differences. Data structure was analyzed by bioinformatics, which showed a strong effect of sex with high similarity of male vs. female expression profiles during chronic intoxication and at peak withdrawal irrespective of genetic background. However, during abstinence, striking differences were observed instead between the lines/phenotypes irrespective of sex. Because sex was the strongest influence on neuroadaptive changes overall, confirmation analysis compared males vs. females. Notably, results revealed distinct inflammatory signaling between males and females at peak withdrawal, with a pro-inflammatory inflammotoxic phenotype in females but in contrast overall suppression of immune signaling in males. Thus, the early response to chronic intoxication is strongly influenced by sex while pathways that are altered during a period of abstinence are dependent on genotype. Combined, these results suggest that each stage of the addiction cycle is influenced differentially by sex vs. genetic background and support the development of distinct translational targets for stage- and sex-specific therapies for the treatment of alcohol withdrawal and the maintenance of sobriety.
2014-09-17 | GSE56247 | GEO
Project description:Repeated excessive alcohol consumption is a risk factor for alcohol use disorder (AUD). Although AUD has been more common in men than women, women develop more severe behavioral and physical impairments. However, relatively few new therapeutics targeting development of AUD have been validated. Here, to gain a better understanding of molecular mechanisms underlying alcohol intake, we conducted a genome-wide RNA-sequencing analysis in female mice exposed to different modes (acute vs chronic) of ethanol drinking. We focused on transcriptional profiles in amygdala including the central and basolateral subnuclei, brain areas previously implicated in alcohol drinking and seeking. We found distinct gene expression patterns and canonical pathways induced by both acute and chronic intake. Surprisingly, both drinking modes triggered similar transcriptional changes, including up-regulation of ribosome-related/translational pathways and myelination pathways, and down-regulation of chromatin binding and histone modification. Notably, multiple genes that were significantly altered with alcohol drinking, including Atp2b1, Hspa4, Slc4a7, Sbno1, Ubxn2b, Nfkb1, Nts, and Hdac2, had previously been associated with human AUD via GWAS or other genomic studies. In addition, subsequent analyses of hub genes and upstream regulatory pathways predicted that voluntary ethanol consumption affects epigenetic changes via histone deacetylation pathways, oligodendrocyte and myelin function, and the oligodendrocyte-related transcription factor, Sox17. Overall, our results suggest that the expression of oligodendrocyte-related genes in the central and basolateral subnuclei of the amygdala is sensitive to voluntary alcohol drinking. These findings suggest potential molecular targets for future therapeutic approaches to prevent the development of AUD, particularly in women, due to repeated excessive alcohol consumption
2022-11-28 | GSE208014 | GEO
Project description:Alcohol Use Disorder (AUD) is a complex psychiatric disorder with strong genetic as well as environmental risk factors. One risk factor for developing AUD is binge drinking. High Drinking in the Dark mice (HDID-1) have been selectively bred from genetically heterogeneous mice (HS/Npt stock) for attaining high blood alcohol concentrations (BAC) after a 4-hour drinking session in which a single bottle containing 20% ethanol is available and serve as a genetic model of binge drinking. To discover molecular mechanisms underlying the genetic predisposition to binge drinking, we characterized global gene expression in 7 brain regions across the addiction neurocircuit, precisely excised using laser capture microdissection from male, ethanol-naive HDID-1 and control mice Brain regions included in the analysis are prefrontal cortex (PFC), nucleus accumbens core (AcbC), nucleus accumbens shell (AcbSh), bed nucleus of the stria terminalis (BNST), basolateral amygdala (BLA), central amygdala (CeA), and ventral tegmental area (VTA)
2017-01-10 | GSE93311 | GEO
Project description:Ethanol is the most common substance of abuse in the US, and abuse can lead to physical dependence, addiction, brain damage and premature death. The cycle of alcohol addiction has been described as a composite consisting of three stages: intoxication, withdrawal and craving/abstinence. As a complex brain disorder, there is evidence for both a genetic contribution to risk and sexually-dimorphic responses in alcoholism, but an overall understanding of the biological contributions and the neuroadaptive underpinnings of alcohol addiction is limited. Utilizing novel genetic animal models with highly divergent withdrawal severity, Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) selected lines of mice and by examining both sexes, the distinct or common contributions of response to alcohol genotype/phenotype and of sex to addiction stages over time were characterized. Transcriptional profiling was performed to identify neuroadaptive changes as a consequence of chronic intoxication in the medial prefrontal cortex (mPFC). Significant expression differences were identified for each line and tracked over a behaviorally-relevant time course that covered each stage of alcohol addiction; i.e., after chronic intoxication, during peak withdrawal, and after a defined period of abstinence. Females were more responsive to ethanol with higher fold expression differences. Data structure was analyzed by bioinformatics, which showed a strong effect of sex with high similarity of male vs. female expression profiles during chronic intoxication and at peak withdrawal irrespective of genetic background. However, during abstinence, striking differences were observed instead between the lines/phenotypes irrespective of sex. Because sex was the strongest influence on neuroadaptive changes overall, confirmation analysis compared males vs. females. Notably, results revealed distinct inflammatory signaling between males and females at peak withdrawal, with a pro-inflammatory inflammotoxic phenotype in females but in contrast overall suppression of immune signaling in males. Thus, the early response to chronic intoxication is strongly influenced by sex while pathways that are altered during a period of abstinence are dependent on genotype. Combined, these results suggest that each stage of the addiction cycle is influenced differentially by sex vs. genetic background and support the development of distinct translational targets for stage- and sex-specific therapies for the treatment of alcohol withdrawal and the maintenance of sobriety. A total of 32 microarrays were run with 4 biological replicates per treatment, line, and sex. Selection replicates (i.e. WSP-1 and WSP-2) for each treatment, line, and sex were collapsed to improve statistical power (n=4) and to facilitate in the identification of phenotype related effects and exclude selection artifacts. For comparisons, EtOH regulation was determined by comparing 4 arrays from (for example) Male WSR EtOH treated versus 4 arrays from Male WSR Air treated arrays.
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Project description:Alcohol use disorder (AUD) is a life-threatening disease characterized by compulsive drinking, cognitive deficits, and social impairment that continue despite negative consequences, which are driven by dysfunction of cortical areas, such as the orbitofrontal cortex (OFC), that normally balances decisions related to reward and risk. In this study, proteomics and machine learning analysis of post-mortem OFC brain samples collected from individuals with AUD revealed dysregulation of presynaptic (e.g., AP2A1) and mitochondrial proteins that predicted the occurrence and severity of AUD. Alcohol-sensitive OFC proteins also mapped to abnormal social behaviors and interactions. Validation using reverse genetics, we found that prefrontal Ap2a1 regulates alcohol drinking in genetically diverse mouse strains. Furthermore, we demonstrated sexual dimorphism in human OFC proteins that regulate extracellular matrix structure and signaling. Together, these findings highlight the impact of excessive alcohol consumption on the human OFC proteome and identify important cross-species cortical mechanisms underlying AUD.
2023-10-09 | PXD041727 | Pride