Phenotypic and gene expression features associated with variation in chronic ethanol consumption in heterogeneous stock collaborative cross mice.
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SUBMITTER: Hitzemann R
PROVIDER: S-EPMC7749084 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Of the more than 100 studies that have examined some aspect of the relationships between excessive ethanol consumption and the brain transcriptome, relatively few rodent studies have examined the effects of chronic consumption. The current study allowed 114 heterogeneous stock collaborative cross mice to freely consume 10% ethanol for 3 months (13 weeks), with a water choice. RNA-Seq data were then used to identify transcriptional differences within the central nucleus of the amygdala, a brain region known to impact ethanol preference. Average week 1 preference for consuming ethanol over water was modestly correlated with average preference for the final week of the study, and over the course of the 3-month trial, a sex-difference emerged. In females but not males, there was a significant escalation of preference from week 1 to week 13 and significant alignment of the transcriptome with average week 13 ethanol preference and consumption was found for female, but not male mice. The genes significantly correlated with preference were enriched in annotations associated with cilium movement, cilium organization, extracellular region and collagen-containing extracellular matrix. For the females, 376 of the total 415 genes that correlated with ethanol preference in the gene co-expression network were associated with a single network module that was enriched in genes with an astrocyte annotation. The key hub node in the module was the master regulator, orthodenticle homeobox 2 (Otx2). These data support an important role for the extracellular matrix and primary cilium in individual differences in ethanol preference and consumption in a genetically diverse population of mice.
2020-05-29 | GSE151410 | GEO
Project description:Phenotypic and Gene Expression Features Associated with Variation in Chronic Ethanol Consumption in Heterogeneous Stock Collaborative Cross Mice
| PRJNA635694 | ENA
Project description:The Collaborative Cross (CC) is a panel of reproducible recombinant inbred mouse strains with high levels of standing genetic variation, affording an unprecedented opportunity to perform experiments in a small animal model containing controlled genetic diversity while allowing for genetic replicates. Here, we advance the utility of this unique mouse resource for immunology research because it allows for both examination and genetic dissection of mechanisms behind adaptive immune states in mice with distinct and defined genetic makeups. This approach is based on quantitative trait locus mapping: identifying genetically variant genome regions associated with phenotypic variance in traits of interest. Furthermore, the CC can be utilized for mouse model development; distinct strains have unique immunophenotypes and immune properties, making them suitable for research on particular diseases and infections. Here, we describe variations in cellular immune phenotypes across F1 crosses of CC strains and reveal quantitative trait loci responsible for several immune phenotypes.
| S-EPMC5728448 | biostudies-literature
Project description:BackgroundThe current study focused on the extent genetic diversity within a species (Mus musculus) affects gene co-expression network structure. To examine this issue, we have created a new mouse resource, a heterogeneous stock (HS) formed from the same eight inbred strains that have been used to create the collaborative cross (CC). The eight inbred strains capture > 90% of the genetic diversity available within the species. For contrast with the HS-CC, a C57BL/6J (B6) × DBA/2J (D2) F2 intercross and the HS4, derived from crossing the B6, D2, BALB/cJ and LP/J strains, were used. Brain (striatum) gene expression data were obtained using the Illumina Mouse WG 6.1 array, and the data sets were interrogated using a weighted gene co-expression network analysis (WGCNA).ResultsGenes reliably detected as expressed were similar in all three data sets as was the variability of expression. As measured by the WGCNA, the modular structure of the transcriptome networks was also preserved both on the basis of module assignment and from the perspective of the topological overlap maps. Details of the HS-CC gene modules are provided; essentially identical results were obtained for the HS4 and F2 modules. Gene ontology annotation of the modules revealed a significant overrepresentation in some modules for neuronal processes, e.g., central nervous system development. Integration with known protein-protein interactions data indicated significant enrichment among co-expressed genes. We also noted significant overlap with markers of central nervous system cell types (neurons, oligodendrocytes and astrocytes). Using the Allen Brain Atlas, we found evidence of spatial co-localization within the striatum for several modules. Finally, for some modules it was possible to detect an enrichment of transcription binding sites. The binding site for Wt1, which is associated with neurodegeneration, was the most significantly overrepresented.ConclusionsDespite the marked differences in genetic diversity, the transcriptome structure was remarkably similar for the F2, HS4 and HS-CC. These data suggest that it should be possible to integrate network data from simple and complex crosses. A careful examination of the HS-CC transcriptome revealed the expected structure for striatal gene expression. Importantly, we demonstrate the integration of anatomical and network expression data.
| S-EPMC3091732 | biostudies-literature
Project description:Purpose: Traditional whole-tissue sequencing approaches do not fully capture brain cell-type specific effects of chronic alcohol. Therefore, the purpose of this study was to identify the specific transcriptome alterations in astrocytes due to chronic alcohol. Methods: We performed RNA-sequencing on astrocytes isolated from the prefrontal cortex (PFC) of C57BL/6J mice following chronic every-other-day alcohol consumption. Results: Differential expression analysis revealed alcohol-induced gene expression changes unique to astrocytes that could not be identified using whole tissue homogenate analysis. Enrichment analysis revealed involvement of calcium-related signaling and regulation of extracellular matrix genes in the astrocyte response to alcohol abuse. Conclusion: Our study presents the first focused analysis on the astrocyte transcriptome following chronic alcohol consumption, provides a framework for studying the functional response of astrocytes to alcohol and the possible astrocyte-specific effects of alcohol. In addition, our data represents a novel resource for groups interested in biological functions of astrocytes in the adult mouse PFC.
2018-01-10 | GSE92457 | GEO
Project description:Male Wistar rats weighing 90-120 g were acclimatized for one week and fed standard laboratory chow, at which time the animals were divided into two groups. Animals were then pair-fed for 8 weeks a regular laboratory chow and water “ad libitum” or Lieber-DeCarli diet (36% calories from ethanol). Control animals received the iso-caloric amount of dextrose to replace ethanol. After 8 weeks of differential feeding rats were euthanized, the pancreas immediately dissected and stored at -80?C until RNA isolation. RNA expression was analyzed using Affymetrix RAE230A gene chips Keywords: stress response, disease state analysis
2006-07-01 | GSE3311 | GEO
Project description:Alcohol addiction is a common affliction with a strong genetic component [1]. Although mammalian studies have provided significant insight into the molecular mechanisms underlying ethanol consumption [2], other organisms such as Drosophila melanogaster are better suited for unbiased, forward genetic approaches to identify novel genes. Behavioral responses to ethanol, such as hyperactivity, sedation, and tolerance, are conserved between flies and mammals [3, 4], as are the underlying molecular pathways [5-9]. However, few studies have investigated ethanol self-administration in flies [10]. Here we characterize ethanol consumption and preference in Drosophila. Flies prefer to consume ethanol-containing food over regular food, and this preference increases over time. Flies are attracted to the smell of ethanol, which partially mediates ethanol preference, but are averse to its taste. Preference for consuming ethanol is not entirely explained by attraction to either its sensory or caloric properties. We demonstrate that flies can exhibit features of alcohol addiction. First, flies self-administer ethanol to pharmacologically relevant concentrations. Second, flies will overcome an aversive stimulus in order to consume ethanol. Third, flies rapidly return to high levels of ethanol consumption after a period of imposed abstinence. Thus, ethanol preference in Drosophila provides a new model for studying aspects of addiction.
| S-EPMC2805771 | biostudies-literature
Project description:BackgroundThe effect of stress on alcohol consumption in humans is highly variable, and the underlying processes are not yet understood. Attempts to model a positive relationship between stress and increased ethanol (EtOH) consumption in animals have been only modestly successful. Our hypothesis is that individual differences in stress effects on EtOH consumption are mediated by genetics.MethodsWe measured alcohol consumption, using the drinking-in-the-dark (DID) paradigm in females from 2 inbred mouse strains, C57BL/6J (B6) and DBA/2J (D2), and 35 of their inbred progeny (the BXD family). A control group was maintained in normal housing and a stress group was exposed to chronic mild stress (CMS), consisting of unpredictable stressors over 7 weeks. These included predator, social, and environmental perturbations. Alcohol intake was measured over 16 weeks in both groups during baseline (preceding 5-week period), CMS (intervening 7-week period), and post-CMS (final 4-week period).ResultsWe detected a strong effect of CMS on alcohol intake. A few strains demonstrated CMS-related increased alcohol consumption; however, most showed decreased intake. We identified 1 nearly significant quantitative trait locus on chromosome 5 that contains the neuronal nitric oxide synthase gene (Nos1). The expression of Nos1 is frequently changed following alcohol exposure, and variants in this gene segregating among the BXD population may modulate alcohol intake in response to stress.ConclusionsThe results we present here represent the first study to combine chronic stress and alcohol consumption in a genetic reference population of mice. Differences in susceptibility to the effects of stressful environments vis-à-vis alcohol use disorders would suggest that the differences have at least some basis in genetic constitution. We have also nominated a likely candidate gene underlying the large individual differences in effects of stress on alcohol consumption.
| S-EPMC8287762 | biostudies-literature
Project description:Chronic ethanol consumption is associated with not only the alteration of metabolic profiles in biofluids but also the composition of the gut microbiome. Our understanding of the importance of the intestinal microbiota as well as the disturbances elicited by ethanol intervention is limited by the fact that previous analyses have primarily focused on biofluids and liver tissue metabolome; the metabolic profiles of the gastrointestinal (GI) contents are rarely investigated. In this study, we applied a metabonomics approach using a high performance liquid chromatography-time-of-flight mass spectrometry (HPLC-TOF MS) and gas chromatography-mass spectrometry (GC-MS) to characterize the metabolic alterations of the contents within the GI tract (stomach, duodenum, jejunum, ileum, cecum, colon, and rectum) in male Sprague-Dawley rats following 8 weeks of ethanol exposure. We obtained a snapshot of the distinct changes of the intestinal content metabolite composition in rats with ethanol exposure, which indicated a profound impact of ethanol consumption on the intestinal metabolome. Many metabolic pathways that are critical for host physiology were affected, including markedly altered bile acids, increased fatty acids and steroids, decreased carnitines and metabolites involved in lipid metabolism, a significant decrease of all amino acids and branched chain amino acids, and significantly decreased short chain fatty acids except for acetic acid, which rapidly elevated as a product of ethanol metabolism. These results provide an improved understanding of the systemic alteration of intestinal content metabolites in mammals and the interplay between the host and its complex resident microbiota and may aid in the design of new therapeutic strategies that target these interactions.
| S-EPMC5672944 | biostudies-literature
Project description:Astrocytes play critical roles in central nervous system (CNS) homeostasis and are implicated in the pathogenesis of neurological and psychiatric conditions, including drug dependence. Little is known about the effects of chronic ethanol consumption on astrocyte gene expression. To address this gap in knowledge, we performed transcriptome-wide RNA sequencing of astrocytes isolated from the prefrontal cortex (PFC) of mice following chronic ethanol consumption. Differential expression analysis revealed ethanol-induced changes unique to astrocytes that were not identified in total homogenate preparations. Astrocyte-specific gene expression revealed calcium-related signaling and regulation of extracellular matrix genes as responses to chronic ethanol use. These findings emphasize the importance of investigating expression changes in specific cellular populations to define molecular consequences of chronic ethanol consumption in mammalian brain.
| S-EPMC6033697 | biostudies-literature