title: Voluntary wheel running reduces voluntary consumption of ethanol in mice: identification of candidate genes through striatal gene expression profiling.
abstract: Hedonic substitution, where wheel running reduces voluntary ethanol consumption, has been observed in prior studies. Here, we replicate and expand on previous work showing that mice decrease voluntary ethanol consumption and preference when given access to a running wheel. While earlier work has been limited mainly to behavioral studies, here we assess the underlying molecular mechanisms that may account for this interaction. From four groups of female C57BL/6J mice (control, access to two-bottle choice ethanol, access to a running wheel, and access to both two-bottle choice ethanol and a running wheel), mRNA-sequencing of the striatum identified differential gene expression. Many genes in ethanol preference quantitative trait loci were differentially expressed due to running. Furthermore, we conducted Weighted Gene Co-expression Network Analysis and identified gene networks corresponding to each effect behavioral group. Candidate genes for mediating the behavioral interaction between ethanol consumption and wheel running include multiple potassium channel genes, Oprm1, Prkcg, Stxbp1, Crhr1, Gabra3, Slc6a13, Stx1b, Pomc, Rassf5 and Camta2. After observing an overlap of many genes and functional groups previously identified in studies of initial sensitivity to ethanol, we hypothesized that wheel running may induce a change in sensitivity, thereby affecting ethanol consumption. A behavioral study examining Loss of Righting Reflex to ethanol following exercise trended toward supporting this hypothesis. These data provide a rich resource for future studies that may better characterize the observed transcriptional changes in gene networks in response to ethanol consumption and wheel running.
authors.affiliation: Institute for Behavioral Genetics, Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.|Current address: Department of Psychiatry, University of Utah, Salt Lake City, UT, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Darlington
authors.affiliation: Institute for Behavioral Genetics, Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: McCarthy
authors.affiliation: Institute for Behavioral Genetics, Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Cox
authors.affiliation: Institute for Behavioral Genetics, Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: J
authors.initials: J
authors.lastname: Miyamoto-Ditmon
authors.affiliation: Institute for Behavioral Genetics, Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: X
authors.initials: X
authors.lastname: Gallego
authors.affiliation: Institute for Behavioral Genetics, Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Ehringer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000428:Alcohol Drinking / Q000235:genetics*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism* / Q000502:physiology; D005260:Female; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D053263:Gene Regulatory Networks; D051379:Mice; D008810:Mice, Inbred C57BL; D051938:Munc18 Proteins / Q000235:genetics / Q000378:metabolism; D005082:Physical Exertion / Q000235:genetics*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D012420:Running; D050827:Syntaxin 1 / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D059467:Transcriptome; D000099052:CRF Receptor, Type 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C511044:CAMTA2 protein, mouse; D002148:Calmodulin-Binding Proteins; D050485:GABA Plasma Membrane Transport Proteins; C546258:Gabra3 protein, mouse; D051938:Munc18 Proteins; C404943:Oprm protein, mouse; D015221:Potassium Channels; C455831:Rassf5 protein, mouse; D018019:Receptors, Corticotropin-Releasing Hormone; D011963:Receptors, GABA-A; D017450:Receptors, Opioid, mu; C493419:Slc6a13 protein, mouse; C497938:Stxbp1 protein, mouse; D050827:Syntaxin 1; D015534:Trans-Activators; C000608868:syntaxin 1B, mouse; D000099052:CRF Receptor, Type 1; D043484:Proprotein Convertases
keywords: RNA-Seq; WGCNA; edgeR; ethanol consumption; ethanol preference; hedonic substitution; loss of righting reflex; striatum; tophat; wheel running