title: Effects of selection for ethanol preference on gene expression in the nucleus accumbens of HS-CC mice.
abstract: Previous studies on changes in murine brain gene expression associated with the selection for ethanol preference have used F2intercross or heterogeneous stock (HS) founders, derived from standard laboratory strains. However, these populations represent only a small proportion of the genetic variance available in Mus musculus. To investigate a wider range of genetic diversity, we selected mice for ethanol preference using an HS derived from the eight strains of the collaborative cross. These HS mice were selectively bred (four generations) for high and low ethanol preference. The nucleus accumbens shell of naive S4mice was interrogated using RNA sequencing (RNA-Seq). Gene networks were constructed using the weighted gene coexpression network analysis assessing both coexpression and cosplicing. Selection targeted one of the network coexpression modules (greenyellow) that was significantly enriched in genes associated with receptor signaling activity including Chrna7, Grin2a, Htr2a and Oprd1. Connectivity in the module as measured by changes in the hub nodes was significantly reduced in the low preference line. Of particular interest was the observation that selection had marked effects on a large number of cell adhesion molecules, including cadherins and protocadherins. In addition, the coexpression data showed that selection had marked effects on long non-coding RNA hub nodes. Analysis of the cosplicing network data showed a significant effect of selection on a large cluster of Ras GTPase-binding genes including Cdkl5, Cyfip1, Ndrg1, Sod1 and Stxbp5. These data in part support the earlier observation that preference is linked to Ras/Mapk pathways.
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
authors.forename: A M
authors.identifier: 0000-0002-5456-9468
authors.initials: AM
authors.lastname: Colville
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
authors.forename: O D
authors.initials: OD
authors.lastname: Iancu
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Oberbeck
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
authors.forename: P
authors.initials: P
authors.lastname: Darakjian
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Zheng
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
authors.forename: N A R
authors.initials: NA
authors.lastname: Walter
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Harrington
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
authors.forename: R P
authors.initials: RP
authors.lastname: Searles
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
authors.forename: S
authors.initials: S
authors.lastname: McWeeney
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.|Research Service, Portland Veterans Affairs Medical Center, Portland, OR, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Hitzemann
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics*; D000818:Animals; D000431:Ethanol; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D014644:Genetic Variation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D017423:Sequence Analysis, RNA / Q000379:methods; D020703:ras GTPase-Activating Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D020703:ras GTPase-Activating Proteins; D000431:Ethanol
keywords: Addiction; HS-CC; RNA-Seq; ethanol; mouse; network analysis; nucleus accumbens shell; selection; transcriptome