Regional Differences and Similarities in the Brain Transcriptome for Mice Selected for Ethanol Preference From HS-CC Founders.

Alexandre M. Colville,Priscila Darakjian,Ovidiu D. Iancu,Robert Hitzemann,Shannon K. McWeeney,Christina Zheng,Denesa R. Lockwood,Robert Searles

doi:10.3389/fgene.2018.00300

Alexandre M. Colville, Priscila Darakjian + Show 6 more

Open Access

https://doi.org/10.3389/fgene.2018.00300

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Abstract

The high genetic complexity found in heterogeneous stock (HS-CC) mice, together with selective breeding, can be used to detect new pathways and mechanisms associated with ethanol preference and excessive ethanol consumption. We predicted that these pathways would provide new targets for therapeutic manipulation. Previously (Colville et al., 2017), we observed that preference selection strongly affected the accumbens shell (SH) genes associated with synaptic function and in particular genes associated with synaptic tethering. Here we expand our analyses to include substantially larger sample sizes and samples from two additional components of the “addiction circuit,” the central nucleus of the amygdala (CeA) and the prelimbic cortex (PL). At the level of differential expression (DE), the majority of affected genes are region-specific; only in the CeA did the DE genes show a significant enrichment in GO annotation categories, e.g., neuron part. In all three brain regions the differentially variable genes were significantly enriched in a single network module characterized by genes associated with cell-to-cell signaling. The data point to glutamate plasticity as being a key feature of selection for ethanol preference. In this context the expression of Dlg2 which encodes for PSD-93 appears to have a key role. It was also observed that the expression of the clustered protocadherins was strongly associated with preference selection.

Highlights

Beginning with Lewohl et al (2000) there are more than 200 studies using some form of genome-wide profiling to examine the relationships among alcohol effects, excessive alcohol consumption and the brain transcriptome. Contet (2012) reviewed the existing literature and noted that the genes associated with the risk of excessive consumption and/or the effects of excessive consumption had regionally specific effects on gene expression
In the current study we have focused our investigations on those genes that contribute to at least 80% of network connectivity
This thresholding reduced the number of genes considered for further analyses from ∼15,000 to ∼6,500 in each of the three brain regions

Summary

Introduction

Beginning with Lewohl et al (2000) there are more than 200 studies using some form of genome-wide profiling to examine the relationships among alcohol effects, excessive alcohol consumption and the brain transcriptome. Contet (2012) reviewed the existing literature and noted that the genes associated with the risk of excessive consumption and/or the effects of excessive consumption had regionally specific effects on gene expression. It is important to note that these studies by and large confirmed earlier observations (e.g., Kimpel et al, 2007) that regional differences in gene expression are generally far greater than the effects of treatment, strain or line (e.g., Mulligan et al, 2017). In the current study we explore at the regional level how selection for ethanol preference affects the transcriptome. The short-term selection of the High and Low ethanol preference lines from heterogeneous stock-collaborative cross (HS-CC) founders has been described elsewhere (Colville et al, 2017). After three generations of bidirectional selection, the difference in the ethanol preference ratio was 0.49 vs 0.15 in the High and Low lines, respectively. It is estimated that the HSCC founder strains encompass >90% of Mus musculus genetic diversity (Churchill et al, 2004)

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