Project-003 (P003)

pix_pair_comp7Effects of Chronic Ethanol Consumption on the Mouse Brain Transcriptome

Project Leader: Robert Hitzemann 
Co-Investigators: Tamara Phillips, Ovidiu Iancu

Project P003 examines the mouse brain transcriptome in mice that chronically (3 months) self-administer ethanol in the two-bottle choice procedure (water vs 10% ethanol). Data will be collected in two separate populations of mice (the HS-CC and DO) derived from the 8 founders of the Collaborative Cross that includes 3 wild-derived strains. More than 90% of the genetic diversity available in Mus musculus is represented in the HS-CC and DO. The experimental design parallels that of the macaque project (P002 - Grant);a key goal is to determine if the transcriptional features associated with excessive ethanol consumption in the mouse and macaque are similar. Where they are, the mouse model provides an accessible platform to examine the underlying mechanisms.

The project contains 3 specific aims:

1. To examine in HS-CC mice the relationships between chronic (3 month) ethanol consumption and the brain transcriptome. Data will be collected in six components of the "addiction" neurocircuit : the shell of the nucleus accumbens, the dorsolateral striatum, the prelimibic cortex, the dorsolateral orbital cortex, the central nucleus of the amygdala and the centrally projecting Edinger-Westphal nucleus.  Preliminary data have established that in HS-CC mice, chronic consumption ranges from 1 to 20 g/kg/day, with 25% of the animals consuming >10 g/kg/day. RNA-Seq will be used to extract the expression data;gene networks are analyzed using the weighted gene coexpression network analysis (WGCNA). The goal is to detect hub genes which are highly associated with consumption;these hubs become targets for validation and manipulation in C001. 

2. To use the RNA-Seq data to examine how chronic ethanol consumption has affected alternative splicing.  We approach alternative splicing from a network perspective and look for splicing hubs. 

3. To replicate the experiments and workflows in Aims 1 and 2 using the Diversity Outcross (DO). The DO like the HS-CC is an outbred version of the Collaborative Cross but differs significantly in breeding history, number of families that are maintained and the breeding schemes used to prevent genetic drift Nonetheless, our working hypothesis is that, in the HS-CC and DO cohorts, there will be common (and unique) transcriptional correlates to chronic ethanol exposure. Project P003 provides a link to previous iterations of the PARC that focused on risk factors for excessive consumption. Risk genes in CC mice have been identified and we now ask, what are the role(s) of these genes in sustained excessive consumption?

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