Brain gene expression differences related to ethanol preference in the collaborative cross founder strains

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• The Collaborative Cross (CC) mouse strains offer extensive genetic diversity for studying complex traits.
• C57BL/6J (B6) is a common model for high ethanol preference, but PWK also exhibits high ethanol preference.
• Understanding genetic differences in ethanol preference is crucial for alcohol use disorder (AUD) research.

Purpose of the Study:

• To compare the transcriptomes of high ethanol preference strains (B6 and PWK) with low preference CC strains.
• To identify unique and common differentially expressed genes (DEGs) across brain regions involved in addiction.
• To explore the role of neuroimmune signaling in genetic susceptibility to high ethanol preference.

Main Methods:

• RNA sequencing (RNA-Seq) was performed on three brain regions: central nucleus of the amygdala (CeA), nucleus accumbens core (NAcc), and prelimbic cortex (PrL).
• Differential gene expression (DE) analysis was conducted for pairwise comparisons among CC founder strains.
• Unique DEGs were identified by significant differences (FDR < 0.05) across all other strains; commonly different DEGs were identified between B6, PWK, and the average of other strains.

Main Results:

• The B6 strain exhibited the highest number of unique and highly divergent DEGs compared to other classical inbred strains.
• Fewer than 50 unique DEGs were shared between B6 and PWK across all three brain regions, suggesting distinct genetic signatures for high ethanol preference.
• 338 DEGs were commonly different between B6, PWK, and the average of other CC strains; these were significantly enriched for neuroimmune function genes (FDR < 0.001).

Conclusions:

• B6 and PWK represent distinct genetic pathways contributing to high ethanol preference.
• Neuroimmune signaling pathways are implicated in the genetic risk for high ethanol preference and AUD.
• The CC founder strains and their derived populations are valuable resources for identifying mechanisms and therapeutic targets for AUD.