Justin Q. Anderson1,2, R. Dayne Mayfield3, Ethan Hagmann2,4, Bryan E. Jensen2, Marissa Borrego1,2, Antonia M. Savarese1,2, Olga Ponomareva3, Elizabeth Osterndorff-Kahanek3, Emma Erickson3, Anna Warden3, Nihal Salem3, Molly Matty4, John C. Crabbe1,2, Angela Ozburn1,2

Alcohol use disorders (AUDs) are known to be polygenetic diseases with high (~0.8) heritability for risk, suggesting that dysregulation of gene expression preceding alcohol exposure may underlie risk. Moreover, there may exist multiple and distinct patterns of gene dysregulation that lead to similar risk for AUDs, thus necessitating the study of multiple, distinct models. We directionally selected the High Drinking in the Dark-1 (HDID-1; 44 generations) and a separate, replicate line (HDID-2; 37 generations) for high blood alcohol following a period of binge-like alcohol drinking from the same genetically heterogeneous progenitor stock (HS/Npt). We report the successful inbreeding of both lines, each starting from their 26th respective selected generation, and the preservation of the selected phenotype (n = 10/sex/fluid/strain; 280 mice). The inbred HDID (iHDID-1&2) lines therefore represent two independently derived, genetically stable models for binge-like alcohol drinking. The two replicate inbred lines are also found to be as transcriptionally distinct as they are similar, relative to their founders. We present differential expression results from alcohol naive mice from both inbred strains and their founders. RNA TAG-seq data were analyzed from six brain regions important for addiction: nucleus accumbens, central nucleus of the amygdala, ventral tegmental area, bed nucleus of the stria terminalis, medial prefrontal cortex, and basolateral amygdala (n = 20/sex/strain/region; 120 mice, 720 samples). We discuss common and unique genetic signatures that are consistent across all six brain regions and their upstream regulators as the most likely targets for therapeutic intervention.

1Department of Behavioral Neuroscience, Portland Alcohol Research Center, Oregon Health and Science University, Portland, OR 97239, United States,2Portland Veterans Affairs Medical Center, Research and Development Service, Portland, OR 97239, United States, 3The Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78705, United States, 4University of Portland, Portland, OR 97203, United States