Gene expression profiling in human alcoholics and rodent models of binge drinking and dependence have provided insight into the changes in the brain transcriptional landscape resulting from different drinking paradigms; however, to date it is not clear whether transcriptome changes found in animal models of excessive alcohol consumption are consistent with changes found in human alcoholics. Consilience in gene expression would be a key step toward validating animal models by determining commonalities in molecular plasticity between human and rodent brain. Genomic approaches have successfully identified alcohol-mediated changes in gene expression in animal models of alcoholism. These studies suggest that distinct patterns of gene expression underlie specific alcohol-related phenotypes. Animal models of excessive consumption have been developed to investigate different stages of the alcohol abuse cycle that ultimately lead to dependence, including continuous two-bottle choice, drinking in the dark, and chronic intermittent ethanol exposure. In general, studies have focused on transcriptional changes at a single time point following alcohol treatment; thus, it is difficult to determine if the changes in expression patterns are transient or longer lasting. CIE vapor exposure can be used to achieve and maintain high blood ethanol concentrations in C57BL/6J mice, and it results in increased self-administration of ethanol. Transcriptome profiling immediately following CIE exposure, rather than after subsequent bouts of voluntary drinking, could reveal gene expression and gene network changes associated with induction of ethanol dependence and early withdrawal. We defined global gene expression profiles in BAY 73-4506 amygdala, nucleus accumbens, prefrontal cortex, and liver of C57BL/6J mice exposed to 4 cycles of intermittent ethanol vapor. Tissue was harvested at 3 time points following the last vapor treatment to assess timedependent changes in gene expression. We identified time-dependent gene clusters in AMY and NAC that were enriched with astrocytes, microglia, and oligodendrocyte cell types. These sets of genes were primarily associated with inflammatory response function. In contrast, the PFC was enriched with neuronal genes and displayed a greater diversity in directional expression changes, suggesting that the PFC is under greater transcriptional regulatory control than the AMY and NAC. We also examined the overlap of cell-specific differentially expressed genes at the 0- and 8-hour time points. Microglial genes were the most highly conserved group of cell type-specific genes across these time points for all brain regions. In addition, modules were evaluated for enrichment with differentially expressed genes. All brain regions exhibited a number of ethanol-responsive modules that were also enriched with genes from one or more of the cell-type/functional gene lists. Microglia- and astrocyte-enriched modules showed the most persistent gene expression changes across time and were primarily associated with anti-apoptosis and immune response. In contrast, neuron- and oligodendrocyte-enriched modules showed more transient gene expression changes. For example, neuronal enrichment was only observed in one module at 0- and 8-hours. A single module was enriched with microglia and oligodendrocyte genes as well as ethanol-responsive genes at 0- and 8-hours. Table 3 also indicates differentially expressed module hub genes for each brain region and time point. Specific gene names and level of significance is provided in S4 Table. To further investigate ethanol-responsive modules, we used an effect-size based approach and determined the direction and magnitude of ethanol-induced changes for each coexpression module. Mean t-values were calculated for ethanol-responsive modules identified by WGCNA at each time point. The magnitude and direction of change were relatively consistent in AMY and NAC at 0- and 8-hours. In contrast, these parameters were quite different in the PFC. The greatest consistency in t-value magnitude and direction was observed in liver. The goal of the current study was to determine time-dependent transcriptional changes in brain and liver that result from administration of repeated ethanol vapor. This paradigm has been shown to escalate voluntary drinking in both rats and mice and represents a rodent model of dependence. Our hypothesis was that time- and brain region-dependent changes in expression would be observed, and that at least a subset of genes, would be persistently changed in response to CIE vapor. Animals were sacrificed at 0-, 8-, and 120-hours after the last ethanol treatment to determine whether persistent changes in gene expression would be observed during protracted abstinence.