Ethanol and stress exert a wide spectrum of neuropharmacological and neurophysiological effects that leave both molecular and cellular imprints in the CNS. While some targets of ethanol and stress in the brain have been defined, particularly shifts in neurotransmitter tone, much of the influence of ethanol is mediated by subtle and non-specific modification of allosteric interactions and downstream events that will remain hard to pinpoint and manipulate. The joint effects of ethanol and stress also vary a great deal depending on genetic differences. In this INIA renewal we will use new genomic methods to understand much more about differential vulnerability to alcohol and stress and molecular targets. We exploit a diverse group of strains of mice (BXDs) that model many aspects of human genetic complexity. In Aim 1 we evaluate predisposing differences in gene expression and splicing and the effects that individual differences have on responses to stress and to eventual alcohol consumption. In aim 2 we will study the effects of chronic intermittent ethanol exposure (and animal model of binge drinking) on voluntary alcohol consumption. Here we are asking how the combination of stress and alcohol alters gene expression patterns in an almost permanent way to induce quick relapse when access to ethanol is provided. In aim 3 we will integrate, test, and translate our results from aims 1 and 2 to understand more about the complex molecular and cellular networks that contribute to both vulnerability and allostatic changes in brain function. We will exploit extensive human data sets to test the translational relevance of finding in murine populations. PUBLIC HEALTH RELEVANCE: RELEVANCE (See instructions): This U01 project of INIAStress will be of high significance in understanding at least two critical features of alcoholism: (1) the underlying genetics and neurogenetics of susceptibility to stress and alcohol, and (2) the imprints of allostatic load on gene expression (including alternative isoform usage and production of noncoding RNAs) in different CNS regions and in strains with markedly different responses to alcohol and stress.