Stress is a risk factor for alcohol use disorders (AUDs). Generally, individuals with anxiety disorders such as posttraumatic stress disorder (PTSD) also have elevated rates of AUD, more severe alcohol withdrawal symptoms, and greater relapse risk. Accumulating evidence indicates that immune-related pathways are critical biological components of CNS function and dysfunction. Our published and preliminary results show that canonical cytokines, such as Interleukin (IL)-18, have a profound capacity to affect neuronal function and regulate GABA and glutamate transmission within the amygdala. Notably, IL-18 and its receptors are highly expressed in the amygdala, a brain region that strongly contributes to anxiety- and addictive-related behaviors, and stress history and alcohol exposure increase IL-18 expression. Recent studies in humans found that IL-18 receptor gene expression is associated with distinct PTSD subtypes and that a single nucleotide polymorphism (SNP) in the IL-18 gene (rs1946518) is associated with AUD in a highly traumatized civilian cohort largely comorbid for PTSD. Notably, the same SNP in the IL-18 gene is also associated with amygdala reactivity in anxiety. The goal of this proposal is to 1) identify the cellular mechanisms underlying the essential role of IL-18 in homeostatic regulation of normal neuronal activities and amygdala circuits, and 2) test the hypothesis that IL-18 signaling contributes to the development of maladaptive stress-induced anxiety and AUDs. To accomplish our goal, we will employ innovative and complementary techniques: behavior, electrophysiology, ribosome profiling combined with next generation sequencing, in situ hybridization/RNAScope and immunohistochemistry, as well as pharmacological and viral vector-mediated knock down of the IL-18 system in amygdala. We will determine the interactions of peripheral and central immune elements in healthy and pathological function, comparing Vulnerable vs. Resilient subjects, at the molecular, cellular, circuit and behavioral levels. We will identify the role of IL-18 signaling on synaptic functions in amygdala circuits in both male and female rats using an adapted “2-hit” rat model of stress to generate escalated drinking and high anxiety-like phenotypes for behavioral and physiological studies. Collectively, these studies will elucidate the mechanisms that drive IL-18 dysregulation to contribute to stress-induced anxiety and AUDs, and may identify promising targets for treatment strategies for anxiety disorders and alcoholism.