The Role of Amygdala Outputs in Stress-Induced Escalation of Alcohol Drinking

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PROJECT SUMMARY Alcohol use disorder (AUD) is a major public health problem that affects millions of Americans. Traumatic stress disorders are highly co-morbid with AUD and can contribute to the development of AUD. Rat studies in our lab have shown that traumatic (predator odor) stress produces stress-induced conditioned place avoidance and escalated alcohol drinking in a subset of stressed rats, termed Avoiders, recapitulating the individual differences in stress reactivity seen in humans. Comparisons of predator odor stress-induced neuroadaptations in Avoider and Non-Avoider rats have revealed that corticotropin-releasing factor (CRF) signaling via CRF-1 receptors (CRFR1) in the central amygdala (CeA) represents one mechanism by which predator odor stress alters behavior. However, it is not known whether stress-induced plasticity in CRF-CRFR1 signaling in CeA mediates stress-induced escalation of alcohol drinking in Avoider rats, nor is it known whether altered CRFR1 signaling in CeA mediates post-stress behavior by gating the activity of specific CeA outputs. Here, I propose to test the role of 1) CeA CRF-CRFR1 signaling, 2) CeA projections to lateral hypothalamus (LH), and 3) CeA CRFR1+ projections to LH, in stress-induced escalation of alcohol drinking and reward in Avoider rats. Our overarching hypothesis is that CeALH CRFR1+ neurons mediate traumatic stress-induced escalation of alcohol drinking and reward. I will use a combination of immunohistochemistry, chemogenetics, and anatomical techniques to test this hypothesis. In Specific Aim 1, I will test the hypothesis that Avoider rats will show greater activation of CeALH CRFR1+ neurons than Non-Avoider and Control rats after predator odor stress. In Specific Aim 2, I will test the hypotheses that 1) inhibition of CeALH CRFR1+ neurons will attenuate stress-induced escalation of alcohol drinking and alcohol reward in Avoider rats, and 2) stimulation of CeALH CRFR1 neurons will increase alcohol drinking and alcohol reward in stress-naïve rats. I will use the newly-engineered male and female CRFR1:Cre rats for all experiments. The proposed work will provide information regarding brain circuit mediators and potential drug targets for the treatment of co-morbid AUD and traumatic stress disorders. In addition, this project will provide important training to a promising young alcohol neuroscientist.