Alcohol Vapor Self-Administration in Rats

Abstract The effects of alcohol use disorder are widespread throughout the brain. A fundamental knowledge gap in the field of alcohol research is the identification of the changes in whole-brain networks underlying the critical phases of the addiction cycle: intoxication, withdrawal, abstinence, and relapse. In the previous funding cycle, our lab started identifying these neuronal ensembles, their cellular phenotype, and their networks by focusing on a known region of interest, the central nucleus of the amygdala. While these efforts have been very successful, it has become clear that our research endeavor will benefit from moving away from the classical, biased region-of-interest-based approach to a modern, unbiased, whole-brain approach using single-cell whole-brain imaging. We believe that this innovative approach is required to identify the changes in whole- brain networks underlying the critical phases of the addiction cycle. The overarching goal of this renewal is to continue dissecting the neuronal ensembles of the volitional induction of alcohol dependence using single-cell whole-brain functional connectomics. We will use the rat model of ethanol vapor self-administration that we developed in the previous funding cycle to 1) identify the neuronal ensembles of alcohol intoxication, acute withdrawal, protracted abstinence, and stress-induced relapse and evaluate the contribution of CRF and dynorphin neurons to these networks, 2) compare pharmacological treatments on alteration of whole-brain functional networks and recruitment of CRF and dynorphin neurons, and 3) characterize the functional network of high-intensity binging in dependent rats. This project will provide unbiased brain atlases of the critical phases of the addiction cycle, identify the role of CRF and dynorphin neurons in these neuroadaptations, provide a mechanistic framework for the therapeutic effects of several pharmacological treatments, and identify the specific networks associated with high-intensity alcohol binging, an intensifying trend in alcohol drinking.