Generation and validation of a CRFR1-cre transgenic rat to study alcohol dependence

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Project Summary Alcohol Use Disorder (AUD) is responsible each year for more than 2.5 million deaths worldwide, more than 58 million life years lost worldwide, and $220 billion in financial cost in the United States alone. Furthermore, AUD is highly co-morbid with various other conditions (e.g., traumatic brain injury, post-traumatic stress disorder, anxiety, depression) that are themselves increasing in prevalence, thanks in part to increased clinical awareness. Over the last 20 years, one neural system that has shown significant promise as a potential therapeutic target for AUD and co-morbid disorders is corticotropin-releasing factor (CRF), and especially CRF signaling through the CRF-1 receptor (CRFR1). Recent advances in neuroscience allow for the creation of sophisticated genetic animal models that allow experimenters to target specific neuronal populations and examine their role in network dynamics and behavior, based on afferent innervation, projection target, and/or molecular signature. Here we propose to create one such model by developing and validating a CRFR1:Cre rat for use in pre-clinical studies on the neurobiology of AUD and related psychiatric conditions. This project falls within the scope of the NIAAA mission to support alcohol-related research in neuroscience. This project also meets the criteria for the R21 funding mechanism by supporting investigation of new model systems with the potential for significant impact on biomedical research. The long-term goal of the work proposed in this application is to create a genetic animal model that can be distribited and used by multiple investigators in various pre-clinical neuroscience fields (including but not limited to pre-clinical AUD research) where CRFR1 signaling has been implicated as a promising therapeutic target. The proposed aims will use BAC recombineering to create a CRFR1:Cre rat in partnership with the University of Michigan Transgenics Core, will support creation of a breeding colony of CRFR1:Cre rats, and will support work that performs anatomical, electrophysiological, and behavioral validation of this new genetic animal model.