Role of Dynamic Signaling of NRG3-ErbB4 in the Prefrontal Cortex in Mediating Nicotine Withdrawal Phenotypes

PROJECT SUMMARY/ABSTRACT While several pharmacotherapies are currently available for nicotine dependence, smoking cessation is only 7.5% successful. Recent advances in the study of genetic contributions to nicotine dependence represent a promising avenue for the development of novel smoking cessation therapies. Our lab has shown that variations in the gene for Neuregulin 3 (NRG3) and its cognate receptor ErbB4 are linked to smoking cessation outcomes and may be responsible, in part, for affective nicotine withdrawal (WD) phenotypes. Therefore, the overarching goal of this fellowship-training proposal is to systematically investigate the region-specific, functional role of the Neuregulin Signaling Pathway during nicotine use and WD. To accomplish this, we are evaluating two central aims: 1) Determine the PFC-specific contributions of ErbB4 to nicotine WD related behavioral phenotypes and the mechanism by which they occur, and 2) Characterize expression patterns of NRG3-ErbB4 signaling within the prefrontal cortex and identify the molecular alterations induced during chronic nicotine and WD. Our approach is significant because it utilizes a novel genetic mouse model of nicotine dependence in a multidimensional approach to provide insight into the underlying mechanisms that define the NRG3 signaling pathway and its role in nicotine dependence. Research undertaken in this fellowship will be performed at the University of Kentucky College of Pharmacy under the purview of the Graduate Program in Pharmaceutical Sciences, a multidisciplinary program designed to prepare motivated individuals for academic, industrial, or government careers in pharmaceutical and biomedical research. My mentor, Dr. Jill Turner, has helped develop a training plan for my graduate career that consists of professional development and didactic training in techniques that will develop my understanding and expertise in the field. The outlined training plan will help me to develop expertise in the field of neuropharmacology/genetics of addiction, expand upon my experimental techniques, refine my experimental design and data analysis skills, and continue to work on my presentation and networking skills. The training gained during my graduate career under the guidance of Dr. Turner will provide me with a broad exposure to the neurobiology of substance use disorders; in addition to my research work, these experiences will help me in my future goals of developing novel precision therapeutics for nicotine dependence and other co-morbid psychiatric disorders. The combination of my dedicated mentor that will assist in the development and progression of my training with innovative research venues to conduct and share my research will warrant my success as a well-trained graduate student.