Genetic dissection of lateral habenula neuronal circuitry in cocaine seeking

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 DESCRIPTION (provided by applicant): This K01 Mentored Research Scientist Award will provide support and mentorship to establish the Candidate, Dr. Sunila Nair as an independent researcher in molecular and behavioral neuroscience. The training component of this application will build on my expertise in behavioral neuropharmacology investigating the neural circuits involved in relapse to drugs of abuse and non-drug reinforcers, with training in molecular neuroscience which will enable me to establish my own cutting-edge research program. My advanced scientific training will be focused in two key areas: 1) construction and packaging of viral-mediated gene transfer tools, and 2) training in molecular genetics. The career development activities will be mentored by Dr. John Neumaier (Primary Mentor) and Dr. Eric Turner (Co-Mentor), researchers that possess non-overlapping, but related expertise and exceptional records of mentoring junior faculty. The proposed project will take place in the Department of Psychiatry and Behavioral Neuroscience at the University of Washington, which provides an exceptional environment for high-impact neuroscience research. It is an intellectually stimulating and highly collaborative environment and most senior faculty members have a track record for mentoring junior investigators. The research component will investigate the lateral habenula, an understudied epithalamic nucleus that likely plays a key role in drug taking and seeking behaviors. As part of a previously funded NIH R21 application, I am mapping the neurocircuitry that controls lateral habenula neuronal activity and mediates these behaviors. However, a major roadblock in dissecting the precise functional neurocircuitry of the lateral habenula and its targets is the fact that very little is known about the genetic properties of thes neurons. This brain region is anatomically and functionally heterogeneous and a thorough understanding of the role of the lateral habenula in addiction (and other disorders) will require a complete understanding of the neuropeptides, neurotransmitters, receptors, uptake transporters and other targets that are expressed in this brain region. Further, there is virtually no informatin on the specific patterns of gene expression in lateral habenula sub-regions in rats and if this is altered during complex behavioral tasks. I will use the recently developed `Ribotag' technology in conjunction with DREADD's to interrogate changes in mRNA translation in the lateral habenula and its associated neuronal circuitry during cocaine taking and seeking. The use of this cutting-edge approach will allow me to detect changes in mRNA undergoing active translation in lateral habenular neurons projecting to its key targets during complex behavioral tasks. The scientific goals for this K01 application are firstly, to train in advanced molecular biology and genetics and develop novel tools to answer the above research questions. Secondly, to successfully implement these tools to dissect genetic differences in the role of the lateral habenula in cocaine-taking versus seeking behaviors. Thirdly, to examine pathway-specific genetic differences in lateral habenula in a rat model that incorporates the negative consequences of drug use that closely approximates addiction clinically in humans.