USING THE COLLABORATIVE CROSS MOUSE POPULATION TO INVESTIGATE ENVIRONMENTAL AND GENETIC FACTORS THAT INFLUENCE COMPLEX BEHAVIORS Public Deposited

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  • March 19, 2019
Creator
  • Schoenrock, Sarah
    • Affiliation: School of Medicine, UNC Neuroscience Center, Neuroscience Curriculum
Abstract
  • Affective disorders and substance abuse disorders (SUDs) are highly prevalent within the US and result in substantial burdens on the affected individual, their loved ones, and society. Relatively few effective treatments exist however, due to a lack of understanding regarding the etiology of these complex disorders. Development of affective and SUDs are due to both environmental factors, (i.e. perinatal insults, childhood maltreatment, stressful life events), genetic background and the complex interplay of the two. Using inbred strains of mice can potentially disentangle the two (environment and genetic factors), and elucidate their interactions to aid in the identification of specific mechanisms. However, traditional inbred strains pose some limitations in the variation of genetic diversity present, which limits our ability to capture a full phenotypic range that may better model disease states seen in humans. In this thesis, we use a relatively new population of recombinant inbred strains, the Collaborative Cross (CC), that were designed to have increased genetic, and therefore phenotypic, diversity over traditional inbred strains. We used a panel of female F1 hybrids of CC strains (RIX) to investigate the effects of an environmental factor, nutritional deficiency in the perinatal period, genetic background, parent-of-origin (PO) and any interactions on stress response, anxiety-, and depressive-like behaviors inadulthood. From this phenotypic screen, we identified two RIX lines (RIX 41/51 and 04/17) that were outliers for novelty-induced locomotion, a predictive trait for addiction-related behaviors. We characterized RIX 41/51 and 04/17 for cocaine (COC)-related behaviors and possible underlying mechanisms including COC metabolism, HPA axis dysregulation and dopamine dynamics in the striatum. We also performed QTL mapping for low initial locomotor response to COC using an F2 intercross of CC041/TauUnc and C57BL/6NJ and identified three significant QTLs on Chr 7, 11 and 14. These studies are the first to assess the CC or RIX of CC for addiction-related behaviors and provides evidence that RIX 41/51 and 04/17 are novel models with a unique genetic diversity to study the underlying mechanisms involved in COC-related behaviors.
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Advisor
  • Valdar, William
  • Tarantino, Lisa
  • Pardo Manuel Pardo-Pardo-Manuel de Villena, Fernando
  • Morrow, A. Leslie
  • Besheer, Joyce
  • Kash, Thomas
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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