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A Neurogenetic and Genomic Characterization of Reward-Seeking Behaviors

  • Author(s): James, Alexander Scott
  • Advisor(s): Jentsch, David
  • et al.
Abstract

Because Pavlovian and instrumental processes enabling the prediction and pursuit of desired rewards, as well as the avoidance of dangers and noxious stimuli, they are integral to a wide range of behaviors that we exhibit. The studies presented here combine hypothesis-based studies with hypothesis-free research in order to provide novel insight into the reward-seeking behaviors that shape human behavior, and importantly, when expressed in extreme forms, are components of and risk factors for a range of psychiatric conditions. The first series of studies in this dissertation sought to disentangle the complex role of NMDA-mediated dopamine cell burst firing in reward-related learning, and to test causally, for the first time, predictions made by the incentive salience account of phasic dopamine function. While instrumental learning was impaired in our genetic model of attenuated phasic dopamine release, we found no evidence to support a selective dependency of incentive salience attribution on phasic dopamine release. Rather, our data are congruent with an integrative perspective on the role of phasic dopamine release in reward-driven learning, rather unitary theories of dopamine as a prediction error or incentive salience signal. The second study sought new genomic determinants of variation in reward seeking, using association-level genome-wide scans in an inbred mouse strain panel combined with linear mixed effects modeling, and yielded several quantitative trait loci related to quantitative variation in instrumental responding for sucrose. Transcriptomics data was used to for prioritizing quantitative trait loci genes for future causal studies, and offered a resource for the development of new hypotheses regarding the neurobiology that links genes to behavior in the context of reward-related learning. Moreover, the specific pattern of transcriptomics and genomics data acquired was suggestive of a common underlying genomic and transcriptomics basis for motivational and learning processes in instrumental behavior. The data collected in this dissertation offer new neurobiological understanding of behaviors that are germane to psychiatric conditions, and demonstrate the synergy offered by combining both hypothesis-based and hypothesis-free approaches to behavioral neuroscience research.

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