This revised proposal has been developed in response to PAR-02-062 (Building Translational Research in Behavioral Science). The goal of the proposed work is to demonstrate that an explicitly translational, multidisciplinary approach to defining the role of dopamine (DA) in schizophrenia (SC), is capable of illuminating some of the most poorly understood, most treatment-resistant cognitive and motivational aspects of the illness. Specifically, recent basic research has shown that DA cell firing plays a critical role in the encoding of reward prediction and reward based learning. The proposed work will provide a rigorous test of the applicability of this hypothesis as a framework for understanding the motivational and learning impairments of SC with important implications for schizophrenia therapeutics. To test this hypothesis, we have organized a group of basic and clinical investigators into three scientific modules:1) electrophysiology, 2) neuroimaging, and 3) behavior, with the overall program designed to address different aspects of same theory of DA function. These modules are designed to develop collaborative partnerships with the results of initial pilot experiments used to refine hypothesis for further experimental testing. Initial studies are proposed to document the specific behavioral, electrophysiological, and fMRI Bold signal abnormalities of SC patients during the performance of reward learning paradigms, the impact of different antipsychotics on reward processing in animals, and the physiological sequela associated with reward-driven changes in DA cell firing. Computational modeling will be used to determine whether the experimental results in animals and observed deficits in patients are consistent with the hypothesized role of DA in reward processing. The overall program is designed to develop resources, paradigms, and proof of principle studies that illuminate the nature of DA dysfunction in SC through the application of translational paradigms and models demonstrating the critical role of DA in reward and reinforcement learning. If successful, the proposed work is designed to establish the conceptual foundation and preliminary data needed to support individual RO1 applications and a Translational Center. ? ?
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