Clinical and Computational Studies of Dopamine Function in Schizophrenia

描述（由申请人提供）：本项目为期5年，涉及3所大学，通过行为实验和计算模型，探讨多巴胺（DA）在精神分裂症（SZ）患者强化学习工作记忆（WM）和决策缺陷中的作用。虽然DA功能障碍被认为是SZ的一个基本方面，但对DA在奖励处理中的作用的基础神经科学理解和建模的快速进展仍有待于转化为临床研究。本研究的目的是在一个全面的计算框架内，提供一个关于DA异常如何导致SZ的认知/动机缺陷的综合解释，该框架解决了基底神经节和额叶皮层中DA信号在行动选择、学习和WM中的作用。实验提供了被认为发生在SZ的DA异常导致的损伤类型的模型预测的测试。在目标1-3中，我们测试了正反馈信号处理的缺陷，这种缺陷可能是由于在包括习惯学习、决策制定和WM等任务中的补性DA异常增加所导致的。我们还测试了一种新颖的、基于模型的预测，即眶额叶皮层的DA异常将导致处理奖励和惩罚的相对大小的损害，并设计了实验，这将导致患者相对于对照组表现更好或更差。目标4通过对患者开始治疗前后的测试来解决抗精神病治疗的影响，我们将测试治疗促进从负强化中学习的假设，正如模型所预测的那样。然后将使用计算建模来探索这些行为结果，以确定观察到的行为是否适合基于模型的预测，其中我们已经探索了增加和减少DA信号不同方面的作用，以近似假设的SZ异常。相关性：大多数SZ患者在认知和动机加工方面存在缺陷，导致严重的残疾。这两种类型的损伤可能都涉及到DA系统的异常。因为所有已知的抗精神病药物都会影响DA系统，所以这项工作有望增加对当前治疗如何对这些关键损伤区域产生有益和可能的不利影响的理解。

DESCRIPTION (provided by applicant): This 5 year proposal involving 3 universities explores the role of dopamine (DA) in the reinforcement learning working memory (WM), and decision making deficits of patients with schizophrenia (SZ) through behavioral experiments and computational modeling. While DA dysfunction is thought to be a fundamental aspect of SZ, rapid advances in the basic neuroscience understanding and modeling of the role of DA in reward processing remain to be translated into clinical research. The goal of this proposal is to provide an integrative account of how DA abnormalities may underlie the disabling cognitive/motivational deficits of SZ within a comprehensive computational framework that addresses the role of DA signaling in the basal ganglia and frontal cortex in action selection, learning, and WM. The experiments provide tests of model predictions of the types of impairments that result from the DA abnormalities that are thought to occur in SZ. In Aims 1-3, we test for deficits in processing of positive feedback signals that would be expected to result from abnormal increases of tonic DA across tasks tapping habit learning, decision making, and WM. We also test the novel, model based prediction that DA abnormalities in the orbital frontal cortex will result in impairment in processing the relative magnitudes of rewards and punishments with experiments designed where this will lead patients to perform at superior or inferior levels relative to controls. Aim 4 addresses the impact of antipsychotic treatment through the testing of patients both before and after the initiation of treatment where we will test the hypothesis that treatments facilitate learning from negative reinforcement as predicted by the model. These behavioral results will then be explored using computational modeling to determine the fit of observed behavior to predictions based on models where we have explored the role of increasing and decreasing different aspects of DA signaling to approximate the hypothesized abnormalities in SZ. Relevance: Most SZ patients experience deficits in cognitive and motivational processing, resulting in significant disability. It is likely that abnormalities in the DA system may be involved in both types of impairments. Because all known antipsychotic treatments impact the DA system, the proposed work promises to increase understanding of how current treatments may have beneficial as well as possible adverse effects on these crucial areas of impairment.