Clinical and Computational Studies of Dopamine Function in Schizophrenia

描述（由申请人提供）：这份为期5年的提案涉及3所大学，通过行为实验和计算建模探索多巴胺（DA）在强化学习工作记忆（WM）中的作用，以及精神分裂症患者（SZ）的决策缺陷。虽然DA功能障碍被认为是SZ的一个基本方面，但DA在奖赏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。这个建议的目标是提供一个综合性的帐户DA异常可能是如何在一个全面的计算框架内，解决DA信号在基底神经节和额叶皮层的作用，在行动选择，学习和WM禁用的认知/动机缺陷的SZ。实验提供了模型预测的类型的损害，导致DA异常，被认为是发生在SZ的测试。在目标1-3中，我们测试了正反馈信号处理中的缺陷，这些缺陷预期是由于在习惯学习、决策和WM任务中紧张性DA的异常增加而导致的。我们还测试了新的，基于模型的预测，DA异常的眶额叶皮层将导致在处理奖励和惩罚的相对大小的实验设计，这将导致患者执行相对于对照组的上级或下级的损伤。目标4通过在治疗开始之前和之后对患者进行测试来解决抗精神病药物治疗的影响，我们将测试治疗促进从模型预测的负强化中学习的假设。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与基于模型的预测的拟合，在模型中，我们已经探索了增加和减少DA信号传导的不同方面的作用，以近似SZ中的假设异常。相关性：大多数SZ患者在认知和动机处理方面存在缺陷，导致严重残疾。DA系统的异常可能涉及这两种类型的损伤。由于所有已知的抗精神病药物治疗都会影响DA系统，因此拟议的工作有望增加对当前治疗如何对这些关键的损伤领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.