Clinical and Computational Studies of Dopamine Function in Schizophrenia

描述(申请人提供)：这项为期5年的计划涉及3所大学，通过行为实验和计算模型探索多巴胺(DA)在强化学习工作记忆(WM)中的作用，以及精神分裂症(SZ)患者的决策缺陷。虽然DA功能障碍被认为是SZ的一个基本方面，但对DA在奖赏加工中的作用的基础神经科学理解和建模方面的快速进展仍有待于临床研究。这项建议的目的是在一个全面的计算框架内，对DA异常如何导致SZ的认知/动机障碍提供一个综合的描述，该框架解决了基底神经节和额叶皮质的DA信号在动作选择、学习和WM中的作用。这些实验提供了对被认为发生在深圳的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，这些缺陷预计是由于任务-敲击习惯学习、决策和工作记忆中紧张DA的异常增加造成的。我们还测试了基于模型的新颖预测，即眼眶额叶皮质DA异常将导致处理奖惩相对大小的障碍，实验设计将导致患者的表现高于或低于对照组。目的4通过在治疗开始前和治疗后对患者进行测试来解决抗精神病治疗的影响，其中我们将检验治疗促进从模型预测的负面强化中学习的假设。然后，我们将使用计算模型来探索这些行为结果，以确定观察到的行为是否符合基于模型的预测，在这些模型中，我们已经探索了DA信号的增加和减少不同方面的作用，以近似SZ的假想异常。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。这两种类型的损害都可能与DA系统的异常有关。由于所有已知的抗精神病药物治疗都会影响DA系统，拟议的工作有望增加对当前治疗如何对这些关键的损害区域产生益处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.