Dopamine and Frontostriatal Function

描述（由申请人提供）：本申请旨在了解多巴胺能系统在高级认知功能（如工作记忆和认知控制）中的作用。这些定义有些模糊的术语通常指的是需要两个功能上相反的过程的认知系统：（1）稳定的“在线”信息维护（“认知稳定性”所必需的）和（2）灵活的信息更新响应 新的任务相关信息（“认知灵活性”所必需的）。我们将测试的假设，这些认知过程是高度依赖于精确平衡的多巴胺能传输纹状体和前额叶皮层（PFC）。具体来说，我们将测试的假设，即增加多巴胺在PFC促进认知稳定性，通过增加干扰阻力，而多巴胺在纹状体的增加，促进认知灵活性，通过允许更新新的相关表示。多巴胺能系统的操作已被证明可以调节额-纹状体回路的功能，但这些作用的方向和程度在个体和任务中有很大差异。通过药理学操作和遗传变异的多巴胺在人类中，并测量其影响与功能磁共振成像和PET，我们希望阐明的因素，确定这种大的变异性药物的影响和特点的性质之间的复杂关系多巴胺和认知。多巴胺对于多种神经和精神障碍如帕金森病、创伤性脑损伤、注意缺陷多动障碍、精神分裂症和药物成瘾的病因学和临床表现具有根本重要性。进一步了解多巴胺和认知之间的关系，应该推进我们对这些疾病中认知和行为缺陷的机制的理解，并提供针对特定神经递质系统的药物治疗这种缺陷的新方法。

DESCRIPTION (provided by applicant): This application is directed towards understanding the role of the dopaminergic system in higher cognitive function such as working memory and cognitive control. These somewhat ill-defined terms generally refer to cognitive systems that require two functionally opposing processes: (1) the stable 'on-line' maintenance of information (necessary for "cognitive stability") and (2) the flexible updating of that information in response to novel task-relevant information (necessary for "cognitive flexibility"). We will test the hypothesis that these cognitive processes are highly dependent on precisely balanced dopaminergic transmission within the striatum and prefrontal cortex (PFC). Specifically, we will test the hypothesis that augmentation of dopamine in the PFC promotes cognitive stability by increasing distractor-resistance whereas dopamine augmentation in the striatum promotes cognitive flexibility by allowing the updating of newly relevant representations. Manipulation of the dopaminergic system has been shown to modulate the function of fronto-striatal circuitry, but the direction and extent of these effects vary widely across individuals and tasks. Through pharmacological manipulation and genetic variation of dopamine in humans, and measurements of their effects with both fMRI and PET, we expect to elucidate the factors that determine this large variability in drug effects and characterize the nature of the complex relationship between dopamine and cognition. Dopamine is of fundamental importance to the etiology and clinical manifestations of a wide variety of neurological and psychiatric disorders such as Parkinson's disease, traumatic brain injury, attention deficit hyperactivity disorder, schizophrenia and drug addiction. A further understanding of the relationship between dopamine and cognition should advance our understanding of the mechanisms underlying cognitive and behavioral deficits in these disorders and provide insight into novel approaches to treating such deficits with medications targeted at specific neurotransmitter systems.