Dopamine and Frontostriatal Function

描述(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中的作用，如工作记忆和认知控制。这些定义有些不明确的术语通常指的是认知系统，它需要两个功能相反的过程：(1)稳定的在线信息维护(对“认知稳定性”来说是必要的)和(2)灵活地更新响应信息 与任务相关的新信息(“认知灵活性”所必需的)。我们将检验这一假设，即这些认知过程高度依赖于纹状体和前额叶皮质(PFC)内精确平衡的多巴胺能传递。具体地说，我们将测试这一假设，即PFC中的多巴胺增加通过增加分心干扰抵抗来促进认知稳定性，而纹状体中的多巴胺增加则通过允许更新新的相关表征来促进认知灵活性。对多巴胺能系统的操纵已被证明可以调节额纹状体回路的功能，但这些影响的方向和程度因个人和任务的不同而有很大差异。通过对多巴胺在人类体内的药理操作和遗传变异，以及用功能磁共振成像和正电子发射计算机断层扫描对它们的影响进行测量，我们期望阐明决定药物效应如此大的变异性的因素，并表征多巴胺和认知之间复杂关系的本质。多巴胺对帕金森氏病、创伤性脑损伤、注意力缺陷多动障碍、精神分裂症和药物成瘾等多种神经和精神疾病的病因和临床表现具有重要意义。进一步了解多巴胺和认知之间的关系将促进我们对这些疾病认知和行为缺陷的机制的理解，并为针对特定神经递质系统的药物治疗此类缺陷的新方法提供洞察力。

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.