Dopamine and the Role of Anterior Cingulate Cortex in Executive Processes

为了在相互竞争的需求和欲望之间做出裁决，决策者必须实施行政控制。二 执行控制、自我控制和结果监测的形式与毒品特别密切相关 上瘾。首先，这些特征的变化预示着上瘾和复发的易感性。第二，两者都是慢性的 而急性滥用药物以及戒断，都会在这些特征上产生认知障碍。第三，大脑 与这些认知功能最密切相关的网络也与药物滥用和 渴望。一个特别的大脑区域，前扣带回皮质(ACC)，被认为对两个自我 控制和结果监测以及随后的调整。ACC以其强烈的直接性而著称 来自大脑多巴胺中心的投射。多巴胺是药物成瘾的关键分子，而且 在基于奖励的决策中起着核心作用，但在实践中几乎对其影响一无所知 控制这些过程的系统上的多巴胺。事实上，尽管多巴胺能传入ACC 在执行功能障碍和成瘾中起关键作用，但人们对这种作用知之甚少。因此，我们寻求 阐明支持这些执行过程的电路级神经机制，两者都在正常情况下 在全身性多巴胺的影响下。我们建议，首先，记录单人的反应 神经元在ACC中延迟满足和高风险决策任务中的作用 在这些任务中的执行情况。第二，我们建议表征一种全身性多巴胺激动剂对 在ACC中的行为和单个神经元反应，产生剂量反应曲线并使用特定的激动剂 和拮抗剂，以确定哪些多巴胺受体参与其中。这些目标将发生在被指导的 (K99)阶段。在独立(R00)阶段，我们建议在这些任务中记录ACC中的单个单元 在给予全身多巴胺激动剂后，以确定神经元反应的变化 由多巴胺介导的模式。我们假设，ACC通过抑制来促进管理者的认知 在延迟满足任务中叛逃的诱惑，并通过提供阶段监测信号 预测行为的后续调整。我们还假设，多巴胺会降低自制力和 将增加猴子对最近结果的依赖，并将通过增加Acc的紧张性激发频率来做到这一点 神经元。 我已经在杜克大学神经生物学系做了三年的博士后研究员， 在此之前，我是加州大学伯克利分校的研究生。我一直在做单人单人 8年来猴子清醒行为的生理学研究。在此期间，我在Peer上发表了10篇论文- 回顾了期刊(七位第一作者)，包括《科学》、《神经元》和《当代生物学》，并介绍了我的 在无数的演讲和海报中的想法。我开发了许多新的和复杂的任务来研究复杂 认知过程，并记录在整个大脑的皮质结构中。我的兴趣包括奖励- 以决策为基础，尤其是执行职能。为了克服某些限制， 单一单位研究，我建议将单一单位生理学的方法与制药技术相结合。 由于神经调节器在基于奖励和执行过程中的作用，这两种技术是 天然的互补性。因为它们复杂的认知能力和大脑与 在人类中，猴子是研究执行功能的理想生物。我的丰富经验 单一单元生理学使我成为将药理学方法与生理学结合使用的理想人选。这个 K99/R00奖将使我能够发展药理学的专业知识来做到这一点。我的职业发展计划 呼吁与威廉·韦塞尔密切合作，他是杜克大学的精神病学教授，研究 影响神经递质水平的药物和基因操作对行为和大脑反应的影响 啮齿动物。我还将报名参加杜克大学的药理学课程。最后，我还将获得科学和专业的 我的赞助人迈克尔·普拉特医生提供的咨询。 我将在杜克大学医学院普拉特博士的实验室进行我的指导阶段的研究 中心。普拉特博士是杜克大学的副教授，也是神经经济学的领军人物，目前 作为神经经济学学会的主席，在神经行为学方面，目前正在编辑一本关于 主题。普拉特实验室长期以来一直是这些领域的领先者，并不断产生一流的研究成果。 该实验室的三名博士后已经在研究型大学获得了终身教职。杜克大学本身就是一流的- 排名靠前的研究机构，提供世界级的专家和开放、协作的氛围。给定 普拉特实验室和杜克大学的突出地位，这是进行研究的理想环境 在本申请中描述的。

To adjudicate between competing demands and desires, decision-makers must exert executive control. Two forms of executive control, self-control and outcome monitoring, are especially closely related to drug addiction. First, variations in these traits predict susceptibility to addiction and to relapse. Second, both chronic and acute abuse of drugs, as well as withdrawal, produce cognitive impairments in these traits. Third, the brain networks that are most closely associated with these cognitive functions are also implicated in drug abuse and craving. One brain region in particular, the anterior cingulate cortex (ACC), is thought to be critical for both self- control and outcome monitoring and subsequent adjustment. ACC is distinguished by its strong direct projections from the brain's dopamine centers. Dopamine is a critical molecule in drug addiction, and also plays a central role in reward-based decision-making, but in practice almost nothing is known about the effects of dopamine on the systems that govern these processes. In fact, although dopaminergic inputs to ACC likely have a critical role in executive dysfunction and addiction, this role is poorly understood. We therefore seek to elucidate the circuit-level neural mechanisms that support these executive processes, both under normal conditions and under the influence of systemic dopamine. We propose, first, to record responses of single neurons in ACC in a delay of gratification and a risky decision-making task, so as to understand the role of ACC in these tasks. Second, we propose to characterize the effects of a systemic dopamine agonist on behavior and single neuron responses in ACC, generating a dose response curve and using specific agonists and antagonists to identify which dopamine receptors are involved. These goals will occur during the mentored (K99) phase. During the Independent (R00) phase, we propose to record single units in ACC in these tasks following administration of a systemic dopamine agonist, so as to identify the changes in neuronal responses patterns mediated by dopamine. We hypothesize that the ACC contributes to executive cognition by inhibiting the temptation to defect in a delay of gratification task and by providing a phasic monitoring signal that also predicts subsequent adjustments in behavior. We also hypothesize that dopamine will reduce self-control and will increase monkeys' dependence on recent outcomes, and will do so by increasing tonic firing rates of ACC neurons. I have been a post-doctoral fellow in the Department of Neurobiology at Duke University for three years, and before that I was a graduate student at the University of California Berkeley. I have been doing single-unit physiology in awake behaving monkeys for 8 years. During that time, I have published ten papers in peer- reviewed journals (seven first author), including Science, Neuron, and Current Biology, and have presented my ideas in numerous talks and posters. I have developed many new and complex tasks to study complex cognitive processes, and have recorded in cortical structures across the brain. My interests include reward- based decision-making, and especially on executive functions. In order to overcome some of the limitations of single-unit studies, I propose to combine the methods of single unit physiology with pharmaceutical techniques. Because of the role of neuromodulators in reward-based and executive processes, these two techniques are naturally complementary. Because of their sophisticated cognitive abilities and brains that are similar to those of humans, monkeys are an ideal organism for the study of executive function. My extensive experience with single-unit physiology makes me an idea candidate to use pharmacological methods with physiology. The K99/R00 award will allow me to develop the expertise in pharmacology to do so. My career development plan calls for a close collaboration with William Wetsel, a professor of Psychiatry at Duke who studies the effects of drugs and genetic manipulations that affect neurotransmitter levels on behavior and brain responses in rodents. I will also enroll in a Pharmacology course at Duke. Finally, I will also obtain scientific and professional counseling from my sponsor, Dr. Michael Platt. I will perform the mentored phase of my research in the laboratory of Dr. Platt at the Duke University Medical Center. Dr. Platt is an Associate Professor at Duke and a leading figure in neuroeconomics, currently serving as the president of the Society for Neuroeconomics, and in neuroethology, currently editing a book on the topic. The Platt Lab has long been a leader in these fields, and consistently produces top-notch research. Three post-docs in the lab have gone on to tenure-track positions at research universities. Duke itself is a top- ranked research institution that offers world-class experts and an open, collaborative atmosphere. Given the prominence of the Platt Lab and of Duke University, this is an ideal environment to perform the research described in this application.