Integrative studies of the influence of reward on sequential control in human and nonhuman primates

项目总结/摘要 目标导向和习惯性行为形成了日常行为的全部，例如，煮一杯咖啡; 然而，当结合到更复杂的仪式或任务序列中时，这些行为可能是 奖励驱动的药物寻求和服用成瘾。虽然这样的任务序列看起来很简单， 容易执行，必要的技能可能是复杂的，需要高水平的执行功能， 额叶皮层的监督例如，获取药物的多个子任务（例如获取资金和设置 必须计划并执行（例如压碎或注射药物），以实现 总体目标，其可以进一步取决于序列的奖励属性和/或上下文（例如， 药物的量或优选的药物可用性）。虽然成瘾的特征是 奖励驱动行为背后的额纹状体回路，目前尚不清楚 奖励和顺序任务控制，以及奖励驱动的顺序控制的缺陷是否可能导致 成瘾我们将建立一个跨物种模型，研究奖励对顺序任务控制的影响， 为未来研究开发成瘾行为的新疗法奠定了基础。 拟议培训的总体目标是利用综合的人类和觉醒行为 猕猴的功能磁共振成像。这项研究计划将描述奖励的神经基础， 跨物种的顺序任务控制该研究将建立一个猕猴模型的复杂 顺序控制，独特地利用了猕猴之间的潜在功能同源性， 人类重要的是，这些研究将提供功能磁共振成像方法学和动物研究经验的培训 在一个适合于研究依赖于额叶皮层的高阶行为的模型中。 目标1将测试奖励幅度（1a）和序列完成的时间接近度（1b）是否 人类fMRI研究调节顺序控制的神经相关性。在平行实验中， 猴子的fMRI（目标2）将直接应用与目标1a中用于人类的相同的顺序任务。因此，目标2 将测试跨物种的功能网络同源性，以确定奖励对序列的影响。 行为（2a）。此外，我们将测试猕猴大脑中潜在的顺序控制区域是否显示出 类似于在人类中发现的动力学（2b）。这些研究不仅是第一次检验奖励- 驱动的顺序控制，但将直接比较两个物种的复杂顺序任务的性能。 总之，拟议的研究将建立一个动物模型，使未来的研究， 在连续任务行为中侵入性地操纵人类和猴子神经回路功能;这 这项工作将独特地促进临床和临床前模型中成瘾的跨物种工作。这些 研究结果将有广泛的应用，以了解如何运作可能会出错，在这些电路， 有助于成瘾和帕金森病等疾病的复杂顺序行为。

PROJECT SUMMARY / ABSTRACT Goal-directed and habitual behaviors form the repertoire of daily actions, e.g. making a cup of coffee; however, when combined into more complex rituals or sequences of tasks, such behaviors may underlie reward-driven drug seeking and taking in addiction.! While such task sequences appear simple because they are easily performed, the necessary skills may be complex and require high-level executive function and oversight from the frontal cortex. For example, multiple subtasks to obtain drugs (e.g. obtain money and setup meeting place for exchange) must be planned and then executed (e.g. crush or inject drug) to achieve an overarching goal, which may further depend on the rewarding properties and/or context of the sequence (e.g., amount of drug or preferred drug availability). Although addiction is characterized by dysfunction within frontostriatal circuits that underlie reward-driven behavior, it is unknown whether there is relationship between reward and sequential task control, and whether deficits in reward-driven sequential control may drive addiction. We will establish a cross-species model of the influence of reward on sequential task control, creating a foundation for future studies to develop novel therapies for addictive behaviors. The overarching goal of the proposed training is to utilize integrative human and awake-behaving macaque monkey fMRI in parallel. This research plan will characterize the neural underpinnings of reward and sequential task control across species. The proposed studies will establish a macaque model of complex sequential control that uniquely capitalizes on potential functional homologies between macaques and humans. Importantly, these studies will provide training in fMRI methodology and animal research experience in a model suited to study of higher order behaviors dependent upon the frontal cortex. Aim 1 will test whether reward magnitude (1a) and temporal proximity to sequence completion (1b) in human fMRI studies modulate neural correlates of sequential control. In parallel experiments, awake-behaving monkey fMRI (Aim 2) will directly apply the same sequential task used in humans from Aim 1a. Thus, Aim 2 will test functional network homology across species to determine the influence of reward on sequential behavior (2a). Further, we will test whether brain regions underlying sequential control in macaques show dynamics similar to those found in humans (2b). These studies will not only be the first to examine reward- driven sequential control, but will directly compare complex sequential task performance across both species. Together, the proposed studies will establish an animal model that will enable future studies to invasively manipulate neural circuit function in both humans and monkeys during sequential task behavior; this work will uniquely contribute to cross-species work on addiction in clinical and preclinical models. These findings will have broad applications to understanding how functioning may go awry within these circuits that subserve complex sequential behavior in disorders such as addiction and Parkinson’s disease.