Dopaminergic modulation of nucleus accumbens during prospective and retrospective neuroeconomic decision making

项目总结 2017年，据估计，美国近20%的成年人口患有精神疾病，但有很大一部分 对精神疾病的病理生理学和特定的行为症状尚不清楚。 决策和信息处理的异常与神经精神疾病有关 比如精神分裂症、强迫症和抑郁症。重要的是 伏隔核核(NAC核)多巴胺信号传导到中棘神经元(MSN)的失调 构成了这些异常过程背后的关键神经机制。目前，南汽核心研究 不成比例地侧重于决策的动机和奖励学习方面。然而，存在这样的问题， 强有力的证据表明，决策涉及更复杂的信息处理：做出决策需要 评估实际结果，但也需要对想象的替代结果进行展望和回顾。 因此，研究多巴胺释放和MSN活性在信息处理中的作用具有重要意义。 当代理人在通过深思熟虑做出决定之前前瞻性地想象潜在的结果，以及何时 特工们回想起在“未走过的道路”(反事实推理)中可能会发生什么 想象一下，在通过重新评估做出决定后，时间投资(沉没成本处理)很差。我们的 了解NAC核心多巴胺如何在前瞻性审议中编码这些想象的结果 而且很大程度上缺乏回溯性重新评估，因为还没有行为工具 探索啮齿动物这种类型信息处理的机制是复杂的。创新型 Reish实验室的工作导致了一项名为Restaurant Row的啮齿动物行为任务的开发，该任务 复杂性允许对神经经济行为进行深入的行为分析。这项提议旨在澄清 NAC核心多巴胺动态如何反映深思熟虑、反事实推理和沉没成本评估1) 用光纤光度法同时监测体内多巴胺释放和MSN活性2)操纵 决策过程中特定时间点的内源性多巴胺信号。Restaurant Row拥有巨大的 翻译潜力，并已被改编为非人类灵长类和人类。因此，该工作提出了 这里将在未来为更大的翻译协作做出贡献，以研究这些问题 通过与我在精神病科的临床导师合作，培育出一种新的物种。我的顾问大卫博士 雷迪什和帕特里克·罗斯韦尔博士准备好在技术和专业上指导我，我们一起 我策划了一个与我的职业目标完美匹配的培训计划。通过融入开创性的技术 在这样一个跨学科的环境中进行翻译项目将为我提供所需的培训 成为一名成功的内科科学家，为计算精神病学领域做出贡献。

PROJECT SUMMARY In 2017, it was estimated that nearly 20% of the adult population in the U.S. live with a mental illness, yet much remains unknown about the pathophysiology of psychiatric disease and the specific behavioral symptomatology. Aberrations in decision making and information processing have been implicated in neuropsychiatric diseases like schizophrenia, obsessive-compulsive disorders, and depression. Importantly, dysregulations in nucleus accumbens core (NAc core) dopamine signaling onto medium spiny neurons (MSNs) constitute a key neural mechanism underlying these aberrant processes. Currently, NAc core research disproportionately focuses on the motivation and reward-learning aspects of decision making. There is, however, strong evidence that decision making involves more complex information-processing: making a decision requires evaluation of actual outcomes but also requires prospection and retrospection on imagined alternate outcomes. Therefore, it is important to investigate the role of dopamine release and MSN activity in information processing when agents prospectively imagine potential outcomes before making a decision through deliberation and when agents retrospectively imagine what could have been in the “path untraveled” (counterfactual reasoning) or imagine poor time investments (sunk cost processing) after making a decision through reevaluation. Our understanding of how NAc core dopamine encodes these imagined outcomes during prospective deliberation and retrospective reevaluation is lacking greatly because there have not been behavioral tools with the complexity to probe the mechanisms contributing to this type of information-processing in rodents. Innovative work in the Redish lab has led to the development of a rodent behavioral task, called Restaurant Row, whose intricacy allows for in-depth behavioral analysis of neuroeconomic behaviors. This proposal aims to elucidate how NAc core dopamine dynamics reflect deliberation, counterfactual reasoning and sunk cost evaluation by 1) simultaneous monitoring of in vivo dopamine release and MSN activity using fiber photometry 2) manipulating endogenous dopamine signaling at specific points in decision making. Restaurant Row has tremendous translational potential and has been adapted for non-human primates and humans. Thus, the work proposed here will contribute to a larger translational collaboration in the future to investigate these questions across species through collaboration with my clinical mentors in the Department of Psychiatry. My advisors Dr. David Redish and Dr. Patrick Rothwell are equipped to mentor me both technically and professionally and together we have curated a training plan that perfectly aligns with my career goals. By incorporating pioneering techniques into a translational project in such an interdisciplinary environment will provide the training I need to develop become a successful physician-scientist contributing to the field of computational psychiatry.