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

项目摘要 2017年，据估计，美国近20%的成年人患有精神疾病，但 对于精神疾病的病理生理学和特定的行为症状学仍然未知。 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， 中脑核核心（NAc core）多巴胺信号传导至中型棘神经元（MSNs）的调节异常 构成了这些异常过程背后的关键神经机制。目前，NAC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， 强有力的证据表明，决策涉及更复杂的信息处理：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活性在信息加工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时， 代理人回顾性地想象“未走过的道路”（反事实推理），或者 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 了解在前瞻性审议过程中NAc核心多巴胺如何编码这些想象的结果 回顾性的重新评估非常缺乏，因为没有行为工具， 复杂性，以探讨机制，有助于这种类型的信息处理啮齿动物。创新 在Redish实验室的工作已经导致了一种啮齿动物行为任务的发展，称为餐厅排， 复杂性允许对神经经济学行为进行深入的行为分析。这项建议旨在阐明 NAc核心多巴胺动力学如何反映深思熟虑、反事实推理和沉没成本评估 用纤维光度法同时监测体内多巴胺释放和MSN活性 内源性多巴胺信号在决策的特定点。餐厅街有巨大的 翻译潜力，并已适用于非人灵长类动物和人类。因此，建议的工作 这里将有助于更大的翻译合作，在未来调查这些问题， 通过与我在精神病学系的临床导师合作，我的顾问大卫博士 雷迪什和帕特里克罗斯韦尔博士有能力在技术上和专业上指导我，我们一起 我策划了一个培训计划，完全符合我的职业目标。通过结合先进的技术 在这样一个跨学科的环境中进行翻译项目，将提供我发展所需的培训。 成为一名成功的物理学家，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.