Dopaminergic modulation of prefrontal cortex during working memory

项目摘要 多巴胺（DA）是大脑活动的重要调节剂。前额叶皮层（PFC）中DA信号的中断 被认为是精神分裂症和注意力集中等主要精神障碍的认知缺陷的基础- 缺陷多动障碍（ADHD）。工作记忆（Working Memory，WM）是一种重要的短时记忆认知过程 持有和操纵目标导向的信息，这取决于在PFC DA。然而，尽管几十年来， 研究，在WM过程中PFC细胞的多巴胺能调制的关键电路机制仍然存在， 不太了解。这种知识上的差距反过来又限制了我们更好地了解 这类精神疾病的病理生理学。 本研究的总体目标是使用多种互补的最先进技术， 在一个成熟的参数WM任务中研究PFC中的DA信号。技术限制 阻碍了我们可靠地测量PFC中快速发展的DA信号的能力。我会用 逆行病毒感染工具，以光遗传学区分PFC投射和纹状体投射DA细胞， VTA。我将检验这一假设，即PFC投射DA细胞编码提示显着性信号，门控信息流 使用一种新型的光学DA传感器，我将描述DA动力学的内侧PFC的子区域， 测试假设DA在延迟期短暂增加，这种增加的幅度 与WM性能有关。最后，使用头戴式显微内窥镜， PFC DA释放，同时监测PFC神经元的不同亚群。如果成功，这 该项目将为认知过程中PFC的多巴胺能调节提供一个新的窗口。 我的长期职业目标是研究大脑中认知控制的电路机制， 特别感兴趣的是这些回路的损伤如何导致主要的精神疾病。我有一种强烈 计算和信号处理背景。我接受过严格的行为神经科学训练， 光遗传学、神经生理学和纤维光度学。然而，我需要额外的技术和概念培训 对我的使命至关重要我的导师和共同导师非常适合为这个项目提供关键的指导 和我的职业发展。UCSF环境提供了大量的培训机会， 重点是培养生物医学研究的下一代领导者。其中包括讲 各种内部计划，科学领导和管理研讨会课程，补助金 写作课程和内部评审小组，以及专门为博士后学者寻求的指导机会 独立我计划利用所有的机会提供通过这个指导的职业生涯 发展奖，以建立自己作为一个高效的神经科学家和独立调查员。

PROJECT SUMMARY ABSTRACT Dopamine (DA) is an critical modulator of brain activity. Disruption of DA signaling in the prefrontal cortex (PFC) has been proposed to underlie cognitive deficits in major mental disorders including schizophrenia and attention- deficit hyperactivity disorder (ADHD). Working memory (WM) is an important cognitive process for temporarily holding and manipulating goal-directed information, that depends on DA in the PFC. Yet despite decades of investigation, the key circuit mechanisms underlying dopaminergic modulation of PFC cells during WM remain poorly understood. This gap in knowledge has in turn limited our ability to gain better insights into the pathophysiology of such mental disorders. The overall goal of this study is to use multiple complementary state-of-the-art techniques to investigate DA signaling in PFC during a well-established parametric WM task. Technical limitations have hindered our ability to reliably measure rapidly-evolving DA signals in the PFC. This is now changing. I will use retrograde viral infection tools to optogenetically distinguish PFC-projecting from striatal-projecting DA cells in VTA. I will test the hypothesis that PFC-projecting DA cells encode a cue saliency signal, gating information flow to PFC. Using a novel optical DA sensor, I will characterize the DA dynamics in subregions of medial PFC and test the hypothesis that DA transiently increases during the delay-period, and that the magnitude of this increase is linked to WM performance. Finally, using head-mounted microendoscopes I will optogenetically manipulate PFC DA release while simultaneously monitoring distinct subpopulations of PFC neurons. If successful, this project will provide a novel window onto dopaminergic modulation of PFC during cognitive processes. My long-term career goal is to investigate the circuits mechanisms of cognitive control in the brain with a specific interest in how impairment in these circuits contributes to major psychiatric disorders. I have a strong computational and signal processing background. I have received rigorous training in behavioral neuroscience, optogenetics, neurophysiology, and fiber photometry. Yet, I need additional technical and conceptual training critical to my mission. My mentor and co-mentor are ideally situated to provide critical guidance to this project and to my career development. The UCSF environment provides numerous training opportunities with an emphasis on preparing the next generation of leaders in biomedical research. These include speaking opportunities at various internal programs, scientific leadership and management workshops courses, grant writing courses and internal review panels, and mentoring opportunities specific to postdoctoral scholars seeking independence. I plan to take advantage of all the opportunities provided through this mentored career development award to establish myself as a highly effective neuroscientist and independent investigator.