Dopaminergic modulation of prefrontal cortex during working memory

项目总结摘要 多巴胺(DA)是大脑活动的重要调节剂。前额叶皮质(PFC)DA信号的干扰 已经被认为是包括精神分裂症和注意力障碍在内的主要精神障碍的认知缺陷的基础。 缺陷多动障碍(ADHD)。工作记忆是一种重要的暂时性认知过程 掌握和操纵目标导向的信息，这取决于PFC中的DA。然而，尽管几十年来 研究表明，在西医过程中PFC细胞多巴胺能调制的关键电路机制仍然存在 人们对此知之甚少。这种知识上的差距反过来限制了我们更好地洞察 这种精神障碍的病理生理学。 这项研究的总体目标是使用多种互补的最先进技术来 在已建立的参数WM任务中，研究PFC中的DA信号。技术上的限制有 阻碍了我们在PFC中可靠地测量快速演变的DA信号的能力。这种情况现在正在改变。我会用 逆行病毒感染工具区分PFC投射和纹状体投射的DA细胞 VTA。我将测试这样一种假设，即投射PFC的DA细胞编码提示显著信号，从而控制信息流 敬一等兵。使用一种新的光学DA传感器，我将表征PFC内侧和PFC内侧亚区的DA动力学 检验DA在延迟期内瞬时增加的假设，以及这种增加的幅度 与WM性能有关。最后，使用头戴式显微内窥镜，我将通过光遗传学操作 PFC DA的释放，同时监测不同的PFC神经元亚群。如果成功，这将是 该项目将为了解认知过程中PFC的多巴胺能调制提供一个新的窗口。 我的长期职业目标是研究大脑中认知控制的回路机制 特别感兴趣的是这些回路的损伤如何导致严重的精神障碍。我有一个很强的 具有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 对我的任务至关重要。我的导师和合作导师非常适合为这个项目提供批判性指导 为我的事业发展干杯。加州大学旧金山分校的环境提供了大量的培训机会 强调培养下一代生物医学研究的领军人物。其中包括演讲 参加各种内部计划、科学领导力和管理研讨会课程的机会， 写作课程和内部审查小组，以及特定于寻求博士后学者的指导机会 独立。我计划利用通过这个有指导的职业生涯提供的所有机会 发展奖，使我成为一名高效的神经学家和独立的调查者。

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.