Circuit reconstruction of functionally-identified neurons in deep brain regions: application to grid cells

大脑深部区域功能识别神经元的电路重建：在网格细胞中的应用

• 批准号: 9916209
• 负责人: Alexander Riordan
• 金额: $ 4.6万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2021-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916209
• 关键词: 3-Dimensional; Academia; Affect; Alzheimer' s Disease; Anatomy; Animals; Architecture; Area; Autopsy; Behavior; Behavioral; Birth; Brain; Brain imaging; Brain region; Calcium; Cell physiology; Cells; Cognition; Cognitive; Complex; Data; Development; Dorsal; Electron Microscopy; Engineering; Environment; Foundations; Functional Imaging; Future; Head; Health; Hippocampal Formation; Image; Implant; Location; Medial; Memory; Methods; Microscope; Modeling; Modernization; Monitor; Mus; Neurons; Neurosciences; Operative Surgical Procedures; Optics; Pattern; Phase; Photons; Probability; Procedures; Recurrence; Research; Research Personnel; Rodent; Rotation; Surface; Synapses; System; Techniques; Technology; Testing; Tissues; Training; Work; anatomic imaging; awake; career; connectome; design; entorhinal cortex; experimental study; functional group; insight; instrument; instrumentation; method development; multidisciplinary; multimodality; multiphoton imaging; neural circuit; next generation; novel; post-doctoral training; reconstruction; relating to nervous system; response; skills; theories; two-photon; virtual; virtual reality

Project Abstract Specialized synaptic wiring motifs have been suspected to be essential building blocks of cognition since the birth of modern neuroscience. However the technology to test these ideas has been historically unavailable. The grid cell system in medial entorhinal cortex (MEC), a deep brain area, is an exemplar of this problem. Grid cells are essential for memory and navigation. They are thought to be key in the development of Alzheimer’s disease. Yet the fundamental mechanisms underlying grid cell activity are not understood, owing to technical barriers in assessing grid cells’ wiring patterns. Here I propose to overcome these barriers, by developing a pipeline for circuit reconstruction of functionally-characterized neurons in deep brain areas. My dissertation work thus far (Aim 1) has involved co-development of such a pipeline for surface brain areas, then adaptation of this procedure for deep brain areas, using a combination of implantable optics, multiphoton calcium imaging during behavior, electron microscopy, and multimodal techniques to register both functional and anatomical data. During the independent phase (F99, Aim 2), I will apply this pipeline to grid cells in MEC, enabling definitive refutation or confirmation of the wiring patterns predicted by current theories of grid cell function. I then provide a postdoctoral plan (K00, Aim 3) for the creation of next-generation multiphoton imaging and rodent behavioral technology. This postdoctoral training at the interface of optical design and engineering methods aims to expand current capabilities for monitoring neural activity, reconstructing neural circuits, and testing theories of brain function. Overall this proposal will enable me to develop skills in circuit reconstruction and methods development for neuroscience, enhancing the probability of a career as an independent investigator in academia. Finally, I anticipate that the proposed studies will advance technical capabilities for neuroscience, and provide fundamental insight into the circuit architectures underlying memory and cognition in a brain circuit highly relevant to pressing health needs.

项目摘要 自人类出现以来，专门的突触连接图案就被怀疑是认知的重要组成部分。 现代神经科学的诞生。然而，测试这些想法的技术在历史上一直不可用。 内侧内嗅皮层（MEC）（大脑深处的区域）中的网格细胞系统就是这个问题的一个例子。网格 细胞对于记忆和导航至关重要。它们被认为是阿尔茨海默氏症发展的关键 疾病。然而，由于技术原因，网格细胞活动的基本机制尚不清楚。 评估网格单元接线模式的障碍。在这里，我建议克服这些障碍，通过开发 用于大脑深部区域功能特征神经元电路重建的管道。我的论文 迄今为止的工作（目标 1）涉及共同开发用于大脑表面区域的管道，然后进行适应 结合使用植入式光学器件、多光子钙成像，对大脑深部区域进行该手术 在行为过程中，电子显微镜和多模式技术来记录功能和解剖学 数据。在独立阶段（F99，目标 2），我将将此管道应用于 MEC 中的网格单元，从而使 对当前网格单元功能理论预测的布线模式的明确反驳或确认。我 然后提供博士后计划（K00，目标3）以创建下一代多光子成像和 啮齿动物行为技术。本次光学设计与工程界面的博士后培训 方法旨在扩展当前监测神经活动、重建神经回路和 测试大脑功能的理论。总的来说，这个提案将使我能够培养电路重建的技能 和神经科学方法的开发，提高了独立职业的可能性 学术界的研究者。最后，我预计拟议的研究将提高技术能力 神经科学，并提供对记忆和认知背后的电路架构的基本见解 与紧迫的健康需求高度相关的大脑回路。