CRCNS: Collaboration on high-resolution maps of synapses on hippocampal neurons

CRCNS：海马神经元突触高分辨率图的合作

• 批准号: 8258007
• 负责人: William Lawrence Kath
• 金额: $ 24.33万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258007
• 关键词: Action Potentials; Address; Adolescence; Affect; Alzheimer' s Disease; Apical; Area; Axon; Behavior; Biological Models; Brain; Calcium; Cells; Chicago; Cognition Disorders; Collaborations; Communities; Complex; Computer Simulation; Data; Data Set; Dendrites; Dendritic Spines; Development; Disease; Electrophysiology (science); Epilepsy; Excitatory Synapse; Experimental Models; Functional Imaging; Future; Genetically Engineered Mouse; Germany; Glutamates; Goals; Hippocampus (Brain); Human; Image; Inhibitory Synapse; International; Internet; Interneurons; Label; Lead; Learning; Life; Location; Maps; Measures; Mediating; Memory; Methodology; Methods; Microscopy; Minority; Modeling; Molecular; Motor; Neocortex; Nervous system structure; Neurons; Neurotransmitter Receptor; Online Systems; Pattern; Philosophy; Physiological; Physiology; Positioning Attribute; Postdoctoral Fellow; Process; Property; Publishing; Research; Research Personnel; Resolution; Role; Schools; Science; Sensory; Series; Site; Slice; Societies; Structure; Students; Synapses; Synaptic plasticity; System; Testing; Tissue Microarray; Training; Trees; Underserved Population; Universities; Weight; Work; base; boys; cognitive function; computer studies; data exchange; data modeling; design; girls; high school; hippocampal pyramidal neuron; improved; insight; light microscopy; meetings; member; molecular marker; multidisciplinary; neural circuit; neuronal cell body; patch clamp; programs; research study; simulation; spatial relationship; submicron; tomography; tool; two-photon; voltage; voltage gated channel; web site

DESCRIPTION (provided by applicant): This is a collaborative project between Northwestern University (Nelson Spruston and Bill Kath), Stanford University (Stephen Smith), and the University of Bonn (Stefan Remy). The project will lead to an improved understanding of neurons in the hippocampus, which were selected because of their roles in learning and memory as well as a number of cognitive disorders. Studies of these neurons will also offer insight into neurons in other areas of the brain, many of which have shared structural and functional properties. The goals of the project are as follows: We will collect functional data from hippocampal CA1 pyramidal neurons using patch-clamp recording in brain slices combined with two-photon uncaging of glutamate and two-photon calcium imaging. We will also collect structural and molecular data from the same dendritic branches using array tomography, which provides the highest possible resolution using light microscopy. We will examine the distribution of excitatory synaptic weights, as well as the distribution of inhibitory synapses from different interneuron subtypes. All experiments will be performed for dendrites in different dendritic compartments (e.g., basal versus apical dendrites). By performing both functional and structural experiments in the same neurons, we will be able to correlate and integrate the data sets. We will construct compartmental models of CA1 pyramidal neurons, using the data from the experiments to inform improvements on our existing models of these neurons. The models will be used to generate experimentally testable predictions concerning the integration of synaptic inputs. These predictions will extend beyond the range of experiments performed to constrain the model, so they will constitute predictions designed to inform future work on these neurons. Spruston and Kath have a record of using such predictions to design and perform experiments that lead to new discoveries. We will use the models developed in Aim 2 to examine whether stochastic activation of thousands of excitatory and inhibitory synaptic inputs, combined with the excitable properties of the dendrites and synaptic plasticity rules based on the resulting dendritic voltage changes, can lead to non-uniform gradients of excitatory synaptic weights in CA1 pyramidal neurons. Our working hypothesis is that the natural gradients of voltage that exist in CA1 dendrites can contribute to the development of non-uniform synaptic weights. We will compare the results of these simulations to the results from array tomography studies as a means of determining which activity patterns and synaptic plasticity rules best explain the observed distribution of synaptic weights. Collaboration: All team members will exchange data and interact on a regular basis. The Spruston and Remy labs will perform experiments using patch-clamp recording and two-photon uncaging and imaging. Filled cells from these experiments will be sent to Stanford for array tomography in the Smith lab. Spruston, Kath, Smith and Remy will supervise the integration of array tomography data with functional data, working together with the postdoc and student supported by this project. All members of the group will meet regularly to discuss progress and future plans. Intellectual Merit: The project will provide critical data concerning the structure and function of pyramidal neurons in the hippocampus, which will be used to generate computational models of unprecedented detail. The models will be used to advance our understanding of synaptic integration in dendrites and the contribution of excitable dendrites to synaptic plasticity and the distribution of excitatory synaptic weights in the dendritic tree. The underlying philosophy is that the function of neural circuits, as well as diseases that affect them, cannot be understood without an accurate understanding of the structure and function of the component parts in the circuit. Broader Impacts: The broader impacts of this work include international collaboration and international and multi-disciplinary training of students and postdocs. In addition, our experimental data and computational models will be shared with the larger research community. We will also work with Michael Kennedy, Director of Northwestern's "Science in Society" program, to use our data to generate interactive, web-based educational tools targeting high-school students as well as post-secondary students. Our goal will be to develop visually exciting tools that appeal to a teenage audience. The tools will be promoted through the Science in Society website and through Kennedy's personal interactions with Chicago Public Schools and the Boys & Girls club of Chicago, both of which have large populations of under-served minorities. Stefan Remy will promote these educational tools in Germany. Long term, we believe that these tools could reach national and international audiences.

描述（由申请人提供）：这是西北大学（Nelson Spruston 和 Bill Kath）、斯坦福大学（Stephen Smith）和波恩大学（Stefan Remy）之间的合作项目。该项目将提高对海马神经元的了解，之所以选择海马神经元是因为它们在学习和记忆以及许多认知障碍中发挥着重要作用。对这些神经元的研究还将深入了解大脑其他区域的神经元，其中许多神经元具有共同的结构和功能特性。该项目的目标如下：我们将使用脑切片中的膜片钳记录结合谷氨酸的双光子解笼和双光子钙成像来收集海马 CA1 锥体神经元的功能数据。我们还将使用阵列断层扫描从相同的树突分支收集结构和分子数据，这使用光学显微镜提供了尽可能高的分辨率。我们将检查兴奋性突触权重的分布，以及来自不同中间神经元亚型的抑制性突触的分布。所有实验都将针对不同树突区室中的树突进行（例如，基底树突与顶端树突）。通过在相同的神经元中进行功能和结构实验，我们将能够关联和整合数据集。我们将构建 CA1 锥体神经元的区室模型，利用实验数据来改进我们现有的这些神经元模型。该模型将用于生成有关突触输入整合的可实验测试的预测。这些预测将超出为约束模型而进行的实验范围，因此它们将构成旨在为这些神经元的未来工作提供信息的预测。斯普鲁斯顿和凯丝有利用此类预测来设计和执行实验的记录，从而产生新的发现。我们将使用目标 2 中开发的模型来检查数千个兴奋性和抑制性突触输入的随机激活，结合树突的兴奋特性和基于所得树突电压变化的突触可塑性规则，是否会导致不均匀梯度CA1 锥体神经元兴奋性突触权重的影响。我们的工作假设是 CA1 树突中存在的自然电压梯度可能有助于非均匀突触权重的发展。我们将这些模拟的结果与阵列断层扫描研究的结果进行比较，作为确定哪种活动模式和突触可塑性规则最能解释观察到的突触权重分布的方法。协作：所有团队成员将定期交换数据和互动。 Sruston 和 Remy 实验室将使用膜片钳记录以及双光子解禁和成像进行实验。这些实验中的填充细胞将被送往斯坦福大学史密斯实验室进行阵列断层扫描。 Sruston、Kath、Smith 和 Remy 将与该项目支持的博士后和学生一起监督阵列断层扫描数据与功能数据的集成。该小组的所有成员将定期举行会议，讨论进展和未来计划。智力优点：该项目将提供有关海马锥体神经元结构和功能的关键数据，这些数据将用于生成前所未有的详细计算模型。这些模型将用于增进我们对树突中突触整合、可兴奋树突对突触可塑性的贡献以及树突树中兴奋性突触权重分布的理解。其基本原理是，如果不准确理解神经回路各组成部分的结构和功能，就无法理解神经回路的功能以及影响神经回路的疾病。更广泛的影响：这项工作的更广泛影响包括国际合作以及对学生和博士后的国际和多学科培训。此外，我们的实验数据和计算模型将与更大的研究社区共享。我们还将与西北大学“社会科学”项目主任迈克尔·肯尼迪合作，利用我们的数据生成针对高中生和专上学生的交互式、基于网络的教育工具。我们的目标是开发视觉上令人兴奋的工具来吸引青少年观众。这些工具将通过社会科学网站以及肯尼迪与芝加哥公立学校和芝加哥男孩女孩俱乐部的个人互动进行推广，这两个学校都有大量服务不足的少数族裔。 Stefan Remy 将在德国推广这些教育工具。从长远来看，我们相信这些工具可以覆盖国内和国际受众。