Single-Synapse Analysis of Neocortical Circuit Plasticity

新皮质回路可塑性的单突触分析

基本信息

批准号：
8505730
负责人：
Stephen J Smith
金额：
$ 6.5万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8505730
关键词：
Adhesions Biological Models Brain Characteristics Data Dendritic Spines Development Disease Drug Delivery Systems Dyes Environment Exhibits Experimental Designs Future Glutamates Goals Homeostasis Individual Injection of therapeutic agent Injury Knowledge Learning Link Logic Maps Measurement Measures Memory Memory Disorders Methods Modification Molecular Molecular Profiling Mus Neocortex Nerve Degeneration Neurodegenerative Disorders Neurodevelopmental Disorder Neurons Paired Comparison Parents Pattern Pharmaceutical Preparations Physiological Plastics Population Procedures Proteins Proteomics Protocols documentation Reaction Research Resolution Screening procedure Sensory Signal Transduction Signaling Protein Site Somatosensory Cortex Synapses Synaptic plasticity Testing Tissues Tracer Transgenic Mice Transgenic Organisms Vertebral column Vibrissae Work barrel cortex base classical conditioning conditioning deprivation design experience gamma-Aminobutyric Acid imaging modality improved long term memory molecular marker mouse development neocortical neural circuit novel postsynaptic presynaptic prevent receptor reconstruction research study scaffold sensory system tomography tool

项目摘要

DESCRIPTION (provided by applicant): Synaptic plasticity in many different forms is widely recognized as essential to normal brain development, to homeostasis of the mature brain, and to our abilities to adapt to changing environments and injury and to learn. There is relatively little information, however, to link particular known forms of synaptic plasticity to particular forms or sites of behaviorally relevant brain circuit plasticity. This gap in our knowledge prevents us from efficiently pinpointing synapses of known functional relevance as we explore the molecular, synaptic, and circuit bases of memory and its disorders. The experiments proposed here will exploit unique advantages of the mouse whisker sensory system to explore basic mechanisms of neocortical synaptic plasticity. The work will apply a powerful new high-resolution proteomic imaging method called "array tomography" (AT) to measure molecular and structural characteristics of cortical synapse populations at the level of individual synapses. AT has unique abilities to resolve individual synapses in native circuit tissue context, to measure dozens of distinctive molecular markers (e.g., diverse receptor, transporter, signaling, scaffolding and adhesion proteins) at each synapse, and to do so with very high experimental throughput. Thus, AT can determine a high dimensional molecular signature for each individual synapse in very large populations and differentiate specific synapse subpopulations on the basis of such molecular signatures. The proposed research will develop and apply a novel AT-based screening strategy to search in an unbiased fashion for patterns of structural and molecular change occurring in specific mouse neocortical synapses in reaction to specific sensory adaptation and associative conditioning procedures.

描述（由申请人提供）：许多不同形式的突触可塑性被广泛认为对于正常大脑发育、成熟大脑的稳态以及我们适应不断变化的环境和伤害以及学习的能力至关重要。然而，将特定的已知形式的突触可塑性与行为相关的脑回路可塑性的特定形式或位点联系起来的信息相对较少。当我们探索记忆及其疾病的分子、突触和回路基础时，我们知识上的这一差距使我们无法有效地查明已知功能相关的突触。这里提出的实验将利用小鼠胡须感觉系统的独特优势来探索新皮质突触可塑性的基本机制。这项工作将应用一种名为“阵列断层扫描”（AT）的强大的新型高分辨率蛋白质组成像方法来测量单个突触水平的皮质突触群体的分子和结构特征。 AT 具有独特的能力，可以解析天然电路组织环境中的单个突触，测量每个突触处的数十种独特的分子标记（例如，不同的受体、转运蛋白、信号传导、支架和粘附蛋白），并以非常高的实验通量做到这一点。因此，AT 可以确定非常大的群体中每个突触的高维分子特征，并根据这种分子特征区分特定的突触亚群。拟议的研究将开发和应用一种新的基于 AT 的筛选策略，以公正的方式搜索特定小鼠新皮质突触中发生的结构和分子变化模式，以响应特定的感觉适应和联想调节程序。