Synaptic Circuit Organization of Motor Cortex

运动皮层的突触电路组织

• 批准号: 8303317
• 负责人: Gordon M Shepherd
• 金额: $ 30.84万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303317
• 关键词: Affect; Area; Automobile Driving; Biological Models; Brain; Cerebral hemisphere; Clinical; Data; Data Set; Detection; Disease; Efferent Pathways; Epilepsy; Event; Functional disorder; Future; Health; Impairment; In Vitro; Interneurons; Investigation; Label; Lasers; Link; Location; Maps; Measures; Mediating; Methods; Modeling; Motor; Motor Cortex; Motor output; Movement; Movement Disorders; Mus; Neocortex; Neurologic; Neurons; Output; Paralysed; Paraplegia; Pathway interactions; Pattern; Phenotype; Physiological; Physiology; Plastics; Property; Resolution; Scanning; Sensory; Short-Term Course; Signal Transduction; Slice; Source; Strontium; Surveys; Synapses; Synaptic plasticity; System; Techniques; Testing; Time; Tracer; Wild Type Mouse; Work; base; computerized data processing; gray matter; hippocampal pyramidal neuron; insight; interdisciplinary approach; motor control; motor disorder; motor learning; neocortical; neural circuit; neuropathology; novel; postsynaptic; presynaptic; programs; research study; scaffold; sensory cortex; spatiotemporal

DESCRIPTION (provided by applicant): We propose an experimental program aimed at determining basic cellular/synaptic mechanisms of local synaptic circuit organization in mouse primary motor cortex (M1). We present a multidisciplinary approach using laser scanning photostimulation (LSPS), pair recording, and related techniques for quantitative analysis of neocortical synaptic circuits. Our guiding hypothesis, based on preliminary data, is that local circuits in M1 - unlike sensory cortex - are adapted for `top down' control of motor output signals, in the form of massively convergent excitatory circuits from upper layers (layer 2/3) onto deeper layers (layers 5A, 5B, 6), and that this descending projection is composed of parallel intracortical pathways that are functionally specialized to integrate synaptic signals for corticospinal, corticostriatal, and other major M1 outputs. Our specific aims, testing different aspects of this general hypothesis, are as follows. First, because cortical layering is a primary determinant of cortical `wiring', in brain slice experiments we will record individually from pyramidal neurons located in all cortical layers in M1, and map the laminar and horizontal sources of excitatory synaptic input. This unique connectivity matrix data set will allow us to determine (for the first time for any cortical area) the average overall excitatory circuit organization in terms of the laminar locations of its neurons. Second, because cortical layers contain functionally distinct subclasses of neurons, we will determine the local circuit organization of major M1 neuronal subclasses. We will use retrograde tracers to identify corticospinal, corticocortical, and corticostriatal neurons for LSPS analysis. We will extend this analysis to determine circuit phenotypes for genetically labeled subclasses as well. Third, because the specific circuits identified above are likely to be functionally specialized, we will analyze their synaptic physiology using pair recording methods to measure unitary connection properties, including the amplitude, time course, and short term plasticity of synaptic signals. We will extend this analysis to the level of single-synapse properties through a novel combination of LSPS mapping and strontium treatment to isolate uniquantal events. Fourth, we will develop and use random access photostimulation to examine the efficacy and timing of feedforward synaptic excitation and inhibition within the M1 local circuit. This will reveal mechanisms of synaptic integration and coincidence detection in identified M1 synaptic pathways. The results will provide radically new insights for understanding the synaptic organization of M1 in wild type mice, providing a quantitative, mechanistic framework for future investigations of synaptic circuit pathophysiology in epilepsy, paralysis, and other disorders of voluntary motor control. PUBLIC HEALTH RELEVANCE Voluntary movements depend on synaptic circuits in the motor area of the neocortex (cortical gray matter) in the cerebral hemispheres. Here we propose a systematic, quantitative experimental approach that will elucidate fundamental synaptic signaling mechanisms and pathways in mammalian motor neocortex at the cellular level. The results will provide a much needed quantitative framework for understanding cortical circuit pathophysiology in epilepsy, paralysis, and related motor disorders.

描述（由申请人提供）：我们提出了一个实验计划，旨在确定小鼠初级运动皮层（M1）局部突触回路组织的基本细胞/突触机制。我们提出了一种使用激光扫描光刺激（LSPS）、配对记录和相关技术对新皮质突触回路进行定量分析的多学科方法。我们基于初步数据的指导性假设是，M1 中的局部电路（与感觉皮层不同）适合于“自上而下”控制运动输出信号，其形式是从上层（第 2/3 层）到更深层（第 5A、5B、6 层）的大规模会聚兴奋电路，并且这种下降的投影由平行的皮层内通路组成，这些通路在功能上专门用于 整合皮质脊髓、皮质纹状体和其他主要 M1 输出的突触信号。我们测试这一一般假设的不同方面的具体目标如下。首先，由于皮质分层是皮质“布线”的主要决定因素，因此在脑切片实验中，我们将单独记录位于 M1 中所有皮质层的锥体神经元，并绘制兴奋性突触输入的层流和水平源。这个独特的连接矩阵数据集将使我们能够（第一次对于任何皮质区域）根据神经元的层状位置确定平均整体兴奋性回路组织。其次，由于皮质层包含功能不同的神经元亚类，因此我们将确定主要 M1 神经元亚类的局部回路组织。我们将使用逆行示踪剂来识别皮质脊髓、皮质皮质和皮质纹状体神经元，以进行 LSPS 分析。我们将扩展此分析，以确定基因标记亚类的电路表型。第三，由于上面确定的特定电路可能在功能上是专门的，因此我们将使用成对记录方法来分析它们的突触生理学，以测量单一连接属性，包括突触信号的幅度、时间过程和短期可塑性。我们将通过 LSPS 映射和锶处理的新颖组合来将该分析扩展到单突触特性的水平，以隔离单量子事件。第四，我们将开发并使用随机访问光刺激来检查 M1 局部回路内前馈突触激发和抑制的功效和时间。这将揭示已识别的 M1 突触通路中突触整合和重合检测的机制。这些结果将为理解野生型小鼠中 M1 的突触组织提供全新的见解，为未来研究癫痫、瘫痪和其他自主运动控制疾病的突触回路病理生理学提供定量的机制框架。公共卫生相关性 随意运动取决于大脑半球新皮质（皮质灰质）运动区的突触回路。在这里，我们提出了一种系统的、定量的实验方法，该方法将在细胞水平上阐明哺乳动物运动新皮质的基本突触信号传导机制和途径。研究结果将为理解癫痫、瘫痪和相关运动障碍的皮质回路病理生理学提供急需的定量框架。