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(申请人提供)：我们提出了一个实验方案，旨在确定小鼠初级运动皮质(M1)局部突触电路组织的基本细胞/突触机制。我们提出了一种多学科的方法，使用激光扫描光刺激(LSP)、成对记录和相关技术对新皮质突触回路进行定量分析。根据初步数据，我们的指导性假设是，M1中的局部回路--不同于感觉皮质--适合于对运动输出信号的“自上而下”控制，其形式是从上层(第2/3层)到深层(5A、5B、6层)的大规模会聚兴奋回路，而这种下行投射是由平行的皮质内通路组成的，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。我们的具体目标是检验这个一般假设的不同方面，如下所示。首先，由于皮质分层是皮质“连接”的主要决定因素，在脑片实验中，我们将从位于M1所有皮质层的锥体神经元单独记录，并映射兴奋性突触输入的层流和水平来源。这一独特的连接矩阵数据集将使我们能够(首次对任何皮质区域)根据其神经元的层状位置确定平均整体兴奋性回路组织。其次，由于皮层包含功能不同的神经元亚类，我们将确定主要M1神经元亚类的局部电路组织。我们将使用逆行示踪剂识别皮质脊髓、皮质和纹状体神经元，用于LSP分析。我们将扩展这一分析，以确定基因标记的亚类的电路表型。第三，由于以上识别的特定电路可能是功能专门化的，我们将使用配对记录方法来分析它们的突触生理，以测量一元性连接属性，包括突触信号的幅度、时间进程和短期可塑性。我们将通过LSPs映射和锶处理的新组合将这种分析扩展到单一突触属性的水平，以分离独特的事件。第四，我们将开发和使用随机访问光刺激来检查M1局部回路中前馈突触兴奋和抑制的有效性和时序。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障碍的突触回路病理生理学提供一个定量的机械框架。公共卫生相关性自愿运动依赖于大脑半球新皮质(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，将在细胞水平上阐明哺乳动物运动新皮质中基本的突触信号机制和通路。这一结果将为理解癫痫、瘫痪和相关运动障碍的皮质回路病理生理学提供一个亟需的量化框架。