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项目，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。我们提出了一种多学科方法，使用激光扫描光刺激（LSPS），对记录和相关技术对新皮层突触回路进行定量分析。基于初步数据，我们的指导假设是，M1的局部回路与感觉皮层不同，适合“自上而下”控制运动输出信号，以从上层（第2/3层）到更深层（第5A、5B、6层）的大规模收敛兴奋回路的形式，这种下行投影由平行的皮质内通路组成，这些通路在功能上专门整合皮质脊髓、皮质纹状体、和其他主要M1输出。我们的具体目的是测试这一一般假设的不同方面，如下所示。首先，由于皮层分层是皮层“布线”的主要决定因素，在脑切片实验中，我们将分别记录位于M1所有皮层层的锥体神经元，并绘制兴奋性突触输入的层流和水平源。这种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总体兴奋回路组织。其次，由于皮质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来识别皮质脊髓、皮质皮质和皮质纹状体神经元进行LSPS分析。我们将扩展这一分析，以确定电路表型的遗传标记亚类以及。第三，由于上述确定的特定电路可能具有功能专门化，我们将使用成对记录方法分析其突触生理学，以测量单一连接特性，包括突触信号的振幅、时间过程和短期可塑性。我们将通过LSPS映射和锶处理的新组合来分离独特事件，将这种分析扩展到单突触特性的水平。第四，我们将开发和使用随机通道光刺激来检查M1局部电路中前馈突触兴奋和抑制的有效性和时间。这将揭示突触整合和巧合检测机制在确定的M1突触通路。该结果将为理解野生型小鼠M1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定量的机制框架。自愿运动依赖于大脑半球新皮层（皮层灰质）运动区的突触回路。在这里，我们提出了一个系统的，定量的实验方法，将阐明基本的突触信号机制和途径在哺乳动物运动新皮层的细胞水平。该结果将为理解癫痫、瘫痪和相关运动障碍的皮质回路病理生理学提供一个急需的定量框架。