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）：我们提出了一个旨在确定小鼠初级运动皮层（M1）中局部突触回路组织的基本细胞/突触机制的实验计划。我们提出了一个多学科的方法，使用激光扫描光刺激（LSPS），对记录，和相关技术的定量分析新皮层突触电路。基于初步数据，我们的指导性假设是，M1中的局部回路--与感觉皮层不同--以来自上层的大规模会聚兴奋回路的形式，适合于“自上而下”控制运动输出信号（2/3层）到更深层（层5A、5 B、6），这种下行投射由平行的皮质内通路组成，这些通路在功能上专门整合突触信号，皮质脊髓、皮质纹状体和其他主要M1输出。我们的具体目标是检验这一一般假设的不同方面，具体目标如下。首先，因为皮层分层是皮层“重叠”的主要决定因素，在脑切片实验中，我们将单独记录位于M1所有皮层层的锥体神经元，并绘制兴奋性突触输入的层状和水平源。这个独特的连接矩阵数据集将使我们能够确定（第一次为任何皮层区域）平均整体兴奋性回路组织的神经元层的位置。第二，因为皮质层包含功能不同的神经元子类，我们将确定主要的M1神经元子类的局部电路组织。我们将使用逆行示踪剂识别皮质脊髓，皮质皮质，皮质纹状体神经元LSPS分析。我们将扩展这种分析，以确定电路表型的遗传标记的子类以及。第三，因为上面确定的特定回路可能在功能上是专门化的，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隔离单量子事件，从而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存取光刺激来检查M1局部回路内前馈突触兴奋和抑制的功效和时间。这将揭示在识别的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，为癫痫，瘫痪和其他自愿运动控制障碍的突触回路病理生理学的未来研究提供定量，机制框架。与公共卫生的关系随意的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，我们提出了一个系统的，定量的实验方法，将阐明基本的突触信号转导机制和通路在哺乳动物运动新皮层在细胞水平上。这些结果将为理解癫痫、瘫痪和相关运动障碍的皮层回路病理生理学提供一个非常需要的定量框架。