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Computer Models of Normal and Abnormal Discharge Patterns in Human Motoneurons

人类运动神经元正常和异常放电模式的计算机模型

基本信息

批准号：
8385578
负责人：
RANDALL K POWERS
金额：
$ 47.78万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-02 至 2014-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): All movements are executed as a result of graded activation of different muscles. Muscle activity is controlled by the activation of motoneurons in the brainstem and spinal cord. Each motoneuron drives the muscle fibers it innervates in a one-to-one fashion, thus forming a motor unit. Because muscle fiber action potentials are relatively easy to measure, motoneurons are the only CNS cells whose firing patterns can be readily quantified in human subjects. The cellular mechanisms that drive these firing patterns, however, can only be measured via intracellular studies in animal preparations. The goal of this proposal is to develop a sophisticated computer simulation platform to quantitatively link cellular data from animal preparations to firing pattern data in human subjects. Highly realistic models of human motoneurons will be implemented on field programmable gate arrays (FPGAs). We will employ these models to quantify our present state of knowledge about cellular mechanisms of human motoneuron firing patterns. The simulations will then be used to generate predictions for further experiments both in humans and animals, with the goal of identifying mechanisms underlying the severe deficits in firing patterns that occur in hemiparetic stroke patients. The overall hypothesis of this proposal is that these deficits in firing patterns are primarily due not to alterations in the synaptic input to motoneurons but instead to changes in their intrinsic electrical properties. Normally, motoneuron intrinsic properties are controlled by descending neuromodulatory inputs from the brainstem that release the monoamines serotonin (5HT) and norepinephrine (NE). Thus, changes in intrinsic properties may arise from changes in the input from the brainstem to the spinal cord. The proposal has three specific aims: 1) To develop highly realistic models of human motoneurons using a high-speed (FPGA) simulation platform in conjunction with automatic parameter search algorithms; 2) To use these models to identify potential cellular mechanisms underlying changes in motoneuron firing patterns in hemiparetic stroke; and 3) To carry out new experiments in humans and animal models to test predictions developed in the Aim 2 model analyses. The results of these studies have the potential for substantial clinical impact. Drugs that mimic the effects of two important motoneuron neuromodulators, the monoamines 5HT and NE, have especially strong actions on these cells' properties. Thus, the proposed work will not only provide a new level of understanding of cellular properties of human motoneurons, but also guide development of therapeutic strategies to restore normal motoneuron discharge patterns in stroke patients.

描述（由申请人提供）：所有运动都是由于不同肌肉的分级激活而执行的。肌肉活动由脑干和脊髓中运动神经元的激活控制。每个运动神经元以一对一的方式驱动它所支配的肌肉纤维，从而形成一个运动单元。由于肌纤维动作电位相对容易测量，运动神经元是唯一的中枢神经系统细胞，其放电模式可以很容易地量化在人类受试者。然而，驱动这些放电模式的细胞机制只能通过动物制剂中的细胞内研究来测量。本提案的目标是开发一个复杂的计算机模拟平台，以定量地将动物制剂的细胞数据与人类受试者的放电模式数据联系起来。高度逼真的人类运动神经元模型将在现场可编程门阵列（FPGA）上实现。我们将采用这些模型来量化我们目前的知识状态，人类运动神经元放电模式的细胞机制。然后，这些模拟将用于为人类和动物的进一步实验产生预测，目的是确定发生在轻偏瘫中风患者中的放电模式严重缺陷的潜在机制。这一建议的总体假设是，这些缺陷的发射模式主要是由于在运动神经元的突触输入的改变，而是在其内在的电特性的变化。正常情况下，运动神经元的内在特性是由脑干释放单胺5-羟色胺（5 HT）和去甲肾上腺素（NE）的下行神经调节输入控制的。因此，内在特性的变化可能是由于从脑干到脊髓的输入的变化引起的。该计划有三个具体目标：1）使用高速（FPGA）仿真平台结合自动参数搜索算法开发高度逼真的人类运动神经元模型; 2）使用这些模型来识别偏瘫中风运动神经元放电模式变化的潜在细胞机制; 3）在人类和动物模型中进行新的实验，以测试Aim 2模型分析中的预测。这些研究的结果可能具有重大临床影响。模拟两种重要的运动神经元神经调质（单胺5 HT和NE）作用的药物对这些细胞的特性具有特别强的作用。因此，拟议的工作不仅将提供一个新的水平的理解人类运动神经元的细胞特性，但也指导发展的治疗策略，以恢复正常的运动神经元放电模式中风患者。