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

• 批准号: 7579804
• 负责人: RANDALL K POWERS
• 金额: $ 50.58万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-02 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579804
• 关键词: Accounting; Action Potentials; Acute; Algorithms; Animal Model; Animals; Area; Behavior; Brain Stem; Calcium; Cells; Characteristics; Chronic; Classification; Clinical; Computer Simulation; Computers; Coupled; Data; Exhibits; Felis catus; Goals; Human; Investigation; Knowledge; Link; Measurement; Measures; Mediating; Modeling; Motor; Motor Neurons; Movement; Mus; Muscle; Muscle Fibers; Neuromodulator; Noise; Norepinephrine; Patients; Pattern; Pharmaceutical Preparations; Plastics; Preparation; Property; Protocols documentation; Rattus; Recruitment Activity; Research; Serotonin; Side; Sodium; Speed; Spinal; Spinal Cord; Staging; Stroke; Study models; Synapses; Techniques; Testing; Work; animal data; base; electrical property; hemiparesis; hemiparetic stroke; human subject; insight; monoamine; novel; public health relevance; research study; response; scale up; simulation; therapeutic development; voltage

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. PUBLIC HEALTH RELEVANCE: Cerebral strokes commonly result in a number of movement deficits on the side of the body opposite the stroke (hemiparesis). The proposed research combines computer simulations with experimental recordings in hemiparetic stroke subjects and in animal models to determine the mechanisms underlying movement deficits following stroke. The proposed work will not only provide a new level of understanding of the cellular properties of the cells that drive muscle activity, but also guide development of therapeutic strategies to restore normal muscle activation in stroke patients.

描述（由申请人提供）：由于不同肌肉的分级激活，所有运动均执行。 肌肉活性受脑干和脊髓中运动神经元的激活控制。 每个运动神经元都以一对一的方式驱动肌肉纤维，从而形成一个运动单元。 由于肌肉纤维的作用电位相对易于测量，因此运动神经元是唯一可以在人类受试者中很容易量化的CNS细胞。 但是，只能通过动物制剂中的细胞内研究来测量驱动这些发射模式的细胞机制。 该建议的目的是开发一个复杂的计算机模拟平台，以定量将细胞数据从动物制剂链接到人类受试者中的模式数据。 人体运动神经元的高度现实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关于人类运动神经元点火模式细胞机制的知识状态。 然后，这些模拟将用于生成人类和动物的进一步实验的预测，目的是识别出偏瘫中风患者发生的点火模式中严重缺陷的机制。 该提案的总体假设是，这些发射模式中的这些缺陷主要是由于突触输入对运动神经元的变化，而是由于其内在电气性能的变化。 通常，运动神经元的固有特性是通过释放单胺5-羟色胺（5HT）和去甲肾上腺素（NE）的脑干的降序神经调节输入来控制的。 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而引起的。 该提案具有三个特定的目的：1）使用高速（FPGA）模拟平台与自动参数搜索算法共同开发人体运动神经元的高度现实模型； 2）使用这些模型来识别腹膜中风中运动神经元发射模式的潜在细胞机制； 3）在人类和动物模型中进行新的实验，以测试AIM 2模型分析中发展的预测。 这些研究的结果有可能产生重大临床影响。 模仿两个重要的运动神经元调节剂（单胺5HT和NE）的作用的药物对这些细胞的特性具有尤其强大的作用。 因此，拟议的工作不仅将提供对人运动神经元细胞特性的新水平，而且还指导开发治疗策略，以恢复中风患者的正常运动神经元出院模式。 公共卫生相关性：大脑中风通常会导致人体侧面的许多运动缺陷（偏瘫）。 拟议的研究将计算机模拟与偏瘫中风受试者和动物模型中的实验记录相结合，以确定中风后运动缺陷的机制。 拟议的工作不仅将提供对驱动肌肉活性细胞的细胞特性的新水平，而且还指导开发治疗策略，以恢复中风患者的正常肌肉激活。