Computer Models of Normal and Abnormal Discharge Patterns in Human Motoneurons

描述（由申请人提供）：所有动作都是由于不同肌肉的分级激活而执行的。肌肉活动是由脑干和脊髓运动神经元的激活控制的。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。由于肌肉纤维的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在人类受试者中量化。然而，驱动这些放电模式的细胞机制只能通过动物制剂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，以定量地将动物准备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。我们将使用这些模型来量化我们目前关于人类运动神经元放电模式的细胞机制的知识状态。这些模拟结果将用于对人类和动物的进一步实验进行预测，目的是确定偏瘫性中风患者放电模式严重缺陷的潜在机制。这一提议的总体假设是，这些放电模式的缺陷主要不是由于突触输入运动神经元的改变，而是由于它们内在电特性的改变。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（5HT）和去甲肾上腺素（NE）的下行神经调节输入控制的。因此，内在特性的改变可能是由脑干到脊髓输入的改变引起的。该提案有三个具体目标：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)利用这些模型确定偏瘫卒中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开展新的实验，以测试Aim 2模型分析中得出的预测。这些研究的结果有可能产生重大的临床影响。模仿两种重要运动神经元神经调节剂（单胺5HT和NE）作用的药物对这些细胞的特性有特别强的作用。因此，所提出的工作不仅将提供对人类运动神经元细胞特性的新水平的理解，而且还将指导治疗策略的发展，以恢复中风患者正常的运动神经元放电模式。

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.