Computer simulations of populations of mammalian motor units

描述（由申请人提供）：运动单元是运动输出的基本元素，由运动神经元及其轴突支配的肌肉纤维组成。肌纤维的抽搐通常与运动神经元的动作电位是一对一的，因此运动单元是一个单一的功能实体。尽管如此，大多数实验和模拟研究都倾向于关注运动神经元或肌肉。这种焦点分离严重限制了对正常和病理状态下运动流出的理解。为了弥补这一差距，本提案寻求开发一种高度逼真且经过彻底验证的计算机模拟单个肌肉的运动单元集。我们的研究重点是猫的后肢伸肌，这是目前最完整的实验数据库。限制以往模拟运动单元努力的关键问题是缺乏对神经调节剂在运动神经元突触输入到尖峰输出转换中的作用的理解。我们实验室和许多其他实验室的系统研究现在已经确定了这些神经调节剂的作用，并发现它们在影响运动神经元兴奋性方面非常强大。其中最有效的是血清素（5HT）和去甲肾上腺素（NE），它们通过起源于脑干的轴突在脊髓中释放。5HT和NE促进运动神经元树突中的持续向内电流（PICs），从而将突触输入放大多达5倍。我们已经成功地开发了一个具有PICs的运动神经元的初始模型。此外，我们已经成功地开发了一个很好的肌肉模型来表示肌肉单位。在提议的工作的目标1中，这些初始模型被进一步开发，仔细验证实验数据，并扩展到200多个成员的集合，以准确地代表整个运动池和肌肉。在Aim 2中，我们使用模拟池/肌肉来研究运动流出的结构，重点关注神经调节输入如何改变整体系统增益以及影响运动神经元放电模式和力的噪声波动等细节。该模型在广泛的运动控制模拟中具有很大的应用潜力，但涉及多组神经元和多块肌肉的模拟需要计算效率。因此，在Aim 3中，我们研究了几种不同的方法来简化全套100个运动单元，以实现计算速度的大幅提高。这些目标的成功完成将提供一个生物现实的运动输出模型，可用于运动神经控制的广泛计算研究。这些模拟可用于深入了解运动指令的结构，并识别脊髓损伤等疾病状态下运动系统的缺陷。从长远来看，我们希望开发一个用户界面，以允许电机控制社区广泛使用。

DESCRIPTION (provided by applicant): The motor unit is the fundamental element of motor output and consists of a motoneuron and the muscle fibers that its axon innervates. Muscle fiber twitches are normally 1-to-1 with motoneuron action potentials and thus the motor unit is a single functional entity. Despite this, most studies, both experimental and simulation, tend to focus either on motoneurons or on muscle. This separation of focus has sharply limited understanding of motor outflow in both normal and pathological states. To bridge this gap, this proposal seeks to develop a highly realistic and thoroughly validated computer simulation of the set of motor units for a single muscle. We focus on hindlimb extensors in the cat, for which the most complete experimental database is available. The key issue limiting previous efforts at simulating motor units is the lack of understanding of the effects of neuromodulators on conversion of synaptic input to spiking outputs in motoneurons. Systematic studies in our lab and many others have now identified these neuromodulator effects, and found them to be remarkably strong in influencing motoneuron excitability. The most potent of all are serotonin (5HT) and norepinephrine (NE), which are released in the spinal cord by axons originating in the brainstem. 5HT and NE facilitate persistent inward currents (PICs) in the dendrites of motoneurons, which then amplify synaptic input by as much as 5-fold. We have successfully developed an initial model of the motoneuron with PICs. Moreover, we have successfully developed a good muscle model for representing muscle units. In Aim 1 of the proposed work, these initial models are further developed, carefully validated against experimental data and expanded into the set of more the 200 members needed to accurately represent the full motor pool and muscle. In Aim 2, we use the simulated pool/muscle to investigate the structure of motor outflow, focusing on how neuromodulatory inputs alter overall system gain as well as influence details like motoneuron firing patterns and noise fluctuations in force. This model has great potential for use in a wide range of simulations of motor control, but simulations that involved multiple sets of neurons and multiple muscles require computational efficiency. Thus in Aim 3, we investigate several different approaches for simplifying the full set of 100s of motor units to achieve great increases in computational speed. Successful completion of these aims will provide a biologically realistic model of motor output that can be used in a wide range of computational studies of the neural control of movement. These simulations can be used to generate deep insights into the structures of motor commands and to identify deficits in motor systems in disease states like spinal injury. In the long term, we hope to develop a user interface to allow widespread use by the motor control community. PUBLIC HEALTH RELEVANCE: The motor unit, defined as a motoneuron in the spinal cord, its axon in a peripheral nerve and the muscle fiber it innervates, is the quantal unit of motor control. The proposed simulations of the pool of motor units that form a single muscle can thus be used to identify the organization of synaptic input to motoneurons in both normal and disease states. This information will provide a quantitative guide for development of new therapies for disease states like spinal cord injury.