Physiological significance of persistent inward currents in motor neurons

描述(申请人提供)：运动神经元接收来自许多其他神经元的突触输入，并将这些输入转换为频率编码信息，然后传递到肌肉纤维以引起收缩。通常认为运动神经元产生尖峰的频率与接收到的兴奋性突触输入成比例。然而，现在已经认识到，运动神经元具有活跃的过程，例如可能显著调节突触输入和放电频率输出之间关系的持续内向电流(PIC)。PIC是膜去极化的内在来源，可能导致运动神经元的自持性放电，即在没有突触输入的情况下延长峰电位。对于PIC的功能意义，已经提出了许多观点，无论是在控制正常的运动功能方面，还是作为导致痉挛或肌萎缩侧索硬化症(ALS)的受损过程而言。然而，人们对在什么情况下的实际生理条件知之甚少。 图片被激活。然而，最近已经提出了一种方法来评估清醒的人类受试者的PIC激活，该方法包括从自愿收缩期间记录的运动单位对的活动中量化一个被称为？F的指数。这个项目的第一个具体目标是基于从计算机建模中获得的见解，严格测试F方法的有效性。为此，我们将测量收缩期间运动单位对的F，这四个肌肉的力量上升速度和持续时间不同，这些肌肉的运动神经元被认为具有不同的生成图片的能力。第二个具体目标将确定在自愿收缩过程中观察到的运动单位放电率最初的高增长是否可能是由PIC激活引起的。为此，我们将尝试阻止激活 通过人为地激活运动神经元的强烈抑制输入，并确定这是否消除了运动单位放电率最初的急剧上升，从而完全消除了PIC。总体而言，这个项目很重要，因为它将提供对激活图片的生理条件的洞察。这些信息不仅对理解运动神经元的基本运作至关重要，而且对确定痉挛和肌萎缩侧索硬化症等神经疾病的原因也至关重要。

DESCRIPTION (provided by applicant): Motor neurons receive synaptic inputs from many other neurons and convert these inputs into frequency-coded messages that are relayed to muscle fibers to cause contraction. It is often assumed that motor neurons generate spikes at rates in proportion to the excitatory synaptic input received. It is now recognized, however, that motor neurons have active processes, such as persistent inward currents (PICs) that may markedly modulate the relationship between synaptic input and firing rate output. PICs represent an intrinsic source of membrane depolarization that may lead to self-sustained firing of motor neurons, i.e., prolonged spiking in the absence of synaptic input. A number of ideas have been forwarded as to the functional significance of PICs, both in terms of the control of normal motor function and as an impaired process contributing to spasticity or amyotrophic lateral sclerosis (ALS). Yet, little is known about the actual physiological conditions under which PICs are activated. Recently, however, a method has been proposed to enable assessment of PIC activation in awake human subjects that involves quantifying an index referred to as ¿F from the activities of pairs of motor units recorded during voluntary contractions. The first specific aim of this project is to rigorously test the validity of the ¿F method based on insights gained from computer modeling. For this aim, we will measure ¿F for pairs of motor units during contractions that vary in rate of rise of force and duration in four muscles whose motor neurons are thought to possess differing capacities for generating PICs. The second specific aim will determine whether the initial high gain in motor unit firing rate observed during voluntary contraction is likely caused by PIC activation. For this aim, we will attempt to prevent activation of PICs altogether by artificially activating strong inhibitory inputs to motor neurons and determine whether this eliminates the initial steep rise in motor unit firing rate. Overall, this project is important because it will provide insight into the physiological conditions that activat PICs. Such information is crucial not only for understanding the fundamental operation of motor neurons but also for identifying the causes of neurological disorders such as spasticity and ALS.