Physiological significance of persistent inward currents in motor neurons

描述（由申请人提供）：运动神经元接受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的信息，传递给肌肉纤维以引起收缩。人们通常认为运动神经元产生尖峰的速率与接收到的兴奋性突触输入成正比。然而，现在人们认识到，运动神经元具有活跃的过程，例如持续向内电流（PICs），它可以显著调节突触输入和放电速率输出之间的关系。PICs代表了膜去极化的内在来源，可能导致运动神经元的自我持续放电，即在缺乏突触输入的情况下延长尖峰。关于PICs的功能意义，已经提出了许多观点，无论是在控制正常运动功能方面，还是作为导致痉挛或肌萎缩侧索硬化症（ALS）的受损过程。然而，人们对其实际生理条件知之甚少

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.