Physiological significance of persistent inward currents in motor neurons

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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.