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.

Public Health Relevance

The general goal of this project is to understand how human motor neurons are activated. Motor neurons are neurons that excite muscles to produce movements. The traditional view is that motor neurons generate action potentials in proportion to the level of input received from other neurons. Studies carried out in isolated nervous tissues, however, have shown that motor neurons possess persistent inward currents, a mechanism that may enable sustained firing with little input from other neurons. The main aim of this project is t identify the natural situations under which such persistent inward currents are used by motor neurons. This information is needed to understand how the brain controls movements. Furthermore, since dis- regulation of persistent inward currents has been implicated in spasticity and amyotrophic lateral sclerosis (Lou Gehrig's disease), better understanding of the physiology of persistent inward currents will provide insight into the cause of these disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Musculoskeletal Rehabilitation Sciences Study Section (MRS)
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Chen, Daofen
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University of Arizona
Schools of Medicine
United States
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Revill, Ann L; Fuglevand, Andrew J (2017) Inhibition linearizes firing rate responses in human motor units: implications for the role of persistent inward currents. J Physiol 595:179-191
Potvin, Jim R; Fuglevand, Andrew J (2017) A motor unit-based model of muscle fatigue. PLoS Comput Biol 13:e1005581
Tadros, M A; Fuglevand, A J; Brichta, A M et al. (2016) Intrinsic excitability differs between murine hypoglossal and spinal motoneurons. J Neurophysiol 115:2672-80
Wakefield, Hilary E; Fregosi, Ralph F; Fuglevand, Andrew J (2016) Current injection and receptor-mediated excitation produce similar maximal firing rates in hypoglossal motoneurons. J Neurophysiol 115:1307-13
Tibold, Robert; Fuglevand, Andrew J (2015) Prediction of muscle activity during loaded movements of the upper limb. J Neuroeng Rehabil 12:6
Fuglevand, Andrew J; Lester, Rosemary A; Johns, Richard K (2015) Distinguishing intrinsic from extrinsic factors underlying firing rate saturation in human motor units. J Neurophysiol 113:1310-22
Tadros, M A; Farrell, K E; Schofield, P R et al. (2014) Intrinsic and synaptic homeostatic plasticity in motoneurons from mice with glycine receptor mutations. J Neurophysiol 111:1487-98