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Physiological Function of Persistent Inward Currents in Motor Neurons

Sponsored by National Institute of Neurological Disorders and Stroke

$408.4K Funding
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ABSTRACT Motor neurons receive synaptic inputs from many other neurons and convert these inputs intofrequency-coded messages that are relayed to muscle fibers to cause contraction. It is often assumed thatmotor neurons generate spikes at rates in proportion to the excitatory synaptic input received. It is nowrecognized however that motor neurons have active processes such as persistent inward currents (PICs)that may markedly alter the relationship between synaptic input and firing rate output. PICs represent aneuromodulator-mediated intrinsic source of membrane depolarization that can even lead to self-sustainedfiring of motor neurons i.e. prolonged spiking in the absence of synaptic input. Several ideas have beenforwarded as to the functional significance of PICs both in terms of the control of normal motor function and asan impaired process contributing to various neurological disorders. Indeed some investigators havesuggested that PICs provide the primary source of depolarizing current to motor neurons during all forms ofactivity whereas others speculate that PICs are only active during periods of high stress and arousal. Yet theextent to which PICs contribute to natural motor neuron activity is not known. Therefore the goal of thisproject is to directly ascertain the role that PICs play during voluntary muscle contraction using an animalmodel wherein the ion channels (L-type calcium) thought to be primary mediators of motor neuron PICs areselectively disabled (Aim 1) or enabled (Aim 2). We will do this by recording motor unit activity in plantar flexormuscles of rats voluntarily exerting target isometric forces in the presence and absence of intrathecally injectednimodipine an L-type Ca+2 channel blocker (Aim 1) and serotonin a known promotor of PICs (Aim 2).Changes in motor unit firing rate (and recruitment) recorded under drug conditions will be compared to thesame units recorded prior to drug delivery while the animal holds the same force. These comparisons willprovide direct knowledge of the role PICs play in shaping natural motor unit activity a topic of debate sincethe discovery of PICs in the late 1970s. Furthermore this study will add to our understanding of PICdysfunction implicated in neurological disorders such as spasticity and amyotrophic lateral sclerosis.