The basic element for motor control is the motor unit. A motor unit consists of a motoneuron in the ventral portion of the spinal cord, its axon that travels in the appropriate nerves, and the set of muscle fibers the axon innervates in its target muscle. Our lab studies the motor unit and the spinal circuits that help generate motor unit firing patterns in both normal and pathological states. We are particularly interested in amplification of synaptic input by voltage-sensitive conductances in dendrites of spinal motoneurons and interneurons. The motoneuron is subject to strong neuromodulatory control by fibers that originate in the brainstem and that release the monoamines serotonin or norephinephrine. In the past, it has been assumed that the monoamines increased motoneuron excitability simply by depolarizing them sufficiently to bring them near or above threshold for firing.
However, our lab has recently shown that the increased excitability results from a complete transformation in the way motoneurons process their synaptic inputs. In the absence of monoamines, large amplitude synaptic currents are required to generate high firing rates. With monoaminergic drive, which occurs in the normal waking state, voltage-sensitive channels within the dendrites of motoneurons become capable of producing steady depolarizing currents with large amplitudes. This means that prolonged motoneuron firing at high rates can be produced by small synaptic inputs. This type of highly excitable behavior appears to be the basis of motor tasks involving prolonged force generation, such as posture. Over the past 10 years, we have discovered that this excitability becomes aberrant following neurotrauma or neurodeneration. In spinal injury, we are working to develop new approaches for restoring normal excitability via administration of monoaminergic drugs. In motoneuron disease (amyotrophic lateral sclerosis, ALS), our collaboration with the lab of Teepu Siddique has shown that motoneurons become hyperexcitable very early in disease development. In both cases our work is now attempting to develop new therapeutic strategies.