Grant: Operating Grant

The main goal of this research is to understand the neuronal mechanisms that mediate the development of spasticity and motor dysfunction after spinal cord injury and cerebral palsy. We examine how neurons and neuronal circuits in an injured nervous system adapt to produce the uncontrolled and unwanted muscle contractions that affect the majority of patients with spinal cord injury and cerebral palsy. One of the neurons that we study is the motoneuron that excites the muscles of the limbs to produce movement. Previously, we have shown that after spinal cord injury, the excessive and uncontrolled activity of motoneurons during muscle spasms is mediated, in large part, by the activation of voltage-dependent persistent inward currents (PICs) in the human motoneuron. In human patients we have used dual motor unit recording techniques to estimate the contribution of PIC activation in the motoneuron. In this proposal, we study why motoneurons recover PICs and self-sustained activity after chronic spinal cord injury. Because PICs require the presence of the monoamines serotonin (5HT) and norepinephrine (NE) to activate, and these monoamines are greatly reduced after injury, we examine if PICs recover because the 5HT receptors become spontaneously active without the need for 5HT to bind to the receptor. We also examine how manipulation of the NE system in patients with spinal cord injury affects PIC activation and muscle spasms. Finally, we examine in patients with cerebral palsy if spasticity is produced by augmented activation of the motoneuron by PICs, involuntary descending inputs and/or sensory inputs. These research results will pave the way to develop new pharmacological and rehabilitative therapies to both control spasticity after spinal cord injury and cerebral palsy and augment residual motor movements in these patient groups.