Project 1: Circuit Plasticity
P.I.: Timothy Cope, Ph.D.
Adjunct Professor, Department of Neuroscience, Cell Biology & Physiology
"After nerve damage and regeneration, we lose the stretch reflex in affected muscles, adversely affecting our core balance. We theorize that damage to the PNS creates circuitry problems at the CNS which do not reverse after nerve regeneration."
Regeneration of a cut muscle nerve restores voluntary contraction but fails to re-establish normal sensorimotor function. We find that limb movements are uncoordinated and stretch reflexes are absent, not only in the reinnervated muscle but also in injury-spared synergists. Our recent findings point to multiple unexplored mechanisms within the spinal cord that might act, possibly in combination, to prevent stretch-reflex recovery that would otherwise be accomplished, at least partially, by regeneration.
We propose to test two candidate mechanisms using electrophysiological measures applied to animals in which the nerves supplying a few muscles in the hindlimb are cut, rejoined surgically, and permitted to regenerate and reinnervate their original muscles. The first two aims focus on explaining the obstruction we observe in synaptic transmission between regenerated muscle stretch afferents and motoneurons (IA-MN synapses) within the spinal cord.
Specific Aim 1 is designed to test the hypothesis that transmission at IA-MN synapses during physiologically-relevant firing rates is abnormally depressed because of cellular impairments in IA axons or synapses. Specific Aim 2 will test the hypothesis that transmission in regenerated IA-MN circuits is suppressed by active spinal networks. We will also study the temporal development of areflexia in muscles that are not subject to nerve injury. Specific Aim 3 will examine whether areflexia in injury-spared muscles develops independently of, or secondary to, reinnervation of its synergists. Meeting these aims will substantially increment our knowledge of post-regeneration limits on recovery of spinal synapses and circuits. This knowledge might also assist development of treatments for neurotrauma and neuropathies associated with sensory (proprioceptive) ataxia which share symptoms with the stretch areflexia under study in this project.