Preservation of sensory la afferent boutons on motoneurons after peripheral nerve injury restores synaptic transmissions and rescues whole limb kinematics

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Following peripheral nerve injury (PNI), both sensory and motoneuron (MN) axons degenerate at the site of injury, but both regenerate to their muscle targets. Motoneurons regain the ability to produce muscle force and almost half of group Ia muscle proprioceptors reinnervate muscle spindles and fire in response to changes in muscle length. However, one deficit that remains after PNI is that the central projecting branch of the Ia afferents that forms monosynaptic connections with the MNs dies back and disconnects from the motor pool, never to return even with provisionally successful reinnervation of muscle spindle receptors. This synaptic retraction has a major impact on common motor activities as the central motor network losses the feedback mechanism necessary for postural adjustments. This Ia synaptic loss is dependent on a pro-inflammatory immune response in the ventral horn of the spinal cord. However, suppressing the immune response using the broad-spectrum antibiotic minocycline, completely prevents the structural loss of Ia afferent inputs on axotomized MNs. However, the major questions remain, “are these preserved synaptic inputs functional?” and “does preservation of Ia’s improve recovery of motor behavior?” Objective: Investigate synaptic function and motor behavior when the connections between Ia afferents and MNs are preserved following PNI. Specific Aim 1, Hypothesis: Rescuing Ia - MN spinal circuit network will promote recovery of limb movement. Specific Aim 2, Hypothesis: Physical preservation will rescue function at synapses made by Ia afferents on motoneurons. Specific Aim 3, Hypothesis: Amplification of Ia synaptic current is sufficient to restore sustained firing in motoneurons after injury. These aims are designed to systematically interrogate the function of preserved Ia afferent synapses after nerve injury. All of these experiments will take place at Georgia Tech under the direction of the sponsor, Dr. Tim Cope, and additional guidance from our collaborator Dr. Young-Hui Chang. Both have provided their expertise in the development of this project and will oversee the success of all three aims.