Plasticity of spinal neural networks directly impacts motor control following peripheral nerve injury - Project Summary/Abstract
Following peripheral nerve injury (PNI), sensory and motoneuron (MN) axons degenerate distal to the injury site
but both maintain the ability to regenerate and reinnervate their muscle targets. Motoneurons regain the ability
to produce muscle force and the majority of the muscle afferents (“propriosensors”) reinnervate the muscle
spindles and fire in response to muscle stretch. However, regardless of successful peripheral regeneration,
patients who experience PNI continue to suffer from life-long motor complications such as limb inter-joint
discoordination and muscle co-contraction. The central hypothesis of this proposal is that plasticity in the
connectivity of pre-motor spinal circuits following nerve injury results in permanent motor deficits.
Specific Aim 1 (K99), hypothesis: hyper-excitatory drive to the spinal pre-motor interneurons following nerve
transection promotes muscle co-contraction. Proprioceptor Ia afferent axons that synapse on spinal MNs are
permanently degraded in lamina IX following nerve cut resulting in the loss of the stretch reflex. However, these
same afferents double their synapses in the deep dorsal horn, where a heterogenous population of pre-motor
interneurons reside. One specific subset of these neurons are those that express Isl1. This specific population
of neurons are glutamatergic, project to divergent motor pools, and receive propriosensor input. An imbalance
in synaptic drive to these cells could facilitate muscle co-contraction. This will be investigated using a
combinatory approach with multi-electrode arrays (MEAs) and transgenic models to identify and manipulate the
activity of the Isl1+ neurons using chemogenetics in an attempt to restore normal muscle activity following injury.
Specific Aim 2 (R00), hypothesis: nerve crush abolishes presynaptic inhibition of Ia afferents and results in an
exaggerated stretch reflex force. In difference to a nerve cut, following a crush injury the stretch reflex is not only
restored it results in supra-normal levels of muscle force. One striking anatomical difference between these two
injury types is that Ia afferent synapses are restored on MNs following crush regeneration but they lose a
significant number of presynaptic inhibitory boutons (p-boutons) that gate Ia synaptic transmission. The
hypothesize of this aim is that the loss in p-boutons is responsible for the exaggerated stretch reflex response
after crush. In this aim will utilize chemogenetics to activate and/or suppress Gad2+ interneurons that provide
presynaptic inhibition during the stretch reflex to investigate how modulating the activity of these cells impact the
strength of the reflex. Then, Gad2 interneurons that provide the remaining p-boutons will be stimulated using
chemogenetics to reduces hyperreflexia after crush. Finally, electrical stimulation will be provided to the nerve
after crush to investigate if sustained activity of the afferents prevents the loss of p-boutons and restores normal
muscle force generation in response to stretch.
