Saturday, September 30, 2023
9/30/2023
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.
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