After peripheral nerve injuries axons can regenerate and reestablish connectivity in the periphery;however restored motor function is not normal. Previously we have shown that some deficits, like lack of monosynaptic reflexes, can be explained by the permanent retraction of la proprioceptive synapses from motoneurons. We now propose that circuit reorganizations are relatively global and affect also spinal intermeuronal circuits that exert control over not only injured motoneurons, but also other motor pools controlling the same limb. As a result, a novel limb control pattern emerges that allows some function, but is also clearly pathological. In the proposed work we will seek confirmation for structural changes in spinal interneuronal circuits. The work will parallel functional studies proposed in project 1. We will analyze in detail the synaptic organization of recurrent and reciprocal inhibition, two key inhibitory circuits that modulate and pattern motoneuron firing and therefore muscle contractions. Recurrent inhibition exerts feedback control of motor output through an interposed interneuron named the Renshaw cell that receives direct excitation from intraspinal collaterals of motor axons. Reciprocal inhibition is mediated by la inhibitory interneurons which receive common inputs with certain motor pools, including those from la afferents, and inhibit motoneurons with antagonist action allowing for example smooth flexion-extension alternation during movement. We hypothesize that both interneurons become denervated from respectively, motor axons and la afferents after nerve injury. We propose that these alterations cause major changes in spinal circuitry.
In aim 1 we will test the hypothesis that denervation of Renshaw cells coupled to injured motor axons causes synaptic reorganizations of recurrent inhibition in the whole spinal segment.
In aim 2 we will test the hypothesis that differential la de-afferentation of inhibitory and excitatory interneurons in reciprocal pathways causes a shift in balance favoring excitation. These could explain the excessive co-contraction of antagonists observed after nerve injuries. Detail analyses of connectivity will be performed with a combination of techniques, including novel retrograde transynaptic viral tracing that allows revealing microcircuit connectivity.

Public Health Relevance

The lack of good motor recovery after nerve injuries and despite adequate regeneration of peripheral nerves remains a puzzling question and a complication for patient recovery. The work proposed will challenge the current paradigm of improving regeneration in peripheral nerves and seek an explanation in possible injured-induced reorganizations of spinal motor circuits. This knowledge will allow us to direct future work to seek for the cellular mechanisms of this circuit plasticity and form the basis of future therapeutically approaches.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wright State University
United States
Zip Code
Wang, Xueyong; McIntosh, J Michael; Rich, Mark M (2018) Muscle Nicotinic Acetylcholine Receptors May Mediate Trans-Synaptic Signaling at the Mouse Neuromuscular Junction. J Neurosci 38:1725-1736
Wang, Xueyong; Rich, Mark M (2018) Homeostatic synaptic plasticity at the neuromuscular junction in myasthenia gravis. Ann N Y Acad Sci 1412:170-177
Schultz, Adam J; Rotterman, Travis M; Dwarakanath, Anirudh et al. (2017) VGLUT1 synapses and P-boutons on regenerating motoneurons after nerve crush. J Comp Neurol 525:2876-2889
Wang, Xueyong; Pinter, Martin J; Rich, Mark M (2016) Reversible Recruitment of a Homeostatic Reserve Pool of Synaptic Vesicles Underlies Rapid Homeostatic Plasticity of Quantal Content. J Neurosci 36:828-36
Vincent, Jacob A; Wieczerzak, Krystyna B; Gabriel, Hanna M et al. (2016) A novel path to chronic proprioceptive disability with oxaliplatin: Distortion of sensory encoding. Neurobiol Dis 95:54-65
Romer, Shannon H; Deardorff, Adam S; Fyffe, Robert E W (2016) Activity-dependent redistribution of Kv2.1 ion channels on rat spinal motoneurons. Physiol Rep 4:
Smilde, Hiltsje A; Vincent, Jake A; Baan, Guus C et al. (2016) Changes in muscle spindle firing in response to length changes of neighboring muscles. J Neurophysiol 115:3146-55
McGovern, Vicki L; Massoni-Laporte, Aurélie; Wang, Xueyong et al. (2015) Plastin 3 Expression Does Not Modify Spinal Muscular Atrophy Severity in the ?7 SMA Mouse. PLoS One 10:e0132364
Vincent, Jacob A; Nardelli, Paul; Gabriel, Hanna M et al. (2015) Complex impairment of IA muscle proprioceptors following traumatic or neurotoxic injury. J Anat 227:221-30
Romer, Shannon H; Dominguez, Kathleen M; Gelpi, Marc W et al. (2014) Redistribution of Kv2.1 ion channels on spinal motoneurons following peripheral nerve injury. Brain Res 1547:1-15

Showing the most recent 10 out of 31 publications