Central synaptic impairment persists in sensory and motor neurons that regenerate their peripheral axonal projections after nerve injury. New findings obtained in this grant period suggest that these impairments modify feedback about muscle length and motor activity and cause significant dysfunction of spinal circuits responsible for coordinating muscle activity. This proposal has two objectives in studying the central mechanisms that limit recovery of movement following nerve repair: (1) locate deficits within and imbalances between selected spinal circuits and (2) manipulate activity of afferents in attempt to restore the usefulness of sensory feedback. Experiments designed to meet the specific aims described below all involve electrophysiological study in vivo of adult rat?s months after a selected few muscle nerves are severed and surgically repaired. The physiological studies proposed here will be coordinated with morphological studies in Project 2 in order to enable function-structure interpretations.
Specific Aim 1 is motivated by findings obtained in this grant period which suggest the counterintuitive notion that inactivity of regenerated primary afferents promotes their recovery of synaptic transmission with motoneurons. Experiments will manipulate afferent activity in attempt to rescue central transmission of muscle-length feedback for those afferents which recover stretch sensitivity through peripheral regeneration.
Specific Aim 2 focuses on the recovery of recurrent feedback from motoneurons which is shown by Projects 1 and 2 to be incomplete despite successful regeneration of peripheral motor axons. Resultant modification of the spinal circuit receiving recurrent feedback will be probed in detail to test sites of dysfunction.
Specific Aim 3 will examine apparent imbalances in excitatory and inhibitory spinal circuits associated with dyscoordination of antagonist muscle activity. Meeting these aims will substantially advance this project's long-term goal of explaining the failure to regain normal central transmission from neurons that regenerate successfully in the periphery after nerve injury. These central impairments together with incomplete and misdirected regeneration in the periphery conspire to prevent nerve repair from restoring normal movement. By addressing the causes of deficits in purposeful movement, this project advances the mission of the NINDS to improve treatment of neurological disorders.

Public Health Relevance

When severed nerves regenerate they can restore the ability to move the affected arms and legs, but that movement is often less effective than normal. Studies proposed here will test a method for fixing some problems, and go on to discover the cause for other difficulties in coordinating movement.

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