We designed this program project to coordinate synergistic research efforts around the central theme that nerve regeneration is not synonymous with functional recovery. We are uniquely focused on changes occurring in the sensorimotor motor circuits that are responsible for coordinating muscle activity and purposeful limb movement. In the aftermath of peripheral nerve transection and regeneration, spinal circuits do not regain normal feedback about movement from the centrally-projecting axon branches of either primary afferents or motoneurons. In the previous funding period, we discovered that these centrally- projecting axons and their spinal connections are permanently lost or altered, even when peripheral axon branches successfully reconnect with appropriate targets. Three projects, each led by an established investigator who brings unique experimental expertise and conceptual insight to the program, will advance our knowledge of the response of spinal circuits to peripheral nerve injury and regeneration. Project 1 will apply electrophysiological methods in vivo to test a proposed treatment to improve outcome following peripheral nerve injury. Project 2 will use a novel viral retrograde labeling technique to ask questions about circuit reorganization that have previously been impossible to address. Together, Projects 1 and 2 will test the hypothesis that circuit changes in the spinal cord triggered by peripheral nerve injury are more global than the monosynaptic reflex. The results will shed light on the nature of the changes that explain the modification in motor control and behavior after injury. Project 3 will define the pathway that underlies in vivo signaling that occurs via spontaneous vesicle release at the neuromuscular junction and will determine whether this pathway also signals synaptic stripping from motoneurons following peripheral nerve injury. All three projects will be assisted by the Cellular Imaging, Surgery and Tissue Processing Core Facility (Core B). This core provides the support and expertise necessary to ensure consistency and quality of procedures for all three PPG research projects. An external advisory committee reviewing our program project in 2010 concluded, this is an unusually interactive group with significant intellectual interactions evidet in many of the projects. It is our hope that continued close collaboration between projects, will bring significant added value as we move towards development of therapy to promote recovery following nerve injury. Public Health Relevance: Our overarching goal is to improve recovery following injury to the nervous system. Our specific focus is recovery of spinal cord motor function following peripheral nerve injury. Because similar cellular and synaptic changes might also operate as consequence of central nervous injuries, this work will also inform efforts to promote recovery from nervous system injuries after insults such as stroke and spinal cord injury.
Discl aim er: The critiques and criterion scores from individual reviewers are provided below in an essentially unedited form. These were prepared prior to the review meeting and may not have been updated or revised subsequent to the discussion at the meeting. Therefore, they may not fully reflect the final opinions of the individual reviewers at the close of group discussion o the final majority opinion of the group. The Resume and Summary of Discussion above summarizes the final outcome of the group discussion. OVERALL PROGRAM EVALUATION

Public Health Relevance

Our overarching goal is to improve recovery following injury to the nervous system. Our specific focus is recovery of spinal cord motor function following peripheral nerve injury. Because similar cellular and synaptic changes might also operate as consequence of central nervous injuries, this work will also inform efforts to promote recovery from nervous system injuries after insults such as stroke and spinal cord injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS057228-10
Application #
9001373
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Chen, Daofen
Project Start
2015-12-16
Project End
2018-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
10
Fiscal Year
2016
Total Cost
$758,727
Indirect Cost
$51,377
Name
Georgia Institute of Technology
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30318
Wang, Xueyong; Rich, Mark M (2018) Homeostatic synaptic plasticity at the neuromuscular junction in myasthenia gravis. Ann N Y Acad Sci 1412:170-177
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
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

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