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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
2P01NS057228-06A1
Application #
8562551
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
6
Fiscal Year
2013
Total Cost
$256,819
Indirect Cost
$11,500
Name
Wright State University
Department
Type
DUNS #
047814256
City
Dayton
State
OH
Country
United States
Zip Code
45435
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Rotterman, Travis M; Nardelli, Paul; Cope, Timothy C et al. (2014) Normal distribution of VGLUT1 synapses on spinal motoneuron dendrites and their reorganization after nerve injury. J Neurosci 34:3475-92
Deardorff, Adam S; Romer, Shannon H; Sonner, Patrick M et al. (2014) Swimming against the tide: investigations of the C-bouton synapse. Front Neural Circuits 8:106
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
Zhang, Jingming; Lanuza, Guillermo M; Britz, Olivier et al. (2014) V1 and v2b interneurons secure the alternating flexor-extensor motor activity mice require for limbed locomotion. Neuron 82:138-50
Koesters, Andrew; Engisch, Kathrin L; Rich, Mark M (2014) Decreased cardiac excitability secondary to reduction of sodium current may be a significant contributor to reduced contractility in a rat model of sepsis. Crit Care 18:R54
Deardorff, Adam S; Romer, Shannon H; Deng, Zhihui et al. (2013) Expression of postsynaptic Ca2+-activated K+ (SK) channels at C-bouton synapses in mammalian lumbar -motoneurons. J Physiol 591:875-97
Nardelli, Paul; Khan, Jaffar; Powers, Randall et al. (2013) Reduced motoneuron excitability in a rat model of sepsis. J Neurophysiol 109:1775-81
Wang, Xueyong; Wang, Qingbo; Yang, Shuzhang et al. (2011) Impaired activity-dependent plasticity of quantal amplitude at the neuromuscular junction of Rab3A deletion and Rab3A earlybird mutant mice. J Neurosci 31:3580-8
Bullinger, Katie L; Nardelli, Paul; Pinter, Martin J et al. (2011) Permanent central synaptic disconnection of proprioceptors after nerve injury and regeneration. II. Loss of functional connectivity with motoneurons. J Neurophysiol 106:2471-85

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