Prior research has shown that neurons within the spinal cord are sensitive to response-outcome (instrumental) relationships. Rats with complete spinal cord transections can learn to maintain the hindlimb in a flexed position if leg shock is delivered when the leg is extended (response- contingent shock). Using this simple preparation, we have shown that stimulation alters the capacity for spinal learning in a bidirectional manner. Training with response-contingent shock promotes later spinal learning. Conversely, nociceptive stimulation that is independent of leg position (uncontrollable shock or peripheral paw injury) inhibits future spinal learning and impairs locomotor recovery after contusive spinal cord injury (SCI). Prior work has found that these impairments in spinal learning depend on a maladaptive form of glutamate-mediated plasticity that impairs future use-dependent plasticity in the spinal cord. The cellular mechanisms regulating this plasticity of plasticity (""""""""metaplasticity"""""""") are not well-understood. Our hypothesis is that the cytokine tumor necrosis factor a (TNFa) within the spinal cord plays a critical mechanistic role in spinal learning impairments after uncontrollable stimulation. TNFa is released in elevated levels after SCI or nociceptive stimulation. TNFa has recently been found to alter synaptic plasticity within the injured spinal cord by increasing trafficking of the glutamate AMPA receptor (AMPAR) to the plasma membrane of spinal neurons. Preliminary data suggest that TNFa-induced AMPAR trafficking may contribute to spinal learning impairments after SCI. Intrathecal delivery of an AMPAR agonist or TNFa impairs spinal learning. Conversely a TNFa inhibitor promotes spinal learning.
Aim 1 establishes the dose-response and temporal features of these TNFa-mediated effects.
Aim 2 evaluates TNFa mRNA and protein levels in the spinal cord after uncontrollable stimulation using qRT-PCR, ELISA, in situ hybridization and immunofluorescence.
Aim 3 examines TNF-induced trafficking of AMPARs to the plasma membrane of spinal neurons after uncontrollable stimulation by biochemical and confocal microscopy methods.
Aim 4 tests the therapeutic potential of a TNFa1 inhibitor for promoting use-dependent plasticity and recovery of function after contusive SCI. Our long-term goal is to unravel the mechanisms that regulate adaptive spinal plasticity, allowing patients to re-establish essential functions, while limiting the maladaptive plasticity that can lead to spasticity or intractable pain. By defining key mechanisms that disable spinal cord learning and recovery of function, we hope to provide novel therapeutic targets that promote spinal cord learning and neurorehabilitation after SCI.

Public Health Relevance

Project Narrative/Public Health Relevance Statement Spinal cord Injury (SCI) produces a devastating syndrome that is characterized by loss of motor control and mobility, as well as sensory dysfunction and pain. The proposed project explores cellular mechanisms that regulate a form of spinal cord learning that is thought to contribute to recovery of function after SCI. These studies may provide a novel target for improving recovery after SCI.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Kleitman, Naomi
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Huie, J Russell; Morioka, Kazuhito; Haefeli, Jenny et al. (2017) What Is Being Trained? How Divergent Forms of Plasticity Compete To Shape Locomotor Recovery after Spinal Cord Injury. J Neurotrauma :
Haefeli, Jenny; Huie, J Russell; Morioka, Kazuhito et al. (2017) Assessments of sensory plasticity after spinal cord injury across species. Neurosci Lett 652:74-81
Awai, Lea; Bolliger, Marc; Ferguson, Adam R et al. (2016) Influence of Spinal Cord Integrity on Gait Control in Human Spinal Cord Injury. Neurorehabil Neural Repair 30:562-72
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Nielson, Jessica L; Haefeli, Jenny; Salegio, Ernesto A et al. (2015) Leveraging biomedical informatics for assessing plasticity and repair in primate spinal cord injury. Brain Res 1619:124-38
Huie, J Russell; Stuck, Ellen D; Lee, Kuan H et al. (2015) AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury. eNeuro 2:
Grau, James W; Huie, J Russell; Lee, Kuan H et al. (2014) Metaplasticity and behavior: how training and inflammation affect plastic potential within the spinal cord and recovery after injury. Front Neural Circuits 8:100
Garraway, Sandra M; Woller, Sarah A; Huie, J Russell et al. (2014) Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: role of tumor necrosis factor alpha and apoptosis. Pain 155:2344-59
Ferguson, Adam R; Irvine, Karen-Amanda; Gensel, John C et al. (2013) Derivation of multivariate syndromic outcome metrics for consistent testing across multiple models of cervical spinal cord injury in rats. PLoS One 8:e59712
Yuh, Esther L; Cooper, Shelly R; Ferguson, Adam R et al. (2012) Quantitative CT improves outcome prediction in acute traumatic brain injury. J Neurotrauma 29:735-46

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