Prior research has shown that neurons within the spinal cord are sensitive to response-outcome (instrumental) relations. Learning in the isolated spinal cord has been studied by cutting communication with the brain using a thoracic transection. Transected rats given shock to one hind leg whenever the leg is extended learn to maintain the leg in a flexed position, thereby minimizing net shock exposure. Rats given shock independent of leg position (uncontrollable shock) do not learn and exhibit a learning deficit when later tested with controllable shock. Evidence suggests that uncontrollable stimulation impairs learning because it induces a form of central sensitization that saturates NMDA receptor mediated plasticity. Uncontrollable stimulation also impairs recovery after a contusion injury. Just 6 min of stimulation 24 hrs after injury leads to poor sensory/motor recovery and this effect is evident 6 weeks later. Uncontrollable stimulation also increases the incidence of renal failure and signs of neuropathic pain. Our working hypothesis is that unregulated nociceptive transmission (pain signals) engages cellular mechanisms that impair recovery after spinal injury. Our long-term objectives are to identify: the circumstances that cause this effect, the neurobiological mechanisms involved, and procedures that can be used to block the adverse effect of uncontrollable nociceptive stimulation.
Three aims are proposed that will detail the stimulus conditions that impact recovery, the relative role of brain systems, and the relation to central sensitization. The experiments build on a decade of research detailing the conditions, and neurobiological mechanisms, that impact function in the isolated spinal cord.
Aim 1 examines the stimulus conditions that affect recovery. It is recognized that a moderate contusion spares some sensory fibers that allow pain transmission to supraspinal structures. It is not known whether, and how, brain systems contribute to the long-term effects of stimulation on recovery. If brain systems are involved, less intense, and more widely spaced, stimulation should impact recovery.
Aim 2 will clarify the role of brain systems using physiological and pharmacological manipulations that impact spared fibers. We also examine whether stimulation affects recovery in the absence of input at, or below, the site of injury.
Aim 3 will evaluate whether the induction of central sensitization (through peripheral inflammation) impairs recovery and whether pharmacological manipulations that prevent central sensitization have a protective effect. The loss of tissue after neural injury reflects the net effect of both the acute injury and secondary processes that extend from hours to days after injury. By identifying factors that influence these secondary processes, treatments can be developed to reduce their harmful effects. Treatments now used to control pain in other situations (e.g., an epidural) could benefit recovery. The present grant will evaluate this possibility. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD058412-02
Application #
7502211
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Nitkin, Ralph M
Project Start
2007-09-28
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$297,528
Indirect Cost
Name
Texas A&M University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
078592789
City
College Station
State
TX
Country
United States
Zip Code
77845
Lee, Kuan H; Huang, Yung-Jen; Grau, James W (2016) Learning about Time within the Spinal Cord II: Evidence that Temporal Regularity Is Encoded by a Spinal Oscillator. Front Behav Neurosci 10:14
Lee, Kuan H; Turtle, Joel D; Huang, Yung-Jen et al. (2015) Learning about time within the spinal cord: evidence that spinal neurons can abstract and store an index of regularity. Front Behav Neurosci 9:274
Strickland, Eric R; Woller, Sarah A; Garraway, Sandra M et al. (2014) Regulatory effects of intermittent noxious stimulation on spinal cord injury-sensitive microRNAs and their presumptive targets following spinal cord contusion. Front Neural Circuits 8:117
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
Grau, James W (2014) Learning from the spinal cord: how the study of spinal cord plasticity informs our view of learning. Neurobiol Learn Mem 108:155-71
Hoy, Kevin C; Huie, J Russell; Grau, James W (2013) AMPA receptor mediated behavioral plasticity in the isolated rat spinal cord. Behav Brain Res 236:319-26
Grau, James W; Huie, J Russell; Garraway, Sandra M et al. (2012) Impact of behavioral control on the processing of nociceptive stimulation. Front Physiol 3:262
Woller, Sarah A; Moreno, Georgina L; Hart, Nigel et al. (2012) Analgesia or addiction?: implications for morphine use after spinal cord injury. J Neurotrauma 29:1650-62
Huie, J R; Garraway, S M; Baumbauer, K M et al. (2012) Brain-derived neurotrophic factor promotes adaptive plasticity within the spinal cord and mediates the beneficial effects of controllable stimulation. Neuroscience 200:74-90
Baumbauer, K M; Lee, K H; Puga, D A et al. (2012) Temporal regularity determines the impact of electrical stimulation on tactile reactivity and response to capsaicin in spinally transected rats. Neuroscience 227:119-33

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