Prior research has shown that neurons within the spinal cord can support some simple forms of learning. Learning in the isolated spinal cord can be studied by cutting communication with the brain by means of a thoracic transection. Transected rats given shock to one hind leg whenever the leg is extended soon learn to maintain the leg in a flexed position that minimizes net shock exposure, a form of instrumental conditioning. Rats that receive shock independent of leg position (uncontrollable shock) do not learn and exhibit a learning deficit when later tested with controllable shock. This learning deficit can be prevented, and reversed, by training with controllable shock. Instrumental training also enables learning when subjects are tested with a more difficult response criterion. Our hypothesis is that instrumental training enables learning within the spinal cord, and has a protective effect, because it promotes the synthesis and release of the neurotrophin BDNF.
Aim 1 explores this hypothesis using pharmacological techniques. The necessity of BDNF is evaluated using drug manipulations that disrupt BDNF function. Sufficiency is examined by artificially applying BDNF to the spinal tissue. If BDNF plays a key role, disrupting BDNF should eliminate the beneficial effect of instrumental training and the application of BDNF should have a protective effect. Preliminary data suggest that training with controllable shock up-regulates BDNF mRNA expression while uncontrollable stimulation down-regulates expression.
Aim 2 uses assays for mRNA expression to examine the duration of these effects and their anatomical locus. Protein assays will evaluate how this expression affects BDNF levels and the signal pathways involved. Prior work has shown that uncontrollable, but not controllable, stimulation disrupts recovery after a spinal contusion injury. We outline a novel procedure to maximize the beneficial effect of controllable stimulation and seek evidence that instrumental training has a lasting effect in a contusion model. Additional work will evaluate whether training affects recovery because it promotes the release of BDNF. The long-term goal of this research is to characterize the mechanisms that underlie spinal plasticity at both a functional and neurobiological level. Instrumental training provides a model of a common behavioral technique (functional electrical stimulation [FES]) used to foster recovery after spinal injury in humans. By identifying key instrumental relations, and the neurochemical systems involved, we hope to develop more effective procedures to promote recovery. Further, procedures designed to promote neural growth across an injury require techniques to shape the appropriate pattern of neural innervation. Instrumental training could provide the procedure needed to select adaptive neural connections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041548-08
Application #
7576784
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Kleitman, Naomi
Project Start
2001-04-01
Project End
2011-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
8
Fiscal Year
2009
Total Cost
$358,860
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
Grau, James W; Huang, Yung-Jen (2018) Metaplasticity within the spinal cord: Evidence brain-derived neurotrophic factor (BDNF), tumor necrosis factor (TNF), and alterations in GABA function (ionic plasticity) modulate pain and the capacity to learn. Neurobiol Learn Mem 154:121-135
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:
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
Huie, J Russell; Baumbauer, Kyle M; Lee, Kuan H et al. (2012) Glial tumor necrosis factor alpha (TNF?) generates metaplastic inhibition of spinal learning. PLoS One 7:e39751

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