Both experimental animals and humans can regain the ability to stand or to step after a complete spinal cord transection. The ability to execute these tasks depends on specific training regimens, illustrating the importance of motor leading in the spinal cord. Low-thoracic transection and subsequent training leads to a persistent increase in the total inhibitory capacity of the lumbar spinal cord, exhibited by increases in GAD67, a GABA-synthesizing enzyme, and its mRNA, as well as in the alpha-1 subunit of glycine receptor and in gephyrin, a protein associated with glycine receptors. However, repetitive hindlimb training, such as stepping, returns the levels of GAD67 and glycine receptors towards normal. The central hypothesis of this proposal is that task-specific, repetitive training selectively modulates the inhibition within sensorimotor pathways associated with the execution of that task. Using a robotic device, we will test this hypothesis with a well-defined standing task in neonatally transected (T12-13) rats. Stand training allows us to compare training-induced changes in neurons associated with plantarflexion (facilitation of the soleus motor pool) and neurons associated with dorsiflexion (inhibition of the tibialis anterior motor pool). We will test three hypotheses: (1) that stand training decreases the inhibitory capacity of specific neurons associated with the ankle dorsiflexor (tibialis anterior); (2) that training selectively alters the ratio of inhibitory and excitatory synapses on the somata of individual motoneurons in motor pools associated with soleus, and (3) that pharmacologically induced changes in motor performance of spinally transected rats reflect these alterations in GABAergic and glycinergic inhibition in plantarflexion- and dorsiflexor-associated neurons as noted in the first two hypotheses. A major innovation in this work is the ability to train motor tasks, and to quantify the kinematics of standing and stepping using a newly developed robotic device. This device will allow us to impose strictly repetitive training and to assess the progress of individual animals with great precision. The proposed studies address the anatomical and molecular bases of the plasticity that may underlie rehabilitative training after spinal injury. This work will lead to better ways of testing the effectiveness of alternative training strategies and associated pharmacological interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040917-02
Application #
6625658
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Kleitman, Naomi
Project Start
2002-04-15
Project End
2007-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$359,766
Indirect Cost
Name
University of California Los Angeles
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Ichiyama, Ronaldo M; Broman, Jonas; Roy, Roland R et al. (2011) Locomotor training maintains normal inhibitory influence on both alpha- and gamma-motoneurons after neonatal spinal cord transection. J Neurosci 31:26-33
Joseph, M Selvan; Bilousova, Tina; Zdunowski, Sharon et al. (2011) Transgenic Mice With Enhanced Neuronal Major Histocompatibility Complex Class I Expression Recover Locomotor Function Better After Spinal Cord Injury. J Neurosci 89:365-372
Tillakaratne, N J K; Guu, J J; de Leon, R D et al. (2010) Functional recovery of stepping in rats after a complete neonatal spinal cord transection is not due to regrowth across the lesion site. Neuroscience 166:23-33
Khristy, Windyanne; Ali, Noore J; Bravo, Arlene B et al. (2009) Changes in GABA(A) receptor subunit gamma 2 in extensor and flexor motoneurons and astrocytes after spinal cord transection and motor training. Brain Res 1273:9-17
Jindrich, Devin L; Joseph, M Selvan; Otoshi, Chad K et al. (2009) Spinal learning in the adult mouse using the Horridge paradigm. J Neurosci Methods 182:250-4
Bigbee, Allison J; Crown, Eric D; Ferguson, Adam R et al. (2007) Two chronic motor training paradigms differentially influence acute instrumental learning in spinally transected rats. Behav Brain Res 180:95-101
Ichiyama, Ronaldo M; Broman, Jonas; Edgerton, V Reggie et al. (2006) Ultrastructural synaptic features differ between alpha- and gamma-motoneurons innervating the tibialis anterior muscle in the rat. J Comp Neurol 499:306-15
Ahn, S N; Guu, J J; Tobin, A J et al. (2006) Use of c-fos to identify activity-dependent spinal neurons after stepping in intact adult rats. Spinal Cord 44:547-59
Havton, Leif A; Broman, Jonas (2005) Systemic administration of cholera toxin B subunit conjugated to horseradish peroxidase in the adult rat labels preganglionic autonomic neurons, motoneurons, and select primary afferents for light and electron microscopic studies. J Neurosci Methods 149:101-9
Edgerton, V Reggie; Tillakaratne, Niranjala J K; Bigbee, Allison J et al. (2004) Plasticity of the spinal neural circuitry after injury. Annu Rev Neurosci 27:145-67