About 250,000 Americans suffer from spinal cord injury (SCI). SCI causes a loss of descending drive from the brain to the spinal Central Pattern Generator (CPG) networks that organize and drive locomotion. As a consequence, the spinal neurons and their synaptic connections undergo slow plastic changes that can lead to dysfunction and retard locomotor recovery. While changes in motoneuron properties after SCI have been measured, the effects of SCI on identified CPG interneurons have not yet been studied. The major hypothesis of this proposal is that the loss of descending inputs to the CPG after SCI causes slow homeostatic compensatory changes in the locomotor CPG network, due to changes in the intrinsic properties of component neurons and/or their synaptic interactions and sensory inputs. These changes may vary between different neuron types. Chronic treatment with monoamine agonists initiated immediately after injury may prevent or alter these homeostatic changes, enhancing locomotor recovery. These hypotheses will be tested in the adult mouse spinal cord, where genetic tools have been developed to identify and label several classes of interneurons that participate in the locomotor CPG. We have recently developed a perforated patch method that for the first time allows stable recordings from adult spinal interneurons. This method will be used to compare the properties and synaptic interactions of identified CPG interneurons in control animals and after SCI. The proposal has four specific aims. First, study the effects of SCI on the intrinsic electrophysiological properties and modulation of genetically identified CPG interneurons. Second, examine the biophysical and molecular changes in ion channel and receptor function which cause the changes in CPG interneuron firing properties. Third, examine changes in synaptic drive and its plasticity between identified spinal neurons after SCI, and in sensory drive to these interneurons. Finally, test whether chronic serotonin/dopamine agonist treatment can prevent or alter the homeostatic changes that occur after SCI, and determine the optimal time course for this treatment. These experiments should yield valuable information on the consequences of SCI for neurons and networks below a lesion that are not themselves damaged by the injury, but change their properties as a consequence of the loss of normal inputs from the brain. Studies of monoamine agonist treatment will provide a mechanistic explanation for how this improves locomotor recovery, and may give new information on optimal use of this treatment to help maintain the locomotor CPG in a functional state during the time for repair of descending inputs to assist in the restoration of locomotion.

Public Health Relevance

This work will identify changes in neuronal activity and synaptic interactions that may disturb normal spinal locomotor network function after spinal cord injury. We will study the time course and cellular and synaptic mechanisms by which chronic monoamine agonist treatment can enhance locomotor recovery after SCI. These studies will determine whether monoamine agonist treatment reduces or alters the homeostatic changes in locomotor network function, to help restore movement after SCI.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Chen, Daofen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cornell University
Other Basic Sciences
Earth Sciences/Resources
United States
Zip Code
Goeritz, Marie L; Ouyang, Qing; Harris-Warrick, Ronald M (2011) Localization and function of Ih channels in a small neural network. J Neurophysiol 106:44-58
Ouyang, Q; Patel, V; Vanderburgh, J et al. (2010) Cloning and distribution of Ca2+-activated K+ channels in lobster Panulirus interruptus. Neuroscience 170:692-702
Johnson, Bruce R; Schneider, Lauren R; Nadim, Farzan et al. (2005) Dopamine modulation of phasing of activity in a rhythmic motor network: contribution of synaptic and intrinsic modulatory actions. J Neurophysiol 94:3101-11
Harris-Warrick, R M; Coniglio, L M; Levini, R M et al. (1995) Dopamine modulation of two subthreshold currents produces phase shifts in activity of an identified motoneuron. J Neurophysiol 74:1404-20