Our overall goal is to take advantage of the extraordinary activity-dependent plasticity of the mature motor systems, to achieve significant repair of the damaged corticospinal tract (CST) after brain or spinal cord injury.
We aim to promote the motor functions of the CST spared after an incomplete injury. These spared connections are sparse and weak;by themselves, they cannot exert significant motor control. Our rat studies use a unilateral pyramidal tract lesion (PTX) that eliminates all CST axons from one motor cortex (M1). This lesion eliminates most of the CST on the affected contralateral spinal cord, with only sparse ipsilateral CST axons remaining. PTX produces significant sprouting from the spared ipsilateral CST, which we hypothesize is adaptive because M1 electrical stimulation after injury promotes this sprouting, leading to motor recovery. PTX also produces proprioceptive afferent sprouting and spinal neuron changes that we hypothesize are maladaptive, because they can lead to spasticity and weakness.
Aim 1 will determine the activity dependence of spinal reactive changes after unilateral CST lesion. We hypothesize that activity loss, not just the physical loss of connections, is an important trigger for reactive changes after injury. We will unilaterally inactivate M1 to determine the activity dependence of CST changes (Aim 1A) and impairments in spinal interneuron and motoneuron function (Aim 1B). We will determine the effects of optogenetic activation of spinal interneurons on reactive spinal changes produced by M1 inactivation (Aim 1C).
In Aim 2 we will determine the role of spinal cord activation in abrogating maladaptive segmental changes after injury and in promoting the motor functions of the spared CST. We hypothesize that stimulating spinal circuits after injury will increase their response to signals from spared CST axons.
Aim 2 A directly tests this hypothesis using the optogenetic approach to activate spinal interneurons with temporal precision, and trans-spinal direct current stimulation (tsDC), an activation approach with translational potential. Spinal stimulation provides segmental activation after CST loss.
In Aim 2 B we will determine if tsDC promotes sprouting of spared CST connections, abrogates maladaptive spinal changes and, together, strengthens the M1-to-muscle pathway.
In Aim 2 C we will determine if tsDC promotes behavioral recovery after PTX.
Aim 3 will harness short-term functional M1 plasticity and spinal activation in combination, to strengthen CST connections, enhance CST outgrowth, and promote motor function after injury. We combine "top down" M1 activation with "bottom up" spinal activation to achieve novel therapeutic insights. We hypothesize that potent short-term plasticity, produced by high-frequency patterned M1electrical stimulation, strengthens and produces sprouting of spared CST axons. Augmented CST signals will now be amplified by spinal activation.
In Aim 3 A we study the acute effects of patterned M1 stimulation, alone and combined with tsDC, on CST transmission and M1 intracortical circuits.
Aim 3 B will determine if CST sprouting, connection strength, and locomotor recovery are promoted by chronic patterned M1 stimulation, and if tsDC affects the response.
Aim 3 C combines cortical and spinal stimulation to restore distal forelimb motor function in a clinically relevant cortical lesion model.

Public Health Relevance

The overall goal of our experiments is to promote motor function after spinal cord or brain injury. We focus on the corticospinal tract, the principal moto control pathway in humans. Using a rat model, we increase neural activity of the motor cortex and/or spinal cord after injury, by electrical stimulation and other means, to restore lost connections to spinal cord motor control centers.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS064004-07
Application #
8735198
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Jakeman, Lyn B
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
City College of New York
Department
Physiology
Type
Other Specialized Schools
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10031
Carmel, Jason B; Kimura, Hiroki; Martin, John H (2014) Electrical stimulation of motor cortex in the uninjured hemisphere after chronic unilateral injury promotes recovery of skilled locomotion through ipsilateral control. J Neurosci 34:462-6
Jiang, Yu-Qiu; Williams, Preston T J A; Martin, John H (2013) Rapid and persistent impairments of the forelimb motor representations following cervical deafferentation in rats. Eur J Neurosci 38:3702-11
Carmel, Jason B; Kimura, Hiroki; Berrol, Lauren J et al. (2013) Motor cortex electrical stimulation promotes axon outgrowth to brain stem and spinal targets that control the forelimb impaired by unilateral corticospinal injury. Eur J Neurosci 37:1090-102
Asante, Curtis O; Martin, John H (2013) Differential joint-specific corticospinal tract projections within the cervical enlargement. PLoS One 8:e74454
Martin, John H (2012) Systems neurobiology of restorative neurology and future directions for repair of the damaged motor systems. Clin Neurol Neurosurg 114:515-23
Carmel, Jason B; Kim, Sangsoo; Brus-Ramer, Marcel et al. (2010) Feed-forward control of preshaping in the rat is mediated by the corticospinal tract. Eur J Neurosci 32:1678-85
Carmel, Jason B; Berrol, Lauren J; Brus-Ramer, Marcel et al. (2010) Chronic electrical stimulation of the intact corticospinal system after unilateral injury restores skilled locomotor control and promotes spinal axon outgrowth. J Neurosci 30:10918-26
Li, Qun; Brus-Ramer, Marcel; Martin, John H et al. (2010) Electrical stimulation of the medullary pyramid promotes proliferation and differentiation of oligodendrocyte progenitor cells in the corticospinal tract of the adult rat. Neurosci Lett 479:128-33