Repairing spinal injuries is an important yet elusive goal of modern medicine. Our group has recently demonstrated that intraspinal stimulation may lead to some level of plasticity and recovery after incomplete spinal cord injury. One challenge in complete regeneration of the brain and spinal cord is that the presence of peri-neuronal nets limits plasticity at synapses in the adult central nervous system. Chondroitinase ABC (ChABC) is an enzyme known to dissolve chondroitin sulphate proteoglycans in these plasticity-inhibiting peri-neuronal nets. When delivered near a spinal cord injury, ChABC can lead to significant levels of recovery. Our goal is to determine whether the combination of intraspinal stimulation and ChABC augments recovery after incomplete spinal cord injury. Our experimental paradigm involves training rats in a forelimb reaching task before performing incomplete contusion injuries at the C4 vertebral level. Spinal stimulating wires are then implanted below the injury, and animals are randomly assigned to one of two groups that receive ChABC or ChABC + spinal stimulation. Animals are then given daily spinal stimulation treatments and are tested at the forelimb reaching task for several months to assess their level of recovery. We expect to see rats that receiving the ChABC treatment succeed at the reaching task with greater frequency than those that only receive spinal stimulation. In addition, these ChABC-treated rats should, over time, regain a greater degree of skilled motor-function than their stimulation-only counterparts. In related experiments, spinal stimulation triggered from brain activity may be an even more powerful and specific cue for plasticity. Additional experiments may test the combined effects of ChABC with brain-triggered stimulation, even in the uninjured adult spinal cord. If this is indeed the case, our work could lead to an effective combination therapy for repairing human spinal injuries.

There are currently very few effective treatments to repair damage resulting from spinal cord injury (SCI). The project I have been working on in the Moritz Lab involves the exploration of Intraspinal Microstimulation (ISMS) and its ability to promote functional recovery after SCI in a rodent animal model. Our group employs a unilateral incomplete spinal cord contusion injury using the Ohio State University contusion device at the level of the fourth lamina in the cervical spine, or C4. We then place stimulating wires in the spinal cord, specifically in the ventral gray matter caudal to the injury at C6-C8, in order to deliver ISMS to the motor pools innervating the triceps and other forelimb muscles. My independent project in the lab is a histological analysis of triceps and forelimb muscles taken from the SCI models to determine whether the use of ISMS preferentially recruits fatigue resistant (FR) muscle fibers in the affected forelimb of these rats. After paresis resulting from SCI, muscles atrophy and undergo a "slow-to-fast" transition in the myosin heavy chain (MHC) isoform content. My goal is to examine whether ISMS can slow or even reverse this slow-to-fast conversion after SCI. I am using immunohistochemistry to differentiate muscle fiber types in the triceps muscle. I stain for the unique MHC isoform that is expressed by the various slow and fast type fibers. My hypothesis is that there will be a higher population of type I and type IIA FR fibers in the stimulated muscles of ISMS group than in the control group, which will mostly consist of fast fatigable types IIB and type IID. The long-term goal of my project is to determine the benefits of using ISMS as a neural prosthesis and regenerative therapy for individuals who have suffered from spinal cord contusion injuries.

 Mycobacterium tuberculosis infection is a leading cause of death worldwide, but the full details of how the human immune system responds to these bacteria are not known. Our lab studies CD1 proteins which allow T-cells to respond to bacterial lipids. We discovered that low expression of CD1A on dendritic cells is associated with an increased susceptibility to tuberculosis; however, the molecular details of CD1A-deficiency are not known. I cloned and analyzed the CD1A promoter from four CD1A-deficient and five control individuals. I identified twelve genetic variations in the CD1A promoter. Of these, eight were single nucleotide polymorphisms (SNPs), three were insertions or deletions, and one was a variable tandem repeat. One SNP (-199 T/C) and the variable tandem repeat showed an association with CD1A-deficiency. A T/T genotype at position -199 from the transcription start site correctly identified five out of five control subjects while a C/C genotype identified three out of four CD1A-deficient subjects. The variable tandem repeat was a string of 20 to 60 thymine bases. The CD1A-deficient subjects showed uniform repeat lengths, while the repeat lengths among control subjects were variable. These data identify two loci within the CD1A promoter that will be the target of future studies aimed at understanding the molecular mechanism of CD1A-deficiency.

Thanks to advances in safety equipment and emergency care, most spinal cord injuries that occur in people today are incomplete, leaving a portion of the spinal cord neural tissue intact. Further, recent research has shown that there is plasticity and axonal sprouting following injury, expanding the possibilities for rehabilitation from what was once considered a permanent and unrecoverable injury. Our goal is to enhance this process and work towards functional recovery. Dopamine, a powerful neurotransmitter involved in processes such as learning, memory and motivation, plays an integral role in brain plasticity. We are currently testing whether pairing dopamine release with functional movements can increase plasticity of the remaining active pathways and lead to increased functional recovery following an injury in the same way that it can form powerful associations between behaviors and reward sensations. Recently concluded tests followed the recoveries of two rats which received dopamine-releasing electrical brain stimulation paired with functional movements of an impaired limb following identical unilateral cervical spinal cord injuries. These rats activated the stimulation by using their impaired forelimb to push a lever which activated their medial forebrain bundle, a key pathway in the mesocorticolimbic dopamine system. One of these animals showed a significant recovery, nearly to full pre-injury movement capability, and much greater than control animals that received no dopamine stimulation (results in the second animal were inconclusive). Ongoing experiments will compare animals receiving dopamine-releasing stimulation paired with movement of the injured limb to control animals where phasic dopamine release is uncorrelated with movement. These experiments may lead directly to novel methods for promoting nervous system recovery from injury by using dopaminergic pathways to promote and reinforce neural plasticity. This may lead to therapies which allow people with incomplete spinal cord injuries to improve functional motor skills.