Date of Award
Spring 2021
Document Type
Dissertation - Restricted
Degree Name
Doctor of Philosophy (PhD)
Department
Biological Sciences
First Advisor
Blackmore, Murray G.
Second Advisor
Buchanan, James T.
Third Advisor
Mynlieff, Michelle
Abstract
Spinal cord injury (SCI) is a condition that has plagued humans for centuries, and still there is no effective treatment to restore neuronal deficits caused by trauma. Unlike the peripheral system, the mature central nervous system is highly limited in intrinsic regenerative capacity. The signaling from the brain to the spinal cord and through the corticospinal tract (CST), important in fine motor control, through the gray matter and out to the muscles through motoneurons is highly specialized to each muscle signal. Within the gray matter the cells representing extensor and flexor muscles are positioned close together, making individual cell to cell connections imperative for appropriate activation of one muscle over the other. The work presented here studies the CST in axon growth studies following injury, utilizing a known growth-promoting gene therapy (KLF6) and novel rehabilitation to in an attempt to enhance sprouting and functional recovery of the tract. Using the unilateral pyramidotomy model the CST is left transected on one side, with the other side intact. A cortical injection into the motor cortex representing the CST on the intact side is injected with a tracer virus or a tracer virus + KLF6 to trace and treat the intact CST and measure axon sprouting into the denervated tissue. The initial study found that the intact CST will only sprout in the presence of an injury response. Also, KLF6 will only induce axon sprouting in the CST in the presence of injury. Next by probing the time course over which KLF6 induces axon sprouting it became clear that at 4 weeks post injury significant sprouting into the denervated cord existed. In a following study the 4-week time point was used to bring in task-based rehabilitation. Animals received cortical injections of tracer or tracer + KLF6 and pyramidotomies and 4 weeks later the rehabilitation group began task-based pellet retrieval and general walking rehabilitation for 10 weeks. Each week all animals were assessed for pellet retrieval and wheel walking behavior. At the end of the experiment the axon sprouting in the cervical cord was measured in all animals. Neither KLF6 nor rehabilitation effected behavioral measures, but KLF6 continued to promote sprouting as seen in the previous experiments. A preliminary study of an intensive forced-use rehabilitation, constraint-induced movement therapy (CIMT) was use on animals that had received unilateral pyramidotomies. This experiment sought to intensively rehabilitate the affected limb following injury but found no behavioral or axon sprouting differences between treated and control groups. Collectively, this work attempted to improve axon growth following injury. Ultimately, it identified basic principles concerning sprouting, the injury requirement for sprouting, and the time course of sprouting, all of which are critical information for further studies involving timed rehabilitative intervention.