UBC Theses and Dissertations
Regeneration and plasticity of descending motor pathways following spinal cord injury Hilton, Brett Jason
Spinal cord injury (SCI) results in paralysis due in part to the inability of central nervous system (CNS) axons to regenerate following their transection. However, after anatomically incomplete SCI, partial spontaneous recovery can often occur. I studied the regeneration and plasticity of descending pathways involved in forelimb motor function following SCI to better understand the mechanisms underlying axon regeneration failure and spontaneous motor recovery. In Chapter 2, I developed an injury model in adult mice that results in complete axotomy of the rubrospinal tract and sustained deficits in forelimb motor function. I found that when a left dorsolateral funiculus crush injury was instigated at vertebral level C4, there were sustained deficits in left forelimb function while when the same injury was instigated at vertebral level C6, there was spontaneous recovery in left forelimb function to baseline levels. In Chapter 3, I used the injury model developed in Chapter 2 in conditional PTEN KO mice to test the hypotheses that 1) PTEN deletion promotes rubrospinal axonal regeneration following SCI and 2) Aging significantly diminishes the regenerative capacity of PTEN deleted rubrospinal neurons. I found that when PTEN was deleted within rubrospinal neurons in 4 week old mice, there was significant rostral axon growth and regeneration past the lesion site to ~1 mm relative to controls. However, when PTEN was deleted within rubrospinal neurons in 7-8 month old mice, while rostral axon growth occurred, there was no caudal regeneration. Thus, there is an age-dependent decline in regeneration of CNS neurons. In Chapter 4, I used optogenetic and chemogenetic tools to assess motor cortical plasticity in adult mice. I found that following ablation of the dorsal corticospinal tract, the motor cortex is able to re-establish output to the limbs and the minor dorsolateral corticospinal tract representing 3% of direct spinal cord transmission is able to partially mediate spontaneous recovery. Taken together, these data demonstrate an age-related decline in axon regeneration in the adult mammalian CNS and show that a minor corticospinal pathway is necessary for spontaneous recovery following SCI.
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