UBC Theses and Dissertations
UBC Theses and Dissertations
Motoneuron response to axonal injury McPhail, Lowell Thomas
Axonal injury in the spinal cord of the central nervous system (CNS) in higher vertebrates results in the atrophy or death of the injured motoneuron population, contributing to a failure in functional regeneration. In contrast, following an axonal injury in the peripheral nervous system (PNS) motoneurons typically survive and if given the appropriate conditions, regenerate their axons back to their target muscles. Therefore, analysis of the survival and regeneration of PNS motoneurons in response to injury may increase our understanding of injury in the CNS and thus facilitate a treatment for CNS injuries. Rodent facial motoneurons are an excellent model to examine the effect of PNS axon injury as it is a well-defined system that is readily accessible to experimental manipulation. In this thesis I utilized this well established model of peripheral nerve injury to reveal several new findings related to the motoneuron response to nerve injury. Facial motoneurons display a differential susceptibility to injury depending on the developmental age of the animal. Following facial nerve injury in the neonatal rat the majority of the motoneurons die by an apoptotic mechanism; whereas, in the adult rat the majority of the motoneurons survive a similar injury. One possible explanation for this age dependant survival in response to injury is the level of survival-promoting factors such as the inhibitor of apoptosis proteins, NAIP and XIAP. However I found that the survival of adult compared to neonatal facial motoneurons is not due to the level of expression of these two inhibitory apoptotic proteins (NAIP and XIAP). There has also been a long standing belief that chronic nerve injury of mouse facial motoneurons results in the death of the majority of these neurons. However, I observe that many more chronically injured mouse facial motoneurons survived in an atrophied state that had been previously reported. This discrepancy is due in part to the difficulty in identifying atrophied neurons using Nissl stains or other neuronal phenotypic markers such as NeuN that are affected by axotomy leading to an underestimation of the surviving population. I determined that in addition to the increased survival of these neurons, if chronically injured mouse facial motoneurons are subjected to a second nerve injury, the motoneurons re-express genes related to regeneration. Furthermore, I determined that the neuroma that forms at the end of a proximal stump following chronic nerve resection may be a source of factors that are capable of controlling this gene re-expression within the motoneurons. Finally, despite their atrophy, I demonstrated that chronically injured mouse facial motoneurons not only survive and re-express regeneration related genes, but are able to regrow their axons if provided with a suitable environment such as a pre-degenerated nerve graft.
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