The studies of this proposal take advantage of a unique mutant mouse in which axons that have been separated from their cell bodies survive in the amputated state, and do not exhibit degenerative changes for many days. This """"""""Ola"""""""" mutation initially discovered in a sub-strain of C57Bl/6J mice at a breeding colony in Bichester, England, provides a unique opportunity to evaluate the relationship between cellular events that occur following injury, and test hypotheses about cause and effect relationships. However, the mutation has an even greater potential significance, because it may endow neurons (or at least axons) with an unusual ability to survive injury. The goal of the present project is to explore these two possibilities. The experiments of Specific Aim 1 compare the relationship between different cellular responses in Ola mice and control mice to evaluate cause and effect relationships. Previous studies of the temporal relationships between different cellular events in normal animals have led to a number of hypotheses about the cascade of cellular events set into motion by injury. The Ola mutation leads to a substantial delay in one of the key events (axonal degeneration), that has been proposed as the trigger for subsequent events. If degeneration is a key stimulus, these secondary processes should be delayed in Ola mice. We will evaluate the temporal relationships between axonal degeneration and other cellular processes including A) removal of dying terminals; B) synapse replacement; C) loss and re-appearance of dendritic spines; D) macrophage activation; and E) reactive changes in astrocytes. The experiments of Specific Aim 2 seek to determine whether the Ola mutation endows neurons with a unusual resistance to injury, and if so define the nature of that resistance. In Ola mice, axons that are separated from their cells of origin survive and remain physiologically functional for up to 2 weeks. This could reflect a delay in the onset of degenerative changes in axons that are nevertheless still destined to die, or could reflect an enhanced ability of axons to resist injury. If it is the latter, the mutation may provide important clues about ways to promote the survival and function of injured neurons. This may be especially important when CNS trauma leads to a slow death of axons that are injured but still live after the initial trauma (for example, in the case of spinal cord injuries). We will evaluate the susceptibility of neurons in Ola mice to different forms of injury, including A) contusion injury of the spinal cord; and B) ischemic cell death. We will then go on to evaluate the effect of the mutation on several well- characterized forms of neuronal degeneration including C) retrograde degeneration; D) transneuronal degeneration. E) Finally, we will assess whether the mutation affects the survival of neurons in transplants. The latter may provide clues about how to promote the survival of transplanted neurons.
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