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Examining spinal axonal degeneration and regeneration with in vivo imaging and experimental spinal cord injury /

  • Author(s): Lorenzana, Ariana Joy Orduna
  • et al.
Abstract

Spinal cord injury is a permanent, physically, and occasionally mentally, debilitating condition with no robust panacea available. Currently, there are 5.6 million Americans living with spinal cord injury, with and estimate of 10,000-12,000 new injuries per year [1]. The permanency of the functional deficits after spinal cord injury is due to the inability of central nervous system (CNS) axons to regenerate, which in turn is attributed to a multitude of neuron-intrinsic and extrinsic factors. Studies of spinal cord injury have traditionally been hampered by the difficulty of identifying regenerating axons, a myriad of confounding variables, and limited temporal and spatial resolution. The main goal of my thesis work is to develop in vivo imaging with 2-photon microscopy to study spinal axon responses to injury in living mice, and to start to apply this experimental paradigm to the studies of axon growth regulators. I have found that in vivo imaging is a powerful tool to investigate the dynamic responses of spinal axons to axonal injury. In Chapter 2, the main and publication- ready part of my thesis, I describe the baseline axonal dynamics, including degeneration and regeneration, after laser-mediated axotomy in the mouse spinal cord. The data depict the detailed behaviors of single sensory axons over hours (acute), days (sub-acute), weeks (sub-chronic), and months (chronic). An earlier phase of axon degeneration is followed by later phases of axonal regeneration, pruning and remodeling up to 6 months after the initial axotomy. Branch points and nodes of Ranvier emerge as important determinants of axonal degeneration and regeneration following injury. It will be difficult, if not impossible, to gain such insights from conventional models of spinal cord injury. In Chapter 3, I describe efforts to apply this imaging paradigm to examine the effects of deleting the prototypical myelin associated axon growth inhibitor, Nogo. I found that Nogo deletion slows the acute degenerative process, and also (regeneration results coming). Chapter 4 describes my collaborative effort with another lab member to examine the effect of combined deletion of Nogo and PTEN, a neuron-intrinsic inhibitor of regeneration. The results provide proof of principle evidence that manipulating both intrinsic and extrinsic growth regulators may lead to further enhancement in axonal growth after injury. My involvement in this project was meant to complement my imaging studies, which used a minimal laser injury model. In Chapter 5, I provide perspective for future endeavors

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