Augmenting Activity Dependent Plasticity for the Repair of Spinal Cord Injury

  • Author / Creator
    Batty, Nicholas J.
  • This thesis investigates how to bolster activity dependent neuronal plasticity in conjunction with rehabilitative motor therapy to increase recovery following spinal cord injury in rats. My work focuses primarily on the injured corticospinal tract (CST) and how boosting intracellular signalling pathways related to activity dependent plasticity can lead to an increase in motor recovery.
    In chapter 2, I follow up on previous work from the Fouad laboratory that demonstrated benefits of electrical stimulation on the motor forelimb cortex prior to spinal cord injury. This experiment demonstrated an increase in axonal collateralization in the rat CST. My experiment explores the effects of a single session of stimulation immediately after SCI in rats and how it can increase the benefits of functional rehabilitative therapy.
    Chapter 3 serves as an introduction to the cAMP signalling pathway, which is the focus of the experiments in the following two chapters. This chapter introduces the role of cAMP and its downstream effectors, protein kinase A (PKA) and exchange protein activated by cAMP (EPAC), in neurite outgrowth.
    Following a laboratory rotation in the laboratory of Dr. Sipione, where I learned to plate primary cortical neurons, I brought the protocol back to the Fouad laboratory where I tested the effects of EPAC and PKA agonists on neurite outgrowth in vitro. Chapter 4 describes the effects of these agonists and demonstrates an exciting novel complementary effect of simultaneous application of both agonists on neurite outgrowth. This complementary finding led us to follow up on previous Fouad laboratory results, where PKA inhibition led to an increase in functional recovery after SCI, and test these effects in vivo.
    Chapter 5 describes my in vivo experiment utilising both EPAC and PKA agonists together administered to the motor forelimb cortex innervating the injured CST alongside motor rehabilitative therapy. Following SCI, animals had osmotic mini-pumps containing either saline, an EPAC agonist, or both an EPAC agonist and a PKA agonist installed with the cannula in the moto cortex for localized drug delivery. Despite previous findings, administration of both agonists did not result in an increase in functional recovery after training, nor did it increase spinal plasticity of the CST.
    A comprehensive understanding of how the cAMP pathway affects recovery after SCI and how it could be bolstered to increase the effects of rehabilitative motor therapy in the clinic is imperative for future SCI research. Whilst my final in vivo experiment using both agonists yielded negative results, the findings from this thesis build a strong foundation for further exploration into the signaling cascade behind activity dependent plasticity and how it can be optimized for improved recovery.

  • Subjects / Keywords
  • Graduation date
    Fall 2021
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.