Mechanism of Training Induced Functional Gains and CST Sprouting after SCI: The role of PKA Signaling

  • Author / Creator
    Wei, David Z
  • Currently the most effective treatment in humans for promoting recovery after spinal cord injury (SCI) is rehabilitative training. However, training is not equally effective for all injury severities and usually does not lead to complete recovery. As a result, there is a need for treatments that can augment recovery in addition to training. One possible approach may be to first gain an understanding of how training promotes recovery. For example, animal studies of training induced recovery have previously found that motor recovery after spinal cord injury is associated with increased sprouting of the corticospinal tract (CST), a tract important for voluntary motor control. Increasing the activity of the secondary messenger cyclic AMP (cAMP) may also promote neurite sprouting and functional recovery in spinal cord injured rats. This occurs mainly through activation of the cAMP effector Protein Kinase A (PKA), as PKA inhibition prevents the growth promoting effects of increased cAMP activity in vitro. However it is currently unclear whether PKA inactivation also inhibits behavioral recovery. We hypothesized that increased cAMP-PKA signaling is necessary for CST sprouting and behavioral recovery after SCI, and inhibiting PKA signaling would inhibit these effects. We tested this possibility by infusing the PKA inhibiting compound Rp-cAMPS, through cannulation into the forelimb primary motor cortex (fM1) of partially C4 lesioned rats. Rats were then trained on the single pellet grasping (SPG) task for 4 weeks. At the end of training, and contrary to our hypothesis, we observed improved grasping success in the Rp-cAMPS treated group (Rp: 40.3 ± 5.4%, saline: 23.6 ± 5.7%, P=0.046), and increased CST sprouting into the grey matter rostral to the lesion compared to saline treated rats (Rp: 0.9 ± 0.2% fibers/mm, saline: 0.5 ± 0.08% fibers/mm, P=0.046). This recovery was not due to differences in lesion sizes (saline=22.3 ± 2.3%, RpcAMPS=26.7 ± 4.5%, P=0.41). However we did not detect a significant correlation between fiber sprouting and grasping success (r=0.06, P=0.82). We next searched for an alternative mechanism that may account for the increased sprouting, and examined whether Rp-cAMPS affected inflammation. We observed no differences in the number of IBA1 expressing cells (a marker for microglia), or IBA1 expression in fM1 between groups. In conclusion, our results demonstrated that Rp-cAMPS infusion into fM1 improved grasping recovery and sprouting of the injured CST in rats. Because this is contrary to what is known about the function of PKA signaling, these results suggest more research is required to better understand the role of the cAMP signaling pathway in CST sprouting and behavioral recovery after SCI.

  • Subjects / Keywords
  • Graduation date
    Fall 2015
  • Type of Item
  • Degree
    Master of Science
  • 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.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
  • Supervisor / co-supervisor and their department(s)
  • Examining committee members and their departments
    • Colbourne, Fred (Psychology)
    • Posse de Chavez, Elena (Pharmacology)
    • Ali, Declan (Biological Sciences)
    • Misiaszek, John (Occupational Therapy)