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Project

Stimulation to Enhance Migration and Synaptic Integration of Neural Grafts

Funder: Craig H Neilsen Foundation

Funding period
USD 150 K
Funding amount
Abstract
There is little evidence of long tract regeneration of descending motor associated cortical fibers after injury. There are significant barriers to regrowth including a relatively slow rate of axon extension during spontaneous regeneration. Researchers have examined various methods to speed up cortical fiber growth or to enhance plasticity of spared circuitry to facilitate new connections. One method to re-establish connections across an injury involves bridging using neural stem cell grafts. This technique is appealing as it may provide a means to more rapidly establish connections across long gaps. New neural stem cell technology has demonstrated significant healthy engraftment and growth in an injured spinal cord; however, despite impressive growth these cells fail to meaningfully connect disrupted circuitry. To facilitate appropriate connectivity, we have developed a non-penetrating and completely untethered epidural ventral spinal stimulator (VSS) to target specific motor circuitry of the wrist and paw in rats. It is our hypothesis that driving activity of specific motor circuitry will cause molecular gradients which will encourage neural stem cell migration and growth towards a target. In a pilot study, we demonstrated a significant change in neural stem cell graft directionality after stimulation. Animals which received VSS had significantly more fiber alignment along the rostral-caudal axis of stimulation, indicating that VSS influences migration and growth of engrafted human neural stem cells. We propose to examine which patterns of stimulation optimally influence human V2a excitatory interneuron enriched neural graft 1) migration towards the circuitry of the wrist and hand 2) synapse formation with the motor neuron circuitry of the wrist and hand in a cervical injury model in rats. In aim 1 we will modulate VSS frequency to examine how different stimulation paradigms affect the migration and growth patterns of engrafted V2a enriched neural precursors. We will secondly assess whether targeted stimulation induces preferential migration and growth patterns when selectively stimulating musculature in the paw, forearm or upper limb. In aim 2 we will perform a rigorous analysis of how stimulation patterns affect long-term maturation, survival and maturity of neural stem cell grafts under local spinal stimulation following spinal cord injury. We will pre-transfect cells with a psuedorabies mono-synaptic reporter to characterize how stimulation influences long term synaptic integration of V2a enriched neural precursors. The proposed aims will provide much needed insight into the effects of stimulation on neural grafts and whether local epidural stimulation can provide cues to initiate elegant integration of transplanted cells. (CHN: SCIRTS chn:wdg)
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System

Categories
  • FOR (ANZSRC)

    1109 Neurosciences

  • RCDC

    Injury (total) Accidents/Adverse Effects

  • RCDC

    Regenerative Medicine

  • RCDC

    Neurosciences

  • RCDC

    Spinal Cord Injury

  • RCDC

    Stem Cell Research

  • RCDC

    Neurodegenerative

  • RCDC

    Transplantation

  • HRCS HC

    Neurological

  • HRCS RAC

    1.1 Normal biological development and functioning

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science