Mapping Cell Type-Specific Integration of Transplanted Neurons with Locomotor Circuitry
Funded in: 2020, 2021, 2022
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Problem: Walking function is frequently lost due to the inability of motor commands generated in the brain
Target: Understand the mechanisms by which transplanted cells can modulate motor function
Goal: Developing optimized human cell transplantation therapies
Following spinal cord injury (SCI), locomotor function is frequently lost due to the inability of motor commands generated in the brain to traverse the injury site and modulate limb movement. Reconstructing spinal cord neural circuits for motor control remains a major therapeutic goal of SCI research. Many studies have demonstrated that neural progenitor cells (NPCs) transplanted into sites of SCI can give rise to diverse types of new neurons that synaptically integrate into the injured nervous system, making these cells an attractive candidate for rebuilding motor circuits. Despite this, recovery of motor function in experimental studies has met with variable success. In order to develop cell grafts that can robustly and reproducibly support locomotor recovery, it is necessary to understand the mechanisms by which transplanted cells can modulate motor function.
The researchers hypothesize that specific subtypes of engrafted neurons possess the ability to form new connections with locomotor circuits, and support the recovery of leg movement, following SCI. They will test this hypothesis through two specific aims, using a clinically relevant thoracic spinal cord contusion model in mice. First, the scientists will characterize the types of transplanted neurons that form new synaptic connections onto spinal cord motor circuits. Second, they will manipulate the activity of transplanted neurons to determine which types are capable of stimulating leg muscle activity. Results of this work will reveal critical new knowledge regarding the capacity of specific graft neuronal subtypes to modulate locomotor function. This knowledge will be a critical step toward the goal of developing optimized human cell transplantation therapies that can support the highest degree of functional recovery. Findings from this work will establish a new foundation of biological knowledge that will ultimately lead to improved therapeutic efficacy in human trials.