Synaptic connectivity between host and grafted neural stem cells after spinal cord injury
Funded in: 2016, 2017, 2018
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Problem: After transplantation of NSCs into a spinal cord lesion, little is known about the connections between the graft and the neurons in the host nervous system
Target: Imaging and electrophysiological techniques to visualize specific connections between graft and host
Goal: Understanding how an NSC graft functionally integrates with host nerves will give us a starting point from to refine transplantations
Neural stem cells (NSCs) have the potential to reconstitute adult spinal cord tissue lost by spinal cord injury (SCI), and they may ultimately act as a new relay for communication between neurons above and below the site of injury. Thus, the advent of successful NSC transplantation gives researchers new hope for restoring sensory and motor function in individuals with SCI. However, little is known about the neural connections, called synapses, made between grafted NSCs and the neurons in the host nervous system. In order to optimize NSC therapy and make these grafts ideal conduits for meaningful functional recovery, we must characterize the functionality and distribution of these synapses.
Using a rodent model of severe SCI, we will image the simultaneous activity of large populations of neurons within NSC grafts and adjacent host spinal cord in awake, behaving animals; this will allow us to understand how signals are transmitted into and across NSC grafts on a large scale. Furthermore, we will probe the fine details of synaptic connectivity in individual cells in isolated, live tissue through imaging and electrophysiology. To isolate individual circuits, we will employ genetic techniques to light-activate specific populations of host and graft nerve fibers and characterize the responses in their target neurons. Finally, we will use transsynaptic tracing techniques to visualize the specific connections between graft and host neurons.
We expect to find a mixed population of neurons in NSC grafts with different functionalities, most of which will have a baseline of connectivity with populations of host spinal cord and brain neurons. Understanding how a NSC graft functionally integrates with host nerves will give us a starting point from which we can move forward to refine neural stem cell preparations for the best possible patient outcome.