Dissecting Connectivity and Function of Transplanted Interneurons in the Injured Spinal Cord
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abstract
Injury to the cervical spinal cord results in an immediate and permanent loss of hand function due to massive disruption of neural circuitry. There are currently no effective therapies that can improve neurological outcomes for individuals living with spinal cord injury (SCI). New neurons can be provided to injury sites via transplantation of neural progenitor cells (NPCs). These cells differentiate into diverse subtypes of neurons that support the establishment of new synaptic connections with neurons in the injured host nervous system. Multiple studies have reported modest gains in forelimb function following NPC transplantation in preclinical cervical SCI models; however, the underlying mechanisms by which engrafted neurons promote functional recovery are unclear. In order to develop more effective neural replacement strategies that can robustly and reproducibly improve recovery of hand function, it is critical to develop a fundamental understanding of how engrafted neurons synaptically and functionally integrate into injured forelimb motor circuitry. To address this gap in knowledge, we will utilize a mouse model of SCI to characterize the contributions of NPC grafts to forelimb functional recovery. First, we will determine how varying the phenotypes of transplanted neurons influences graft synaptic integration into the injured nervous system. We have shown that NPC grafts can be enriched for distinct classes of neurons. We will use this strategy to determine how manipulating graft cellular composition influences integration with injured motor circuits. Second, we will determine whether graft neuron activity is sufficient to functionally modulate forelimb motor circuits. Through chemogenetic modulation of engrafted neurons, we will interrogate the functional contributions of graft activity to electrophysiological responses in the forelimb muscles. We will also determine whether graft activity is acutely required for the execution of skilled forelimb motor function. Finally, we will examine whether activity-based rehabilitation can increase synaptic integration of grafts into forelimb motor circuits and improve motor functional recovery. This study will establish a new and critical framework regarding the ability of engrafted neurons to integrate into and functionally modulate injured forelimb motor circuitry. Moreover, this work will highlight the critical importance of graft cellular composition in restoring functional outcomes. Our strategy to functionally interrogate NPC grafts has applications for broader work focused on restoring locomotor or autonomic outcomes after spinal cord injury. Results of this study will reveal new biological mechanisms by which neural grafts can provide therapeutic benefits. These findings will constitute a critical body of knowledge that will accelerate research efforts to develop more therapeutically effective human cells for clinical treatment of spinal cord injury.
