The Role of Corticospinal Neurons in the Recovery of Dexterous Forelimb Function After Spinal Cord Injury

PROJECT SUMMARY: The adverse effects of spinal cord injury (SCI) on corticospinal function are not restricted to the damaged spinal cord, but also disrupt motor representations within the cortex. SCI results in altered cortical maps that represent motor output, with representations above the level of injury expanding into affected cortical areas. Rehabilitation is necessary for both the recovery of corticospinal-dependent forelimb function and the commensurate reorganization of disrupted cortical motor maps. Both the underlying circuit mechanisms that support cortical reorganization after SCI as well as the necessity for the reorganized circuitry to support functional recovery, remain unknown. For injured corticospinal neurons to contribute to functional recovery, they must be integrated into cortical motor networks. The long-term goal is to develop therapeutic interventions for supporting functional recovery after SCL The overall obiective for this proposal is to determine how specific rehabilitation after SCI promotes remodeling of corticospinal circuits and the contribution of injured corticospinal neurons to motor recovery. The central hypothesis is that corticospinal-dependent rehabilitation after SCI directs the structural remodeling of injured corticospinal neurons resulting in their incorporation into functional motor ensembles. The rationale for the proposed research is that determining the properties of rehabilitative training that promote successful corticospinal circuit incorporation into cortical motor networks after SCI will be crucial for developing effective rehabilitative strategies. The following three specific aims are proposed: 1) Identify the nature of structural and connectivity changes that occur in injured corticospinal neurons during rehabilitation-mediated recovery from SCI; 2) Identify the changes in the functional connectivity of injured corticospinal neurons during rehabilitation-mediated recovery from SCI; and 3) Identify the contribution of injured corticospinal neurons to motor recovery after SCL For the first aim, the approach will be to image structural changes of injured corticospinal dendritic arbors in response to rehabilitation. In the second aim, the approaches will be to use 2-photon imaging to record the activity of injured corticospinal neurons during rehabilitation and to use retrograde transsynaptic tracing to identify presynaptic inputs. In the third aim, the approach will be to optogenetically control injured corticospinal neurons in awake, behaving mice to determine their contribution to recovery. The proposed studies are innovative in that they shift the focus of spinal cord rehabilitation onto the circuit mechanisms of cortical network plasticity. The proposed studies are significant because they will elucidate the mechanisms by which circuit remodeling influences recovery and will inform combinatorial strategies that target cortical plasticity to fully realize the effects of axonal sprouting and regeneration. The expectation is that completion of the proposed research will determine the role for injured corticospinal neurons in the recovery of functional motor networks after SCI_ These findings will establish a foundation to guide the development of therapeutic strategies targeting movement recovery after CNS injury.