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Post-Doc Award: Dissecting and Strengthening Corticospinal Connections After Spinal Cord Injury Using Advanced Neuroscience Methods

RESEARCH PROJECT: 
In Progress

Spinal cord injury (SCI) leads to functional deficit that doesn’t  improve over time. Long standing view in the field of neurorehabilitation is that little to no recovery is possible after adult mammalian SCI. However, there is evidence that significant spontaneous recoveries in motor, sensory or other neurological functions occur after SCI in human. The existence of spontaneous recovery raises the possibility that intrinsic structural rearrangement are occurring after SCI. Previous studies suggest that SCI induces axonal sprouting and this injury-induced plasticity is correlated with functional recovery. Moreover, based on activity-dependent plasticity and the fact that some descending motor axons are usually spared by injury, electrical stimulation of the unimpaired side of the brain has been found to  strengthen the spared CST connections and improve functional recovery after CST injury. However, the mechanisms underlying spontaneous recovery after cervical contusion SCI is not known, and it has never been shown that the spontaneous or enhanced functional recovery is specifically mediated by the sprouting axons. Thus, in this study, the circuits responsible for spontaneous forelimb motor recovery after cervical hemicontusion SCI will be identified with viral tracers. The identified circuit will be strengthened and recovery of skilled forelimb function will be promoted after chronic cervical SCI with motor cortex stimulation. Finally, the causal relation between sprouting and functional recovery after SCI will be addressed by using pathway-specific inactivation technique.

Hypothesis

1. Axon sprouting from the largely spared ipsilateral CST mediate spontaneous recovery of forelimb function after cervical contusion SCI.

Tracer methods and expected results

Tracer methods and expected results 1. Anterograde viral tracers are injected into forelimb (FL) motor cortex. Tissue is sectioned coronally at cortex, C4 (lesion site) and C6 spinal cord. Anterogradely labeled axons are represented as dots in the tract and branching lines in the gray matter. The red is not shown in the gray matter.

2. Electrical stimulation to motor cortex will augment cortically-evoked muscle responses and functional recovery through double-crossed CST connection.

Methods and expected anatomical results

Methods and expected anatomical results 2. Viruses for inactivation work as anterograde tracer. AAV1-DIO-hM4Di is injected into ipsilateral forelimb motor cortex (FL). AAV9-Cre is injected into C5-C7 spinal cord of injured side. Anterogradely labeled axon are represented as dots in the tract and branching lines in the gray matter.

Expected behavioral results

Expected behavioral result. Spontaneous functional recovery and enhanced recovery with brain stimulation are degraded by ipsilateral CST inactivation. CNO, circuit specific inactivation with Cre-dependent DREADD and colzapine-N-oxide (CNO) administration; STIM, electrical stimulation.

Funding

GRANT: 
Non-Federal
January 1, 2016 to February 28, 2019
Grant Number: 
Contract Number: DOH01-C30859GG-3450000
New York State Department of Health (NYSDOH)
Spinal Cord Injury Research Board (SCIRB)
Investigators: 
Principal Investigator
Postdoctoral Research Fellow