Restoring function after severe spinal cord injury through bioluminescence-driven optogenetic stimulation of spinal circuitry

Authors:
E. D. PETERSEN, A. PAL, J. ZENCHAK, E. D. SHARKEY, L. SHAFAU, A. PENA, M. PRAKASH, U. HOCHGESCHWENDER;
Central Michigan Univ., Mount Pleasant, MI

Eric D. Petersen, Graduate Student , Central Michigan University

Lab Team Abstract:
The ability to manipulate specific neuronal populations of the spinal cord following spinal cord injury (SCI) could potentially prove highly beneficial for rehabilitation in patients through maintaining and strengthening still existing neuronal connections and/or facilitating the formation of new connections. A non-invasive and highly specific approach to neuronal stimulation is bioluminescent-optogenetics, where genetically expressed light emitting luciferases are tethered to light sensitive channelrhodopsins (luminopsins, LMO); neurons are activated by the addition of the luciferase substrate coelenterazine (CTZ). This approach takes advantage of utilizing ion channels for current conduction while activating the channels through application of a small chemical compound, thus allowing non-invasive stimulation and recruitment of all targeted neurons. Rats were transduced in the lumbar spinal cord with AAV2/9 expressing the excitatory LMO3 under control of the synapsin or the Hb9 promoter. A day after contusion injury of the thoracic spine, rats received either CTZ or vehicle every other day for 2 weeks. We found activation of either interneuron or motor neuron populations below the level of injury to significantly improve locomotor recovery. This is the first example of non-invasive activation of an optogenetic component as a potential therapy following spinal cord injury. We are utilizing morphological and histological methods to identify mechanisms underlying improvements in locomotion. The findings will provide a foundation for a rational approach to spinal cord injury, thereby advancing approaches for functional recovery after SCI in the preclinical arena.

Abstract Citation
*E. D. PETERSEN, A. PAL, J. ZENCHAK, E. D. SHARKEY, L. SHAFAU, A. PENA, M. PRAKASH, U. HOCHGESCHWENDER;
Central Michigan Univ., Mount Pleasant, MI. Restoring function after severe spinal cord injury through bioluminescence-driven optogenetic stimulation of spinal circuitry. Program No. 138.10. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.

Grant Support: NIH Grant MH101525, NIH Grant EY026427, NIH Grant NS099709
NSF Grant 1464686, NSF Grant 1707352, W.M. Keck Foundation

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