Biological light stimulation to restore function after SCI

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 (BL-OG), 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. This project will test the hypothesis that increasing neuronal activity below the level of injury via excitatory LMOs will facilitate recovery following SCI by keeping existing neuronal connections active and therefore intact, facilitating the formation of new connections by increasing neuronal plasticity, and strengthening connections of spinal neurons with ascending and descending pathways. These predictions will be tested by expressing LMOs in interneurons versus motor neurons, assessing the effects on spinal cord circuitry and muscle engagement through electrophysiological recordings, and utilize morphological and histological methods to identify mechanisms underlying improvements in locomotion. The project will determine which neuronal population has the greatest effect on recovery outcomes when stimulated, how stimulation modulates activity of spinal networks and can lead to muscle engagement and uncover potential mechanisms underlying the effectiveness of neuronal stimulation. 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. (CHN: SCIRTS chn:wdg)