CELL AND CAMP COMBINATORIAL THERAPY INDUCES CORTICOSPINAL TRACT REGENERATION AFTER SPINAL CORD INJURY

Spinal cord injury (SCI) is a devastating lifelong condition that hampers quality of life due to chronic motor and sensory deficits. Corticospinal neurons in the motor cortex are essential for fine motor control in humans¹. When these neurons are damaged after SCI, their axons degenerate alongside the projecting tract (CST), causing an important loss of motor functions^2,3. The current consensus identifies both inhibitory extrinsic signals and limited intrinsic regenerative capacity as limiting factors for neuronal regeneration⁴. Accordingly, intrinsic and extrinsic therapies have been individually tested to promote CST regeneration, with limited success. In this study, we combined two strategies to overcome the limited CST regeneration in a rat model of incomplete SCI. Specifically, we employed a novel optogenetic approach (bPAC) to induce on-demand increases in cAMP levels in CST neurons, together with intramedullary NPC transplantation at the thoracic injury epicenter. When we evaluated the synergistic effects of CST neuromodulation and transplantation, we observed increased graft survival and robust CST regeneration exclusively when both therapies were applied in combination. We then assessed the number of neurons projecting axons beyond the lesion site. Analysis of short thoracic propriospinal neurons (T5–T8) revealed a significant increase only in the neuromodulated group, whereas transplanted groups showed a reduction in the number of labeled neurons. In contrast, analysis of cortical neurons showed a significant increase in both the neuromodulated and the combined neuromodulated/transplanted groups. In conclusion, although CST rescue through transplantation is beneficial, excessive graft extension may compromise other neural circuits.