: Over the past 40 years, increasing demand for spinal cord injury (SCI) repair strategies has driven extensive research, yet critical recovery mechanisms remain poorly understood. Key gaps include the temporary loss of spinal reflexes during spinal shock and the dynamics of "injury potentials," which spread rapidly from the impact site, similar to cortical spreading depression (CSD). While traditionally spinal shock has been viewed as unavoidable, targeted interventions could potentially mitigate SCI pathology and improve recovery. Additionally, immediate changes in brain circuitry post-SCI remain debated, with limited markers for assessing early neuronal and glial damage. Early supraspinal biomarkers, including neuron-specific enolase (NSE), S-100β, and microRNAs, may further refine injury severity assessments. The potential for spontaneous spinal circuit repair is often underestimated, yet molecular evidence suggests preserved interneuronal networks may support functional reconnections. Pediatric SCIs show superior self-repair, highlighting unique plasticity mechanisms that could be leveraged for therapeutic benefit. While in vivo models mimic human pathology, ex vivo neonatal rodent models allow continuous electrophysiological recordings of spontaneous and evoked neuronal activity during SCI, revealing how lumbar locomotor circuits integrate afferent input post-injury. Using an ex vivo neonatal SCI model, we demonstrate real-time network changes in the brain and spinal cord. Our model enables modulation of the extracellular ionic environment and afferent stimulation. By integrating ex vivo models, molecular biomarkers, and insights from early developmental stages, we can uncover novel mechanisms of an acute SCI or refine neuromodulatory strategies to promote recovery of functions.
