TRANSCRIPTOMIC INSIGHTS INTO EARLY REGENERATIVE AND NON-REGENERATIVE NEURONAL RESPONSES TO INJURY

Spinal cord injury (SCI) remains a devastating condition with no effective treatments, largely due to the limited regenerative capacity of central nervous system. Conversely, peripheral nerve injury (PNI) triggers a robust regenerative response, making it a valuable model for identifying molecular drivers of neuronal repair. To investigate early genetic regenerative programs versus non-regenerative responses, the transcriptomic profiles of rat motor and sensory neurons were analyzed 24h after SCI or PNI, using laser capture microdissection and mRNA sequencing. Differential expression analysis revealed markedly distinct transcriptional responses between injury paradigms, with regenerating PNI-affected neurons displaying broader and more dynamic gene regulation than SCI-affected neurons. More than 1600 genes were regulated after PNI, compared with only ~150 genes regulated in SCI conditions, highlighting a robust regenerative-associated transcriptional program. Within the regenerative PNI condition, 133 genes were commonly regulated in motor and sensory neurons. Enrichment analyses revealed conserved regeneration-related processes across both neuronal types, including responses to stress and inflammation, intracellular signaling, transcriptional regulation, lipid metabolism, and development recapitulation. Despite these shared programs, sensory neurons exhibited a substantially stronger transcriptional response than motor neurons, with over 1400 versus ~300 deregulated genes, respectively. Sensory neurons regulated genes involved in neurodevelopment, neuritogenesis, and cytoskeletal organization, which were largely absent in motor neurons at 24h post-injury. Among the genes commonly regulated in PNI, 111 were exclusive to this injury paradigm and define a focused set of candidate therapeutic targets. These genes will be prioritized for functional validation to assess their therapeutic potential to enhance repair after SCI.