CAMP-INDUCED TRANSCRIPTIONAL PROFILING PROVIDES INSIGHTS INTO THE BIOLOGY OF SPINAL CORD INJURY HEALING

Spinal cord injury (SCI) is a neurologic condition caused by traumatic or non-traumatic events that disrupt the signals between the brain and the spinal cord resulting in motor, sensory and autonomic impairments. The complexity of SCI pathophysiology underlies the lack of effective treatments. Cyclic adenosine monophosphate (cAMP) is recognized as a critical mediator of spontaneous regeneration, but the molecular mechanisms underlying its regulatory effect is still unknown.
In this on-going study, we developed a rat model for cAMP sustained delivery into projecting corticospinal tract neurons after incomplete SCI. Daily accumulation of cAMP in damaged cortical neurons resulted in the improvement of voluntary locomotion ten days after injury, in comparison with non-stimulated animals.
In order to study the mechanisms supporting the re-establishment of local motor circuits at the SCI site, we performed single nucleus RNA-Seq analysis comparing the transcriptional changes in sham, injured non-stimulated, and injured stimulated rats at ten and thirty days post-injury, for acute and chronic stage evaluation. We were able to cluster different cell types, including glial, endothelial and infiltrated cells. Focusing on 19 neuronal types, organized by their localization and their excitatory or inhibitory phenotypes; neuronal stem cells, ventral excitatory interneurons and motor neurons displayed the highest number of changes within the cAMP signature. For example, ADORA2B that regulates axon elongation shows an altered expression in our model. These data can provide a better understanding of the pathways involved in axonal regeneration, now still under evaluation, and could lead us as to potential therapeutic targets.