Chronic Adaptations in the Dorsal Horn following a cervical spinal cord injury in primates

Abstract

Spinal cord injury (SCI) is devastating, with limited treatment options and variable outcomes. Mostin vivoSCI research has focused on the acute and early post-injury periods, and the promotion of axonal growth, so little is understood about the clinically stable chronic state, axonal growth over time, and what plasticity endures.Here, we followed animals into the chronic phase following SCI, to address this gap. Macaques received a targeted deafferentation, affecting three digits of one hand, and were divided into short (4-6 months) or long term (11-12 months) groups, based on post-injury survival times. Male monkeys were assessed behaviorally, where possible, and all exhibited an initial post-injury deficit in manual dexterity, with gradual functional recovery over two months.We previously reported extensive sprouting of somatosensory corticospinal (S1 CST) fibers in the dorsal horn in the first 5 post-injury months. Here we show that by 1 year, the S1 CST sprouting is pruned, with the terminal territory resembling control animals. This was reflected in the number of putatively ‘functional’ synapses observed, which increased over the first 4-5 months, and then returned to baseline by 1 year. Microglia density also increased in the affected dorsal horn at 4-6 months, and then decreased, but did not return to baseline by 1 year, suggesting refinement continues beyond this time.Overall, there is a long period of reorganization and consolidation of adaptive circuitry in the dorsal horn, extending well beyond the initial behavioral recovery. This provides a potential window to target therapeutic opportunities during the chronic phase.Significance statementMost preclinical studies of spinal cord injury focus on the early phases of recovery, during which the greatest behavioral improvements occur and there is significant sprouting of spared fibers. Here, we extended these observations into the chronic phase, in a primate model of spinal injury affecting hand function, to see if these changes were maintained long term. We show that following an early period of corticospinal (CST) and spared primary afferent sprouting, afferents remain stable while exuberant CST sprouts are pruned back to their baseline range. The presence and activation of microglia demonstrates that this process is driven partly by inflammation. Our findings provide important new insight into the chronic phase of recovery, and the potential for longer term plasticity.