Transneuronal cytokine delivery promotes functional recovery across spinal cord contusion severities via descending circuit plasticity

Intracortical delivery of an AAV2 vector encoding the designer cytokine hyper-interleukin-6 (AAV2-hIL-6) enhances recovery after complete SCI by transneuronally stimulating raphe nuclei. Here, we verified that AAV2-hIL-6 transneuronally activates subcortical neurons in the medulla and evaluated that this strategy enables recovery in clinically more relevant mouse models of mild, moderate, and severe contusion injury.

Across all severities, AAV2-hIL-6 treatment significantly improved locomotor function compared to AAV2-GFP-treated controls. Although lesion size and neuronal loss correlated with contusion severity and were unaffected by the AAV2-hIL-6 treatment, it robustly increased the number and length of descending serotonergic axons in the lumbar cord. Selective ablation of serotonergic neurons abolished these gains, confirming their essential role in functional sensorimotor recovery.