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

Spinal cord injury (SCI) frequently leads to permanent motor and sensory deficits, with complete injuries causing total loss of function below the lesion and incomplete injuries preserving only partial connectivity. 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. However, while AAV2-hIL-6 also reduced corticospinal tract (CST) axon retraction, it did not induce axon regeneration beyond the lesion, suggesting that CST regeneration was not required for recovery. Thus, intracortical AAV2-hIL-6 delivery drives circuit remodeling and functional restoration across contusion severities, highlighting its promise as a regenerative therapy for SCI with spared pathways. • Transneuronal cytokine delivery improves recovery after spinal cord injury. • Cortical AAV2-hIL-6 enhances locomotor recovery after contusive spinal cord injury. • Recovery occurs across mild, moderate, and severe injury severities. • Brainstem serotonergic circuits are activated via transneuronal STAT3 signaling. • Functional recovery occurs without corticospinal regeneration.