Rebuilding spinal circuit function after spinal cord injury through a patient-specific interneuron precision model

Spinal interneurons constitute the physiological core of spinal circuitry, integrating excitatory and inhibitory inputs to generate the rhythmic patterns that drive locomotor, postural, and autonomic control. Their developmental logic, molecular diversity, and adaptive plasticity make them central determinants of functional recovery after spinal cord injury (SCI). Yet most regenerative strategies continue to emphasize cellular replacement rather than the restoration of the physiological integrity of spinal networks. In this article, we reframe spinal repair as the restoration of interneuron-mediated circuit organization rather than cellular replacement alone. We synthesize current insights into how embryonic patterning programs defined by Sonic Hedgehog (SHH), Wnt, and bone morphogenetic protein (BMP) gradients, refined by Notch and retinoic acid signaling, and consolidated by axon guidance cues, establish interneuron diversity, connectivity, and network symmetry that together encode the logic of motor coordination. SCI disrupts this developmental logic, fragmenting excitatory and inhibitory balance and desynchronizing rhythmic modules, while residual circuits retain latent capacity for resynchronization through plasticity and neuromodulation. Building upon this developmental and physiological continuum, we propose the Patient-Specific Interneuron Precision Model (PIPM), a feedback-informed conceptual framework that links patient-specific biological states, including progenitor competence, morphogen sensitivity, metabolic tone, inflammatory burden, and lesion-specific circuit preservation, to circuit-level function and recovery potential. Frameworks such as the PIPM may help integrate molecular, physiological, and clinical dimensions of recovery, providing a path toward more personalized strategies for treating SCI through restoration of interneuron-mediated network organization.