Emerging concept of precise neuromodulation: Genetics-based neuromodulation in spinal cord injury

A significant limitation of spinal cord injury is its restricted ability to repair damaged neural circuits. Overcoming this limitation not only contributes to decoding functional circuit wiring, but also has great potential to promote the precise treatment strategies of spinal cord injury. Current neuromodulation techniques have been hindered by their limited precision. This review introduces the emerging concept of precise neuromodulation, which refers to genetics-based neuromodulation strategies that can selectively manipulate specific cell populations with high spatiotemporal resolution, making them powerful tools for neural circuit modulation. Genetics-based neuromodulation strategies have been shown to target neuronal subtypes and non-neuronal cell types (microglia, astrocytes, oligodendrocytes, and Schwann cells) in the spinal cord. When combined with neuroimaging, electrophysiological, and behavioral techniques, these strategies offer a powerful approach to decoding functional circuit wiring, revealing glia-neuronal bidirectional communication, and investigating regenerated axon integration into spinal cord circuits after spinal cord injury. Notably, genetics-based neuromodulation strategies can precisely reconstruct damaged neural circuits by regulating inherent neuronal excitability, regulating the expression of endogenous neurotrophic factors, and remodeling the spinal cord inhibitory microenvironment. These capabilities allow these strategies to reduce motor impairments, pain, respiratory issues, bladder dysfunction, and autonomic problems resulting from spinal cord injury. When combined with stem cell transplantation, genetics-based neuromodulation strategies have the potential to clarify how graft-derived neurons are functionally integrated into the host neural circuits and promote stem cell differentiation and regeneration. Despite these encouraging advancements, immune responses, surgical complications, off-target effects, and ethical concerns still limit the clinical translation of gene-based neuromodulation strategies. Future research on genetics-based neuromodulation strategies should integrate multiple techniques and artificial intelligence to achieve precise, circuit-level neuromodulation. By establishing a new research paradigm of "precise neuromodulation-functional recovery-clinical translation," this review emphasizes that genetics-based neuromodulation will provide new directions for clinically established neuromodulation techniques. These strategies can facilitate the identification of new targets, optimization of stimulation parameters, and elucidation of underlying mechanisms. Through precise neural circuit reconstruction, these efforts mark revolutionary progress in post-spinal cord injury rehabilitation and the advancement of personalized neuromodulation strategies.