Injury distance limits the transcriptional response to spinal injury.

The ability of neurons to sense and respond to damage is fundamental to homeostasis and nervous system repair. For some cell types, notably dorsal root ganglia (DRG) and retinal ganglion cells (RGCs), extensive profiling has revealed a large transcriptional response to axon injury that determines survival and regenerative outcomes. In contrast, the injury response of most supraspinal cell types, whose limited regeneration constrains recovery from spinal injury, is mostly unknown. Here we employed single-nuclei sequencing in mice to profile the transcriptional responses of diverse supraspinal cell types to spinal injury. Surprisingly, thoracic spinal injury triggered only modest changes in gene expression across all populations, including corticospinal tract (CST) neurons. Moreover, CST neurons also responded minimally to cervical injury but much more strongly to intracortical axotomy, including upregulation of numerous regeneration and apoptosis-related transcripts shared with injured DRG and RGC neurons. Thus, the muted response of CST neuron to spinal injury is linked to the injury's distal location, rather than intrinsic cellular characteristics. More broadly, these findings indicate that a central challenge for enhancing regeneration after a spinal injury is the limited sensing of distant injuries and the subsequent modest baseline neuronal response.

Widening spinal injury research to consider all supraspinal cell types: Why we must and how we can.

The supraspinal connectome consists of dozens of neuronal populations that project axons from the brain to the spinal cord to influence a wide range of motor, autonomic, and sensory functions. The complexity and wide distribution of supraspinal neurons present significant technical challenges, leading most spinal cord injury research to focus on a handful of major pathways such as the corticospinal, rubrospinal, and raphespinal. Much less is known about many additional populations that carry information to modulate or compensate for these main pathways, or which carry pre-autonomic and other information of high value to individuals with spinal injury. A confluence of technical developments, however, now enables a whole-connectome study of spinal cord injury. Improved viral labeling, tissue clearing, and automated registration to 3D atlases can quantify supraspinal neurons throughout the murine brain, offering a practical means to track responses to injury and treatment on an unprecedented scale. Here we discuss the need for expanded connectome-wide analyses in spinal injury research, illustrate the potential by discussing a new web-based resource for brain-wide study of supraspinal neurons, and highlight future prospects for connectome analyses.