Spinal Cord Injury (SCI) refers to damage caused anywhere on the spinal cord and its cells, including nerve cells, often resulting from car accidents, sports mishaps, and other traumas. Despite new rehabilitation methods, patients often face difficulties in regaining movement, sensation, or both. To find out why, a team of scientists from The Council of Scientific and Industrial Research–Center for Cellular and Molecular Biology (CSIR–CCMB), Marquette University in Milwaukee, USA, and The University of Miami Miller School of Medicine, USA has used genetic tools to investigate how specific nerve cells in the brain respond after a spinal cord injury.
Scientists have long known that most mammals, including humans, tend to have limited regenerative ability, especially in the central nervous system, which includes the brain and spinal cord. In the study, the researchers focused on a particular group of neurons called corticospinal tract (CST) neurons. These cells originate in the brain’s cortex and send long cable-like axons down the spinal cord to control movement. By studying mice with SCI, they set out to find how CST neurons change their genetic activity in response to injury and what that tells us about their ability or inability to repair themselves.
Traditionally, scientists measure gene activity by looking at the genetic makeup of the entire contents of a cell. However, neurons are large and can be delicate to handle, particularly if you only want to isolate them after an injury. So, the researchers used single-nucleus RNA sequencing (snRNA-seq), where only the nuclei from individual cells are extracted, and the RNA inside each nucleus is analysed. Ribonucleic acid or RNA molecules contain the genetic information that a cell follows. By comparing the amount and types of RNA present, scientists can figure out which genes are turned on or off.
To obtain the RNA from an injured spinal cord, the team turned to mice. The team performed injuries in the rodents at three specific points. One was a thoracic injury, which was lower in the spinal cord, far from the neuron’s cell body in the brain. Second, a cervical injury, which is higher up and somewhat closer to the brain but still in the spinal cord. Finally, an intracortical injury, which is extremely close to the nerve cell bodies, is within about a millimetre of the cells. By comparing these different scenarios, the scientists aimed to see whether the distance between a neuron’s main body and the injury site influences how strongly that neuron switches on its repair genes. They also used snRNA-seq on nuclei from uninjured cells to act as the control.
After examining thousands of neurons using single-nuclei sequencing, the researchers discovered that when the damage to the CST axons happened far away in the spinal cord, the nerve cells barely changed their activity. Only a modest number of genes switched on or off, far fewer than expected from earlier studies on other neuron types, like sensory neurons in the dorsal root ganglia (DRG). However, when the team moved the injury site very close to the CST cell bodies, like inside the brain itself, the picture radically changed. Suddenly, the CST neurons showed a potent stress response. Many genes related to growth and repair lit up, matching what scientists see in cell types that can somewhat regenerate.
Every cell uses specific genes to respond to stress, injury, or changes in the environment. By capturing which RNA messages were present in each cell’s nucleus, the team built a map of how the neuron’s genetic instruction manual changes after injury. In most spinal injuries, the change was minimal. However, after a nearby injury in the brain, many RNA signatures linked to axon growth, stress pathways, and cell survival became very abundant.
One theory to explain the change in activity with changing distance is that a nerve can sense damage only if the lesion is close enough to send a strong alarm signal back to the cell body. If the axon is cut far away in the spinal cord, that alarm signal might weaken or get lost before reaching the main body of the neuron in the cortex. As a result, the neuron barely notices it needs to switch on repair programs. This also suggests that certain molecules that travel along the axon may be crucial for alerting the cell to an injury.
For further context, the researchers compared CST neurons’ responses to that of other neuron types, like retinal ganglion cells (in the eye) and sensory neurons in dorsal root ganglia (which feed into the spinal cord). They found that when those other neurons get injured near their main body, they mount a significant response, turning on crucial regeneration-associated genes. CST neurons can do this, too, but only if the injury is also near the cell body. When injured in the spinal cord far from the brain, the CST response was muted.
While the study emphasises how distance matters, it’s likely not the only thing that influences repair. For example, some chemical signals, like growth inhibitors in scarring tissue, can also dampen regeneration, and preexisting health conditions could mean less overall capacity for the nerve to recover. The researchers also noticed that a small fraction (roughly 20%) of CST neurons started to show some stress-related genes turned on even after a spinal cord injury. Researchers suspect there could be slight variations between neuron subtypes or subtle differences in how each neuron’s axon was cut, leading to variation in CST response. Moreover, although mice and rats are classic laboratory models for many studies, further research on human cells will be needed to address these limitations and derive any treatment regimens based on the study.
Nevertheless, the research brings us closer to understanding the complexities of brain and spinal cord repair. It shows that proximity matters for brain cells, especially corticospinal neurons. Through large-scale genetic profiling and the precise mapping of single nuclei, the offers hope that we could unlock better ways to trigger nerve repair. While there is still a long road ahead, these insights will guide future research, aiming to transform spinal cord injury care and potentially improve the lives of many people worldwide.
This research article was written with the help of generative AI and edited by an editor at Research Matters.