No two spinal cord injuries (SCIs) are exactly the same. Two people with the same level and grade of injury may have very different functional capabilities. In an uninjured state, the system that controls movement of the body (motor system) is incredibly complex, and a myriad of electrical signals from the brain, as well as the spinal cord, contribute to the generation of voluntary movements. After SCI, this system becomes even more complicated when some important pathways that convey the electrical signals get interrupted, while others remain intact.
The complexity and the variability that results from injury to the motor system can make treatment and recovery difficult. After SCI, we all know that “one size does NOT fit all.” However, in this case, complexity may also afford opportunity. These complexities may actually offer more potential targets for improving function in the central nervous system.
Identifying those targets is the key. Thus far, attempts to effectively map the complex network that composes the motor system have been a piecemeal and focused on few and not all the centers of motor control above the spinal cord. In an effort to better understand how the brain is connected to the spinal cord, scientists at The Miami Project, led by Dr. Pantelis Tsoulfas, Associate Professor, partnered with the laboratory of Dr. Murray Blackemore from Marquette University to utilize a newly developed and powerful research tool. Viral vectors that are transported in the ‘opposite’ direction of the electrical signal, retrograde, are able to move viruses along nerve fibers, from termination of the nerve fiber (synapse) to its point of origination at the cell body (soma). They used AAV2-retro, an adeno-associated virus that has been mutated to deliver genetic material to the cells it infects. The scientists injected AAV2-Retro into the spinal cords of rats, with and without spinal cord injuries, at different levels (cervical and lumbar).
In order to visualize the neurons and their pathways, the team used special methods to “clear” the entire brain, making it transparent, and highlight the nerve cells that took up the AAV2-retro, using markers that fluoresce and therefore making them visible. Finally, with the use of sophisticated software they were able to visualize in 3D the interconnected networks, made up of cell bodies and their projections, from the brain to the spinal cord.
What they saw under the microscope was nothing short of amazing. The researchers were able to see intricate networks of connectivity between the spinal cord and different areas of the brain, including the brainstem, midbrain, and cortex. Within three days of injection, some important pathways, including the corticospinal tract, were clearly visible within intact tissue. Complex branching structures lit up in fluorescence and the microscopic roadmaps between the brain and the spinal cord could be appreciated in fine detail.
“What was interesting to us was the fact that so many cells in different parts of the brain send their nerve fibers to the spinal cord, and populations of cells that might go unnoticed but are important for locomotion can now be surveyed easily. We will be able to assess plastic changes and new connections after the spinal cord injury. Being able to visualize everything, we can gain more understanding of the injury and adapt our therapeutic interventions. Another aspect of this study is this will allow us to survey the regeneration capacity of all cells in one brain that send their fibers to the spinal cord. In the past we had to focus in one or two cell populations in the brain and therefore missing the larger picture,” said Dr. Tsoulfas.
Wang Z, Maunze B, Wang Y, Tsoulfas P, Blackmore MG. (2018). Global Connectivity and Function of Descending Spinal Input Revealed by 3D Microscopy and Retrograde Transduction. J Neurosci. 5;38(49):10566-10581.