A research study was published recently showing that neurotrophins, or growth-inducing molecules, enhance recovery after spinal cord injury. The new work comes from Vanessa Boyce, Ph.D., at the State University of New York at Stony Brook; she is an Associate in the Lorne Mendell lab, a member of the Reeve Research Consortium on Spinal Cord Injury; the Consortium lab of Fred Gage at the Salk Institute collaborated.
Boyce has previously shown that a combination of growth factors called NT-3 and BDNF helped cats with completely cut spinal cords to regain stepping function on a treadmill. These molecules are known to affect regeneration and sprouting of injured axons (nerve fibers). “These molecules cause damaged axons to grow or sprout,” said Boyce. “That’s why they are of interest to those of us who study spinal cord injury – that’s what many in the field are tying to do, to get axons to regrow.”
What’s new in the current paper? “The two molecules,” said Boyce, “do completely different things to the physiology of the cord and to locomotor recovery.”
Boyce’s new paper is titled “Differential effects of brain-derived neurotrophic factor and neurotrophin-3 on hindlimb function in paraplegic rats.” You can read the entire paper if here
-- click on PDF.
Here’s what they did: rat spinal cords were completely transected at the T10 level of the cord. This is important because such a cut removes any and all input from the brain – any activity that happens below the lesion, therefore, is not coming from any brain signal. They made sure the cut was complete using a surgical microscope and a glass probe; they verified the completeness of injury using electrical measurements (electrophysiology, a specialty of the Mendell lab). The gap between the ends of the cord was also filled with a gelfoam material, to ensure that there could be no connection to the brain.
Next, the scientists delivered a virus (technology from the Gage lab) to the distal end of the cord – that’s the end away from the brain. Inside the virus was the genetic coding to produce either BDNF or NT-3. Half the animals got BDNF, half NT-3.
Six weeks later the animals were given several kinds of tests, comparing post-injury to pre-injury responses to heat, walking performance and treadmill locomotion.
From the paper;
The present work further advances our understanding of the restoration of stepping mediated by isolated spinal segments in two major ways. First, it demonstrates that the individual neurotrophic factors BDNF and NT-3, chronically expressed via an AAV construct [the virus vector] delivered at the time of injury, can elicit long-lasting recovery of locomotion. Interestingly, these neurotrophins have disparate effects on the recovery of locomotion following complete SCI in the adult rat.
Both test animal groups showed recovery. That means the growth molecules are somehow activating neural circuits. The BDNF animals were able to step without any training in two challenging tasks; their hindlimb recovery was sustained. The NT-3 group recovered stepping in one of the tasks, but needed additional stimulation of the perineal area (more or less in the pelvic area).
So what’s going on? Said Boyce, “The neurotrophins appear to activate plasticity in the area of the spinal cord known as the CPG, or central pattern generator. Our hypothesis is that they do this by activating these interneurons in the cord.”
The CPG is the basis of many studies, including the work of Reggie Edgerton’s Consortium lab at UCLA. The ability of the cord to initiate stepping patterns independent of brain input is the basis of the big story
last year involving Rob Summers, who recovered stepping after training and epidural stimulation. The spinal cord is “smart,” and one of the ways it figures out these movement patterns is by way of the interneurons, at least that’s what Boyce and her group suspects.
Boyce also noted increased levels of cFos, an indication that gene activity was occurring, which in turn means that BDNF turns on activity in the CPG interneurons.
“So the question is,” said Boyce, “if the interneurons are driving the process, who are they? If we knew that we might better design therapies.”
Boyce, meanwhile, continues her studies of trophic factors and SCI recovery. If the interneurons respond to BDNF, how much is needed? Does too much cause pain? What other molecules might work better? And importantly, will such molecular therapies work on a spinal cord that has been contused (bruised – the more common pathology in humans) rather than transected? Lots more work ahead.