Research in my laboratory is focused on developing therapies for promoting recovery from spinal injuries. When sensory nerves are injured, as often occurs in motor vehicle accidents, the sensory fibers can regrow back to the spinal cord, but further growth is impeded by a lack of neurotrophic factors that stimulate axon growth and by inhibitory factors expressed by myelin in the central nervous system. This inhibition can be overcome by compounds that block the inhibition or that stimulate axon growth directly. We have been studying the effects of two agents on regeneration of sensory axons: a soluble peptide that interferes with myelin inhibition and a naturally occurring neurotrophic factor, artemin. Both agents promote robust regeneration of sensory axons into the spinal cord of adult rats after these axons are disrupted by crushing dorsal roots. Anatomically, the axons grow back into the spinal cord over three to six weeks. The regenerated axons make functional connections with their target neurons in the spinal cord, as evidenced both by electrophysiological recordings of synaptic potentials in the cord elicited by stimulation of peripheral nerves, and by behavioral recovery of the affected limb.

The regeneration promoted by artemin treatments is particularly interesting because the sensory axons grow back to their appropriate target areas in the spinal cord. Sensory axons innervating a small patch of skin regenerate back to the same location in the spinal cord that they occupied before the injury. Similarly, muscle sensory axons, which normally project to deeper spinal layers, regenerate back to deeper layers of the cord. Finally, unmyelinated sensory axons, which mediate nociceptive responses, also regrow back to the same superficial layers of the cord where they normally project. Although other agents have been shown to stimulate regeneration of sensory axons, there is no evidence that this regeneration is specifically targeted to correct regions, as is the case with artemin treatment. These surprising results suggest that molecular cues capable of directing the growth of regenerating axons to their targets are present in the adult, mammalian spinal cord. The implication is that these and other cues may also be available to guide the regeneration of other classes of spinal axons, such as those damaged in other types of spinal injuries. If so, it may be possible to develop generalized strategies for promoting specific regeneration of these axons as well.

Experiments in progress are aimed at determining if regenerating sensory axons can also re-establish their projections to more distant targets in the cord and if the anatomically specific regeneration seen with artemin treatment also results in more specific functional connections, as assessed both electrophysiologically and behaviorally. We are also testing other treatments that would allow regeneration of sensory axons after dorsal roots are broken, rather than simply crushed, and that would be effective even when applied well after the injury occurred. These improvements would greatly increase the applicability of these therapies to real-life situations. Recently, we have begun to investigate changes in the synaptic connectivity of spinal circuits caused by amyotrophic lateral sclerosis, or Lou Gehrig’s Disease, using a mouse model of the disease. This genetic model will allow us to test therapeutic agents that are being developed to treat this debilitating disease. Positions for both graduate students and postdocs are currently available in any of these exciting and translationally relevant research areas.