Andrew Spence, Michel Lemay, and George Smith are Temple researchers working together to try to find breakthrough ways to treat spinal cord injury and understand how the spinal cord organizes movement. Working with undergraduates, graduate students, and postdocs, this interdisciplinary team of three investigators is trying to combine new genetic tools with new robotic and computer vision techniques, to understand how the nervous system produces movement, in health and disease, and in turn improve treatments for neurological problems and injury.

Spinal cord injury (SCI) causes life-long neurological impairment. There is currently no effective treatment, and there are approximately 400,000 patients living with SCI in the United States. Recently, seminal work by Harkema et al. (2011) demonstrated that electrical stimulation of the spinal cord in conjunction with treadmill training can enhance standing, stepping and volitional movements of the leg, in human patients.

Electrical stimulation has limitations and drawbacks, however. The specific neurons that it targets are not entirely known or precisely controlled, and can vary from one individual to the next. It requires surgical implantation of an electrical stimulator. Stimulation requires an external power source to be connected, typically using a cable, in the laboratory.

In this research, we are investigating whether a new type of genetically engineered tool called chemogenetics can overcome these limitations, and open up fundamentally new avenues for treatment and research into SCI. With chemogenetics, genetic and/or surgical techniques are used to place engineered receptors in specific populations of neurons. Subsequently these neurons can be excited or inhibited with simple, systemic administration of an inert drug, over time courses of hours to days.

The potential advantages of chemogenetics are: 1) reproducible genetic targeting of specific cells that aid, and not hinder, recovery, across individuals; 2) the potential for chronically applied therapy in freely moving patients; 3) removal of the requirement for a surgically implanted stimulator and attachment of external power sources; and finally 4) enabling the use of genetic tracing techniques to uncover the spinal circuits that support recovery.

Adapted from Kandel et al, Principles of Neural Science, 2000." below the figure of the spinal cord and arm bones with muscle.

first, we need to validate that these new tools are working and having the desired effect. To that end, we are currently validating that we can modulate reflexes in rodents using electrophysiological measurements. After adding the chemogenetic receptor, we use small electrical stimulations and measurements of muscle activity to quantify the effect of the DREADD activator or inhibitor.

Chemogenetic tools are cutting edge. As with much of basic science, the path to application may be long; especially in this case where gene therapeutic techniques would likely have to be used to add the DREADDs channels in humans. But the potential of genetically targeted treatment is hard to underestimate; it could dramatically reduce side effects, increase the efficacy of treatment, and even make possible levels of recovery that are not achievable by current means.

Presentation Citations:

1. Mechanical Perturbation of Trotting Mice Reveals Trot-to-Bound Transition as a Mechanism for Recovery

Benjamin D. Robertson (tuf84240@temple.edu) and Andrew J. Spence. Temple University, Philadelphia, PA

Biomechanics and Neural control of Movement (BANCOM), 2016-06-12 - 2016-06-17, Deer Creek Lodge and Conference Centre, Mount Sterling, Ohio.

2. How far are we from genetic neuromechanics? Tantalizing prospects and hard challenges using new molecular tools in movement science

Andrew J. Spence1, Simon Wilshin2, Ornella Capellari2, Kim Wells2, Ben Robertson1, Annie Vahedipour- Tabrizi1, Dominic Wells2

1Temple University, Philadelphia, PA

2Royal Veterinary College, London, UK

Biomechanics and Neural control of Movement (BANCOM), 2016-06-12 - 2016-06-17, Deer Creek Lodge and Conference Centre, Mount Sterling, Ohio.

3. Modulation of Large Diameter Sensory Afferent Excitability with DREADDs

Benjamin D. Robertson1 (tuf84240@temple.edu), Michel A. Lemay1, George M. Smith2,3 and Andrew J. Spence1

1Temple University Department of Bioengineering, 2Temple University School of Medicine, 3Shriners Hospitals Pediatric Research Centers

Society for Neuroscience Annual Meeting 2016. San Diego, CA. 2016-11-12 - 2016-11-16.