"Knowing which circuits are important and understanding how they control the essential aspects of walking should put us in a better position to design treatments or implants that restore or activate these pathways," said Martyn D. Goulding, Ph.D., a professor in the Molecular Neurobiology Laboratory.
The Salk research team - led by Goulding- published their findings in the March 9, 2006 issue of the journal Nature. Joint lead authors were Simon Gosgnach, Ph.D. and Guillermo M. Lanuza, Ph.D. in Goulding's laboratory.
Whether fish or fowl, the muscle contractions that allow us to move generally have certain rhythmic properties. It has been known for some time that a central pattern generator (CPG) - specialized groups of neurons in the spinal cord - functions as the control and command center for these rhythmic movements. As such, the CPG lies at the heart of all locomotion. Remarkably, this circuitry functions without any input from the brain, which explains why headless chickens run away from the butcher's block.
"Although people have known about the CPG for a long time, they haven't been able to identify the nerve cells that are part of these circuits. Even at closer inspection, the spinal cord is just a jumbled mass of hundreds of thousands of neurons that all look the same," said Gosgnach.
The Salk team used genetic approaches to identify a subset of neurons, named V1 neurons, as being part of the CPG, and gene targeting methods to selectively disable them in order to observe what happens. "It allowed us to peer into this black box that is the central pattern generator," explained Lanuza.
V1 neurons are so-called interneurons that relay electrical signals between nerve cells in the spinal cord,and motor neurons, the nerve cells that cause muscles to contract.
To explore whether V1 neurons actually contribute to the CPG, Goulding and his colleagues performed electrophysical studies on isolated spinal cords. They found that, while normal spinal cords showed a standard pattern of activity that mimics walking, the rhythmic pattern in spinals cords lacking functional V1 neurons had slowed to a crawl.
"From what we knew about these cells, we were a bit puzzled at first because we had expected to see a loss of coordination," said Goulding. "But after delving into the circuitry further, it made perfect sense. Once excited, motor neurons tend to stay "on" for long periods of time and need to be actively turned off. That is exactly what V1 neurons are doing," explained Goulding. In order to initiate the next step, each burst of motor neuron activity needs to be switched off. Switching off motor neurons more quickly, speeds up the stepping movements, allowing animals to walk, run, or swim faster.
Authors who also contributed to this work include Harald Saueressig, Ying Zhang and Tomoko Velasquez in the Salk's Molecular Neurobiology Laboratory, Edward Callaway, a professor in the System Neurobiology Laboratory, Ole Kiehn and Simon Butt at the Karolinska Institute in Stockholm, Sweden, and Dieter Riethmacher at the Centre for Molecular Neurobiology at the University of Hamburg, Germany.
The Salk Institute for Biological Studies in La Jolla, California is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health, and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.