Fine Balance: Class Of Spinal Cord Neurons Makes Sure That Sides Of Body Don't G

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Fine Balance: Class Of Spinal Cord Neurons Makes Sure That Sides Of

Body Don't Get Ahead Of One Other

http://medicalnewscenter.com/out/out.cgi?

http://www.sciencedaily.com/releases/2008/10/081008150449.htm

Once a toddler has mastered the art of walking, it seems to come

naturally for the rest of her life. But walking and running require a

high degree of coordination between the left and right sides of the

body. Now researchers at the Salk Institute for Biological Studies

have shown how a class of spinal cord neurons, known as V3 neurons,

makes sure that one side of the body doesn't get ahead of the other.

The findings, published in the Oct. 9 issue of Neuron, mark an

important milestone in understanding the neural circuitry that

coordinates walking movements, one of the main obstacles in

developing new treatments for spinal cord injuries. In addition to

establishing a balance between both sides of the body, they found

that the V3 neurons ensure that the stepping rhythm is robust and

well-organized.

" In the case of cervical spinal cord injuries, the spinal network

that drives your limbs and allows you to walk is still there but no

longer receives appropriate activating inputs from the brain. " says

Martyn Goulding, Ph.D., a professor in the Molecular Neurobiology

Laboratory, who led the study. " The fact that the V3 neurons are

important for generating a robust locomotor rhythm makes them good

candidates for efforts aimed at therapeutic intervention after spinal

cord injury. "

V3 neurons are so called interneurons, which relay signals from the

nerve cells in the spinal cord to motor neurons, which cause muscles

to contract. Spinal interneurons form complex networks—commonly

referred to as CPGs, short for central pattern generators—that

function as local control and command centers for rhythmic movements,

which lie at the heart of all locomotion.

Although scientists had known about the locomotor CPG for a long

time, they were unable to identify the nerve cells that make up these

circuits. When Goulding and others began to break the molecular code

that makes these different interneuron cell types, they could start

to unravel the wiring of the spinal cord to see how it works.

Neurons in the brain and spinal cord come in two flavors, excitatory

neurons that transmit and amplify signals and inhibitory neurons that

inhibit and refine those signals. Previously, Goulding and his team

discovered that a subset of inhibitory interneurons, the V1 neurons,

control the speed of motor rhythm and thus set the pace at which

animals walk, while a second group of inhibitory neurons, called V0

neurons, govern the left-right alternating pattern of activity that

is needed for stepping, as opposed to hopping, movements. In their

latest study, they turned their attention to a class of excitatory

neurons, the so-called V3 neurons.

" Most models of the CPG include an inhibitory element that switches

off motor neuron activity on one side in order to initiate the next

step on the other side of the body, which allows you to walk, hop,

skip, and run, " says Goulding. " V3 neurons provide an additional

level of control, which makes sure that when you walk and run, the

intensity of the activity is matched on both sides of the body. If

that were not the case, we would be unable to walk or run along a

straight line. "

In the study, postdoctoral researchers in the Goulding lab

genetically engineered mice to specifically shut off their V3 neurons

and reveal their function. The first author, Ying Zhang, Ph.D., then

performed electrophysiological experiments on spinal cords isolated

from these mice and found that without functioning V3 neurons, the

length of individual motor neuron bursts began to fluctuate

wildly. " Instead of a stable, alternating pattern, we found irregular

oscillations between the left and the right side, " she says.

" A lot of research focused on the left-right coordination, but it has

became clear that different levels of control allow for the fine-

tuning of these rhythmic locomotor patterns, " says Zhang. " This study

will allow us to put together a map of the neurons contributing to

the CPG so that we can think about manipulating the CPG for

therapeutic purposes. "

Since the activity of the motor neurons determines how much the

muscle contracts and for how long, the researchers wanted to know how

this irregular activity pattern of motor neurons influences the gait

of mice strolling down a walkway. Taking advantage of the so-called

AlstR/AL system, which was developed by Salk researcher M.

Callaway, Ph.D., a professor in the Systems Neurobiology

Laboratories, the researchers temporarily shut off V3 neurons in

adult mice and sent them on their way along a narrow Plexiglas

walkway. While the mice still alternated steps with their left and

right hind limbs, the length of each step varied markedly, making it

difficult for them to walk with a smooth cadence.

Researchers in the Goulding laboratory who contributed to this work

include Sujatha Narayan, Ph.D., Geiman, Ph.D., Guillermo M.

Lanuza, Ph.D., Tomoko Velasquez, Ph.D., and Simon Gosgnach, Ph.D.,

who is currently an assistant professor at the University of Alberta,

Edmonton, Canada. Turgay Akay, Ph.D., Dyck, and Keir Pearson,

Ph.D., a professor at the University of Alberta, Edmonton, Canada, as

well as Chen-Ming Fan, Ph.D., a primary investigator at the Carnegie

Institution of Washington, Baltimore, were also involved in this

study.

The research was supported by grants from the NIH and the Human

Frontiers Science Program.