April 13, 2005

In mice, walking (and running) depends on nerve cell chatter during development

Salk News

In mice, walking (and running) depends on nerve cell chatter during development

La Jolla, CA – The ability of a pair of legs to walk in a stepwise fashion with each other appears to be set up during a brief period as an embryo’s spine develops, when a single neurotransmitter takes its turn to “talk” to nerve cells.

In the April 7 issue of the journal Neuron, scientists at the Salk Institute for Biological Studies report these findings based on mice studies, but they say their conclusions could possibly be used to explore what happens to complex rhythmic movement when such chatter among nerve cells is interrupted in humans.

“This might eventually help us understand a variety of ailments that involve loss of movement, like spinal cord injuries, or those that have to do with nerve communications during human fetal development,” said Sam Pfaff, a professor in the Gene Expression Laboratory.

In a more general sense, however, the study offers clues as to how the brain is put together, Pfaff said. “We study the spinal cord, which is a comparatively simple part of the nervous system, to extract rules that explain the workings of the brain,” he said.

The spinal cord is a major site of the circuitry that controls our most basic movements, which is dramatically illustrated by the chicken’s ability to, literally, “run around with its head cut off” – movement that is obviously not controlled by the brain.

Likewise, in mammals rhythmic limb movement, such as legs walking is largely controlled by what researchers call “pattern-generating” neurons within the spinal cord, but little is known about how these circuits are assembled. What is known is that during early development, motor neurons seem to become spontaneously active, and they release acetylcholine, which excites neighboring cells as a form of cell-cell communication.

Therefore, Pfaff and a team of researchers at Salk as well as at Case Western Reserve University looked specifically at the “talk” acetylcholine briefly provided between spinal neurons during the growth of a mouse embryo. The question that the researchers wanted to answer was whether this communication provided any assistance in the assembly of spinal cord circuits that emerge later in development for the control of rhythmic movements such as walking.

So to investigate whether acetylcholine, which is the signal that nicotine mimics, is required for generation of the central pattern generating spinal circuit, the group studied mice that lacked a key enzyme for synthesizing acetylcholine. When these mutant mice were born, the researchers discovered that the spinal circuitry controlling leg movements had not formed properly. In a second experiment, drugs were used to block acetylcholine after the circuits were wired, and the spinal circuitry functioned properly. These results show that use of acetylcholine during a brief stage in fetal development is “critical for the assembly of the spinal circuitry that controls our most basic movements,” Pfaff said.

“There is a narrow window in which acetylcholine is needed to help neurons communicate with each other,” he said. “If it isn’t there, a domino effect takes place that leads to bad wiring of the circuit. It’s a little bit like not paying your electric bill and having the power cut at the end of the month.”

The findings suggest that such wiring may be more nurture than nature, Pfaff said. “One of the debates in science is whether genes or environment help guide organization of the nervous system. In this case, it appears to be nurture,” he explains. “We found that changing how a neurotransmitter signaled neurons had a profound influence on the normal sequence of events involved in development of the spinal cord.

Such changes can occur outside the laboratory, during a woman’s pregnancy, for example. “This kind of significant influence on the ultimate behavior of movement raises a question about potential harm that could come to a human fetus if neurotransmission is significantly altered,” he said. One potential example is use of nicotine during pregnancy, because it is known to influence this pathway he said. “It is also possible, but of course unproven, that an alteration in the sequence of brain stem development could lead to compromised breathing in infants, such as is seen with sudden infant death syndrome,” Pfaff added.

“The study results also suggest that there could possibly be a way to take advantage of the circuitry that already exists in the spinal cord, and find a way to activate it in people with spinal cord injuries,” he said.

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