In the July 8, 2004, issue of the journal Neuron, the researchers describe the specific group of neurons that are responsible for gasping and what happens to these cells when they are deprived of oxygen. Since gasping resets the normal breathing pattern for babies, the scientists suspect that a malfunction in these respiratory pacemakers is the cellular mechanism that leads to SIDS.
"This paper sets the groundwork for everything that has to do with breathing," says lead author Jan-Marino Ramirez, an associate professor of organismal biology and anatomy. "We've now defined the players in the system."
The study follows a paper published in Nature four years ago in which Ramirez and colleagues showed that the same network of respiratory cells in the brainstem controls different forms of breathing: the sigh, the gasp and normal rhythm.
Shortly after the groundbreaking paper, scientists overturned conventional theory that pacemaker neurons drive the entire network of cells. Researchers found that riluzole, a drug that blocks the cell's sodium channel, could silence pacemaker neurons yet the rhythm of the network remained active.
But, according to Ramirez, riluzole didn't disable all of the pacemakers, which is why the rhythm continued. He found that there are two groups of pacemaker neurons, one of which does not depend on sodium channels to operate, but on calcium channels. Only four out of 172 pacemaker cells were not affected by riluzole.
"You have to have a perfect recording in order to get those cells," Ramirez says. "It's not that these neurons are more powerful, just more elusive."
To test the new theory, the researchers not only applied riluzole to silence the sodium-driven pacemakers but also the drug cadmium to silence the calcium-driven pacemakers. The rhythm stopped, confirming that pacemaker neurons actually do drive the network.
To take a step further, the researchers tested the network under a hypoxic state, which is when the cells are deprived of oxygen.
According to the researchers, during hypoxia, the body shuts down most of the cellular respiratory network and focuses its energy on gasping, which is modulated solely by the sodium-driven pacemaker neurons. If that specific neuron is blocked for whatever reason, the body cannot gasp.
This means there may be nothing wrong with a baby's breathing under normal conditions, but if the baby goes into hypoxia from a blocked airway or because the baby sleeps on the tummy and does not receive sufficient oxygen, the baby needs the sodium-driven pacemakers in order to gasp, which wakes the baby and initiates movement or crying.
"Gasping is an important arousal or auto-resuscitation mechanism," Ramirez says. It resets a baby's normal breathing rhythm and also alerts the baby as well as the mother that something is wrong.
The Neuron paper shows that the breathing rhythm is a much more complicated system than previously thought, revealing that the two different states depend on two different pacemakers.
"In normoxia, it's a complicated network, and if you take away one component, the rhythm is apparently undisturbed. However, the network becomes more vulnerable to situations like hypoxia, because under these conditions, respiration relies on only one group of pacemakers that become the critical drivers of the rhythm," Ramirez says.
Harvard University's Hannah Kinney found that children who die of SIDS have decreased levels of serotonin in areas critical for respiration. Although he didn't know it at the time in 2002, Ramirez and colleague Fernando Pena found the missing link: In the pacemaker neurons critical for gasping, serotonin regulates the sodium channel.
Now, Ramirez, along with six of his investigators, are looking more closely at the effects of serotonin on sodium-driven pacemaker neurons. Their work should provide more insight on the body's gasping mechanism, as well as SIDS.
Journal
Neuron