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Two Centers in Brain Command Breathing Rhythm

Until now, scientists believed that a single area in the brain generated breathing rhythm, enabling breathing to speed up or slow down to adapt to the body's activity and position.

But UCLA neurobiologists have discovered that two systems in the brain interact to generate breathing rhythm -- a finding that may translate into better treatment for sleep apnea and sudden infant death syndrome. The journal Neuron reports the findings in its March 6 issue.

"We originally thought that only one brain center was responsible for generating breathing rhythm," explained Dr. Nicholas Mellen, UCLA assistant researcher in neurobiology and principal investigator of the study. "But our research indicates that two cellular networks closely collaborate to control breathing. This brings us an important step closer to understanding how breathing control is organized in the brain."

"Breathing is a good model for understanding brain function in general," said Dr. Jack Feldman, UCLA professor of neurobiology and senior author. "Once we learn how the brain commands humans to breathe, we will gain valuable insight into how the brain produces other meaningful behaviors."

The UCLA finding could enhance prevention, diagnosis and treatment for sleep apnea and sudden infant death syndrome, as well as speed the development of drugs for neurological disorders that can interfere with breathing, such as stroke, multiple sclerosis and Parkinson's disease, he added.

Previously, UCLA neurobiologists located a brain region they identified as the key command post for generating breathing and dubbed it the preBotzinger Complex. When they exposed the preBotzinger Complex nerve cells in a rat's brain to a narcotic, the animal's breathing slowed dramatically. This led the UCLA team to conclude that the preBotzinger Complex served as the brain's headquarters for breathing rhythm.

"Overdoses of narcotics kill people because they slow your breathing until it stops entirely," said Feldman. "The cells in the preBotzinger Complex replicated this phenomenon."

Researchers Hiroshi Onimaru and Ikuo Homma of Showa University in Tokyo, however, had described a second set of brain cells that did not respond to narcotics. They called them "pre-I" cells, for pre-inspiratory, because they are active before inhalation.

The UCLA researchers decided to test the effect of a low amount of narcotics on a rat's breathing. They first tested the drug on a slice of brainstem that did not contain pre-I neurons, and then exposed the drug to a block of brainstem that did contain pre-I neurons.

When the pre-I neurons were present, the animal's breathing slowed continuously. When the cells were absent, however, Mellen and Feldman witnessed a surprising event. Instead of slowing down gradually, the rat's breathing pattern slowed by skipping entire breaths. This suggested that two distinct systems in the brain interact to generate breathing rhythm.

"Exposing the pre-I cells to narcotics still reduced the rat's intake of oxygen, but it did so by skipping beats rather than slowing the rhythm," explained Mellen.

In addition to responding to narcotics differently, the two cellular networks varied in other ways, too. The UCLA team discovered that sensory feedback from the lungs affected the preBotzinger Complex brain cells, but not the pre-I cells. The scientists hypothesize that this is the brain's way of striking a balance between stability and sensitivity.

"Humans breathe no matter what. Yet breathing is an instinctual process," said Feldman. "We do it 24/7 from the second we're born. The process must adapt and be sensitive to all sensory input, yet be extraordinarily stable and reliable."

For example, the act of sitting requires 250 millileters of oxygen per minute to support resting human metabolism. The minute a person stands up and begins to walk, breathing must immediately accelerate to take in 1,000 millileters of oxygen per minute to support the activity.

"Our findings suggest that the pre-I cell system controls stability, while the preBotzinger network responds to sensory feedback," said Mellen. "This division of labor allows breathing to quickly adapt to sensory and other input, yet rapidly return to its normal rhythm."

"Humans and other mammals are the only vertebrate species to possess a diaphragm. This muscle played a key role in our ascending the evolutionary ladder by letting us take in more oxygen to feed our bigger brains," said Feldman. "We think that the preBotzinger Complex also may have evolved to control the diaphragm."

The UCLA data suggests that the preBotzinger Complex is dominant under normal circumstances, but the pre-I cell network also can give rise to the breathing rhythm. Because the two cell networks function in such an integrated manner, scientists cannot readily tease their roles apart. Only the systems' different sensitivity to narcotics revealed their interaction.

The UCLA team will next try to unravel how the two cellular networks communicate in the brain to produce breathing.

The National Institute of Heart, Lung and Blood funded the research. UCLA researchers Wiktor Janczewski and Christopher Bocchiaro were co-authors on the study.

---UCLA

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