NIH study shows astrocytes have active role in controlling breathing rhythm

A new study published in Nature Communications showed that silencing astrocytes in the brain’s breathing center caused rats to breathe at a lower rate and tire out on a treadmill earlier than normal. Researchers were able to modify the rats’ breathing by manipulating the way astrocytes communicate with neighboring cells.

Prior research has suggested that astrocytes may influence activities of neural circuits that control sleep, feeding, and chemosensing via the release of gliotransmitters. However, it remained unclear whether astrocytes have a direct role in modulating motor circuits or have an impact on complex behaviors.

“For decades, we thought that breathing was exclusively controlled by neurons in the brain,” said Jeffrey C. Smith, PhD, senior investigator at the National Institute of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, MD, and a senior author of the study. “Our results suggest that astrocytes actively help control the rhythm of breathing. These results add to the growing body of evidence that is changing the way we think about astrocytes and how the brain works.”

Dr. Smith’s lab investigates how breathing is controlled by the rhythmic firing of neurons in the pre-Bötzinger complex, the brain’s breathing center that his lab helped to discover. For this study, his team worked with Alexander Gourine, PhD, professor, Centre for Cardiovascular and Metabolic Neuroscience, University College London (UCL), whose own lab found that astrocytes in neighboring parts of the brain may regulate breathing by sensing changes in blood carbon dioxide levels.

Researchers tested the role of astrocytes in breathing by genetically modifying the ability of astrocytes in the pre-Bötzinger complex to release gliotransmitters. When they quieted the astrocytes in rats by reducing gliotransmitter release, the rats breathed and sighed at a lower rate than normal. In contrast, when they made the astrocytes chattier by increasing gliotransmission, the rats breathed at higher resting rates and sighed more often.

The team also tested how silencing astrocytes affected the rats’ responses to changes in oxygen and carbon dioxide levels. Although the rats’ breathing rate increased when oxygen levels were lower or carbon dioxide levels were higher, it was still lower than normal.

Silencing astrocytes also decreased the rate at which the rats sighed under lower oxygen levels. Moreover, the rats became exhausted much earlier than normal. They could only run half the distance that normal rats could run on a treadmill before tiring out.

“The primary goal of breathing is the exchange of carbon dioxide and oxygen that is critical for life,” said lead author of the study Shahriar Sheikhbahaei, PhD, formerly a doctoral student at UCL and participant in the NIH Graduate Partnership Program. “Our results support the idea that astrocytes help the brain translate changes in these gases into breathing.”

Finally, the team showed that these astrocytes used adenosine triphosphate (ATP) to communicate with other cells in the brain. Inactivating released ATP reduced resting breathing rates and the frequency of sighs under normal and low oxygen levels.

“Our results expand our understanding of how the brain controls breathing under normal and disease conditions,” said Dr. Smith. “We plan to follow this path to understand how astrocytes help control other aspects of breathing.”

This study was supported by the Intramural Research Program at the NINDS, the Wellcome Trust, British Heart Foundation, the Biotechnology and Biological Sciences Research Council, and the Medical Research Council.

To read more about this study, click here.