CO2-evoked release of PGE2 modulates sighs and inspiration as demonstrated in brainstem organotypic culture

Humans and other mammals breathe air to absorb oxygen into the body and to remove carbon dioxide. We know that in a part of the brain called the brainstem, several regions work together to create breaths, but it is not clear precisely how this works. These regions adjust our breathing to the demands placed on the body by different activities, such as sleeping or exercising. Sometimes, especially in newborn babies, the brainstem’s monitoring of oxygen and carbon dioxide does not work properly, which can lead to abnormal breathing and possibly death. In the brain, cells called neurons form networks that can rapidly transfer information via electrical signals. Here, Forsberg et al. investigated the neural networks in the brainstem that generate and control breathing in mice. They used slices of mouse brainstem that had been kept alive in a dish in the laboratory. The slice contained an arrangement of neurons and supporting cells that allowed it to continue to produce patterns of electrical activity that are associated with breathing. Over a three-week period, Forsberg et al. monitored the activity of the cells and calculated how they were connected to each other. The experiments show that the neurons responsible for breathing were organized in a “small-world” network, in which the neurons are connected to each other directly or via small numbers of other neurons. Further experiments tested how various factors affect the behavior of the network. For example, carbon dioxide triggered the release of a small molecule called prostaglandin E2 from cells. This molecule is known to play a role in inflammation and fever. However, in the carbon dioxide sensing region of the brainstem it acted as a signaling molecule that increased activity. Therefore, inflammation could interfere with the body’s normal response to carbon dioxide and lead to potentially life-threatening breathing problems. Furthermore, prostaglandin E2 induced deeper breaths known as sighs, which may be vital for newborn babies to be able to take their first deep breaths of life. Future challenges include understanding how the brainstem neural networks generate breathing and translate this knowledge to improve the treatment of breathing difficulties in babies.