THREE-PART RHYTHM: There are three stages to mammalian breathing: inspiration, passive expiration (postinspiration), and active expiration—a conditional phase used during labored breathing. Inspiration and active expiration have been linked to rhythm-generating excitatory neural circuits in the medulla: the pre-Bötzinger complex and the lateral parafacial region, respectively. A recent study has revealed a third excitatory network—the postinspiratory complex (PiCo)—that drives postinspiration, suggesting that the coordination of breathing may rely on alternating inhibitory interactions between three networks. © SHRADDHA NAYAK


The paper
T.M. Anderson et al., “A novel excitatory circuit for the control of breathing,” Nature, 536:76-80, 2016.

A lot can happen after we take a breath—from swallowing a sip of coffee to singing in the shower—and the nervous system has to coordinate all these behaviors without sending fluids into the lungs or disrupting airflow. But studying the neural control of breathing has been a challenge, not least because researchers haven’t found all the circuitry involved.

Two breathing phases, inspiration and active expiration (the forced expulsion of air during labored breathing), have each been linked to rhythm-generating excitatory networks in the medulla, the lowest portion of the brainstem. But scientists have been stumped as to the source of excitation generating the third: the passive release of air from the lungs after breathing in, or postinspiration. From this incomplete picture, most models of breathing have assumed that just two rhythm-generating circuits—inspiratory and expiratory—set the timing of all three breathing phases, with coordination coming about as each active phase inhibits the other two.

Jan-Marino Ramirez, a neuroscientist at the University of Washington, has spent much of his career working to refine this model. Over the last decade, he and his colleagues have developed a preparation of horizontal brain slices from baby mice that provides a broad in vitro view of neural activity in the medulla. Using this preparation, the team has finally discovered the excitatory network that generates postinspiration, which the group has named the postinspiratory complex (PiCo).

After so many years of unsuccessful searching, “I thought, ‘Oh, maybe it’s something else,’” Ramirez remarks about initially finding the PiCo. “But then we started the research—isolating this area and showing it’s an independent neural network.”

Through pharmacological and optogenetic experiments, the researchers demonstrated that the PiCo is necessary and sufficient to generate postinspiration in vitro and in adult transgenic mice. What’s more, like the networks driving inspiration and active expiration, the PiCo appears to generate its own rhythm. “That was astonishing to us,” Ramirez says. The team is now exploring a model of breathing coordinated by the interactions of three, not two, rhythm-generating excitatory networks.

“There are a number of seminal results presented here,” says neurobiologist Jeffrey Smith of the National Institute of Neurological Disorders and Stroke who was not involved in the work. He adds that the experiments themselves were “technically sophisticated and involved a variety of elegant approaches,” but that the network’s architecture and activity in vivo will require further investigation.

Ramirez plans to examine the PiCo’s influence on actions occurring during postinspiration. “Can we interrupt vocalization, for example, or swallowing?” Such experiments might explain what happens when the coordination of breathing goes wrong—a common problem that leads to aspiration pneumonia in people with certain neurodegenerative diseases. It could also open a window on how and why we coordinate certain other behaviors, such as the holding of breath during concentration, Ramirez notes. “I think these circuits will allow us to probe higher brain functions,” he says, “which I find very, very exciting.”