All motor behaviors require precise temporal coordination of different muscle groups. Breathing, for example, involves the sequential activation of numerous muscles hypothesized to be driven by a primary respiratory oscillator, the preBötzinger Complex, and at least one other as-yet unidentified rhythmogenic population. We tested the roles of Atoh1-, Phox2b-, and Dbx1-derived neurons (three groups that have known roles in respiration) in the generation and coordination of respiratory output. We found that Dbx1-derived neurons are necessary for all respiratory behaviors, whereas independent but coupled respiratory rhythms persist from at least three different motor pools after eliminating or silencing Phox2b- or Atoh1-expressing hindbrain neurons. Without Atoh1 neurons, however, the motor pools become temporally disorganized and coupling between independent respiratory oscillators decreases. We propose Atoh1 neurons tune the sequential activation of independent oscillators essential for the fine control of different muscles during breathing.
A healthy adult at rest will breathe in and out around 20 times per minute. Each breath requires a complex series of coordinated muscle activity. Inhalation begins with the opening of the airway followed by the contraction of the diaphragm and the intercostal muscles between the ribs, causing the chest cavity to expand. As the lungs increase in volume, the pressure inside them drops and air is drawn in. Relaxation of the diaphragm and intercostal muscles compresses the lungs, causing us to exhale.
Breathing is driven by the brainstem and it cannot be suppressed indefinitely: holding your breath eventually triggers a reflex that forces breathing to resume. The region of the brainstem that controls breathing is called the preBötzinger Complex. However, there is increasing evidence that a second region in the brainstem is also involved. This region, which is called the retrotrapezoid nucleus/parafacial respiratory group, consists of three types of excitatory neurons—Dbx1 neurons, Phox2b neurons, and Atoh1 neurons—but their roles had not been clear. Now, using multiple lines of genetically modified mice, Tupal et al. have teased apart the roles of these three cell types.
These experiments showed that the Dbx1 neurons—which are also found in the preBötzinger Complex—have an essential role in sending the signals from the brain that drive the different muscle activities needed to breathe. The Phox2b neurons modulate breathing based on the level of carbon dioxide in the blood. Atoh1 neurons help control the sequence of respiratory muscle activity during a breath, probably by selectively inhibiting different populations of Dbx1 neurons.
The work of Tupal et al. indicates that distinct populations of neurons within the brainstem independently control two different aspects of breathing: the generation of breathing rhythms, and the coordination of these rhythms. Given that many other physiological processes involve rhythmic activity patterns, this model may help us to understand how the brain generates and controls complex behaviors more generally.