Review Article

Breathing matters

  • Nature Reviews Neurosciencevolume 19pages351367 (2018)
  • doi:10.1038/s41583-018-0003-6
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Breathing is a well-described, vital and surprisingly complex behaviour, with behavioural and physiological outputs that are easy to directly measure. Key neural elements for generating breathing pattern are distinct, compact and form a network amenable to detailed interrogation, promising the imminent discovery of molecular, cellular, synaptic and network mechanisms that give rise to the behaviour. Coupled oscillatory microcircuits make up the rhythmic core of the breathing network. Primary among these is the preBötzinger Complex (preBötC), which is composed of excitatory rhythmogenic interneurons and excitatory and inhibitory pattern-forming interneurons that together produce the essential periodic drive for inspiration. The preBötC coordinates all phases of the breathing cycle, coordinates breathing with orofacial behaviours and strongly influences, and is influenced by, emotion and cognition. Here, we review progress towards cracking the inner workings of this vital core.

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The authors thank W. K. Milsom, T. G. Pitts and numerous colleagues for helpful comments in review and J. Milstein for anatomical drawings that were the basis of Figure 1.

Author information

Author notes

  1. These authors contributed equally: Christopher A. Del Negro, Gregory D. Funk.


  1. Department of Applied Science, Integrated Science Center, William & Mary, Williamsburg, VA, USA

    • Christopher A. Del Negro
  2. Department of Physiology, Neuroscience and Mental Health Institute, Women’s and Children’s Health Research Institute (WCHRI), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada

    • Gregory D. Funk
  3. Department of Neurobiology, David Geffen School of Medicine, Center for Health Sciences, University of California at Los Angeles, Los Angeles, CA, USA

    • Jack L. Feldman


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All authors researched data for the article, made substantial contributions to discussion of content, wrote the article and reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Jack L. Feldman.

Electronic supplementary material


Central pattern generator

(CPG). A network that generates the rhythm and basic motor pattern for behaviours such as locomotion, swimming, chewing and breathing in vertebrate and invertebrate animals.


Breathing typical at rest and in normal air (~21% O2 and trace amounts of CO2).

Breuer-Hering reflexes

Any of several reflexes mediated by mechanical sensory feedback from the lungs that control inflation and deflation of the lungs.

Phrenic premotor neurons

Neurons that project directly to the diaphragmatic motor neurons of the phrenic cervical motor nuclei, some of which receive input from the preBötzinger Complex.


Suprathreshold neuronal depolarizations that drive high-frequency (20–120 Hz) spiking.

Valsalva manoeuvres

Co-contractions of expiratory and inspiratory muscles with a closed glottis, which elevates intra-abdominal pressure.


Smooth, non-turbulent.

Tidal breathing

Periodic inhalation and exhalation of gas in and out of the gas-exchange structure (lungs) along a common pathway (the trachea).

VII nucleus

The facial motor nucleus, the constituent motor neurons of which innervate facial muscles via the seventh cranial nerve.

Phase-sequencing synaptic inhibition

Transitions between phases of a network rhythm that are governed by synaptic inhibition.


Cutting the vagus nerve (cranial nerve X), which removes pulmonary sensory feedback (primarily mechanoreceptive) from the breathing CPG.

Network oscillator

A group of interconnected neurons from which rhythms emerge as a result of synaptic interactions.

Photolytic glutamate uncaging

A technique whereby molecules that chelate glutamate can be cleaved by light at a focal point to locally release the neuromessenger.

Cichlid fish

A large diverse group of ovoid, laterally compressed fish.


Plural of operculum; the hard flap covering the gill slits in fishes.


O2 deficiency.

Aspiration pneumonia

A lung infection that results from the ‘inhalation’ into the lungs of material from the stomach or mouth.

Crural diaphragm

The portion of the diaphragm (the main inspiratory muscle) that surrounds the oesophagus and that, when contracted, prevents gastro-oesophageal reflux.


Complete or partial collapse of a region of the lung that develops when alveoli (the tiny air sacs within the lung) become deflated.