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. Author manuscript; available in PMC: 2026 Feb 19.
Published in final edited form as: Curr Opin Neurobiol. 2025 Jan 28;90:102974. doi: 10.1016/j.conb.2025.102974

The multifunctionality of the brainstem breathing control circuit

Kevin Yackle 1,2,3, Jeehaeh Do 1
PMCID: PMC12914871  NIHMSID: NIHMS2057872  PMID: 39879720

Abstract

Subconscious breathing is generated by a network of brainstem nodes with varying purposes, like pacing breathing or patterning a certain breath phase. Decades of anatomy, pharmacology, and physiology studies have identified and characterized the system’s fundamental properties that produce robust breathing, and we now have well-conceived computational models of breathing that are based on the detailed descriptions of neuronal connectivity, biophysical properties, and functions in breathing. In sum, we have a considerable understanding of the brainstem breathing control circuit. But, in the last five years, the utilization of molecular and genetic approaches to study the neural subtypes within each node has led to a new era of breathing control circuit research that explain how breathing is integrated with more complex behaviors like speaking and running and how breathing is connected with other physiological systems and our state-of-mind. This review will describe the basic role of the key components of the brainstem breathing control circuit and then will highlight the new transformative discoveries that broaden our understanding of these breathing control brain areas. These new studies serve to illustrate the creativity and exciting future of breathing control research.

Introduction to the brainstem breathing control circuit.

The basic breath cycle is composed of two phases, inspiration and expiration, that continuously alternate like two riders on a seesaw to create breathing. Several thousand neurons form the breathing core that generates inspiration and expiration. This core resides in the ventrolateral medulla in two reciprocally connected regions: the preBötzinger complex inspiratory neurons (preBötC) and the Bötzinger complex expiratory neurons (BötC)1 (Fig. 1). These rhythmically active neurons drive nearby spinal cord premotor neurons in the rostral and caudal ventral respiratory groups (rVRG and cVRG) that ultimately command the critical muscles for breathing (Fig. 1). It is the preBötC that acts as a key node to establish the pace for the alternation between inspiration and expiration via its ability to autonomously produce rhythmic firing2. Several other brainstem regions receive and send projections to the preBötC/BötC and serve to modulate the 1) speed and depth of breathing, 2) breath type, and 3) to add additional layers of complexity, like vocalizations and swallows. Brief examples of external influences are the chemosensory signals from the medullary retrotrapezoid nucleus (RTN) and the nucleus tractus solitarius (NTS) which change the speed and depth of breathing in response to stresses like exercise or low oxygen environments3.

Figure 1. Basic breathing control circuit.

Figure 1.

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A. Core components of the medullary breathing control circuit that produce the rhythm and motor outputs. The preBötzinger Complex (preBötC) produces the rhythmic inspiratory pattern and the reciprocally connected Bötzinger Complex (BötC) enables expiration, in part by inhibiting the muscles of inspiration. rVRG, rostral Ventral Respiratory Group inspiratory premotor neurons. cVRG, caudal Ventral Respiratory Group expiratory premotor neurons. breathing MNs, spinal cord motor neurons for key breathing muscles such as the diaphragm.

B. A basic breath airflow pattern. The inspiration (insp.) is a produced by the preBötC indirectly activating the diaphragm. Diaphragm contraction produces a negative pressure in the chest that draws air into the lung. Expiration (exp.) is determined by BötC activity that represses both the preBötC and other inspiratory premotor / motor neurons. In this way, air flows out of the lung by the passive elastic recoil of the tissue.

Decades of studies have described the interactions and functions of each the regions mentioned above (preBötC, RTN, and NTS) in the control of breathing2–6. But current work has focused on expanding the capacities of the breathing control circuit to interact with the entire brain. Dense multiunit recordings of the breathing core (preBötC/BötC) has shown the neural activity tiles the entire breathing cycle, providing a mechanism for any moment of the breath to be recognized and integrated with the activity of widespread brain regions7. This concept harmonizes with recently identified coordination of breathing with general brain physiology and behaviors, including general brain waves, locomotion, metabolism, anxiety, exploration, and pain. This review will briefly touch upon the classic literature for primary components of the brainstem breathing control circuit and then highlight examples of these recent studies that reveal how breathing is re-purposed or aligned with other behavioral outcomes.

The preBötC primarily serves to pace breathing, but it also plays a central role in behaviors that utilize the breath, like vocalization.

The preBötC is the initiator of each inspiration and is thought to set the pace of breathing. The preBötC is a heterogenous collection of excitatory and inhibitory neurons that project to the premotor neurons controlling breathing muscles that produce inspiration2,4,6. They are pre-premotor neurons. Many preBötC neurons show spikes of action potentials during inspiration and a subset even become active just preceding the onset of inspiration. The preBötC is necessary to breathe as its activity generates breathing, and a nascent breathing rhythm persists when all other sensory feedback and other brainstem breathing circuit components are removed8–11. And lastly, the preBötC can produce an autonomous rhythm when explanted in vitro12. The rhythmic capacity stems from recurrent excitation among a specialized group within the preBötC13,14 that can be influenced by either neuronal membrane or synaptic properties15,16. These preBötC characteristics solidify its role for pacing and patterning breathing.

Beyond basic breathing, recent studies have identified an important additional role of the preBötC in phonation17–20 (Fig. 2). This is highlighted to illustrate that the brainstem breathing control circuit is engaged as opposed to bypassed in voicing. Sound is produced by the closure of the laryngeal membranes in the upper airway (“voice-box”) immediately following inspiration, the post-inspiration phase of the breath. In rodents, this streamlines and speeds up the airflow that collides with the laryngeal cartilage to produce an ultrasonic frequency whistle. Upstream midbrain vocalization neural circuits induce the phonation behavior by, in part, activating the premotor neurons that close the larynx19,20. One role of the preBötC is to rhythmically inhibit the vocalization premotor neuron which momentarily pauses the laryngeal closure and reverses the airflow to inspire (Fig. 2A). Essentially, the larynx premotor neurons are instructed to continuously vocalize and the preBötC chops this action into individual breaths that contain sounds.

Figure 2. The preBötC momentarily pauses vocalization commands to produce repeated sounds and syllables.

Figure 2.

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A. Left, the vocal command produces a continuous sound that extends the expiration airflow. Right, the preBötC induces an inspiration (blue bracket) and also phasically inhibits this vocalization command to produce multiple breaths containing vocalizations, and thus, repeated sounds19,20. I, inspiration. E, expiration.

B. The intermediate Reticular Oscillator (iRO) vocalization central pattern generator produces single breaths with syllables by rhythmically engaging the preBötC and laryngeal motor neurons (MNs). Each cycle, the iRO momentarily activates the preBötC to pause expiration (blue bracket) and then drives laryngeal MNs to produce sound17.

A second role of the preBötC in phonation is to pause the vocalization within the breath or to modulate the pitch of the sound as a means to produce syllables and intonation, respectively17,18. In these instances, the preBötC is co-opted by an adjacent vocal pattern generator, called the intermediate Reticular Oscillator (iRO), that ectopically activates the preBötC during the expiration phase of the vocal breath to re-engage the muscles of inspiration which then antagonizes and pauses the expiratory airflow (Fig. 2B). The momentary decrease in airflow can either stop sound production, resulting in discrete syllables, or can lower the pitch of the sound. Basically, the preBötC is ectopically engaged during the vocalization as a mechanism to silence or shift the expiratory airflow and, thus, the sound produced by the larynx. This enables the production of complex patterns of phonation.

This review will not discuss studies that outline the roles of the preBötC in other behaviors like whisking, licking, nose movement, blood pressure, and brain-wide arousal state21–25.

The pH sensitive retrotrapezoid nucleus drives baseline breathing, carbon dioxide hyperventilation, and locomotion induced hyperpnea.

A key homeostatic signal for breathing is CO2/H+. Hypoventilation decreases CO2 release from the lung which acidifies the blood, and this induces hyperventilation as a means to return pH to equilibrium (the hypercapnic ventilatory reflex, HCVR)26. This reflex arises from a small collection of glutamatergic medullary brainstem neurons defined by expression of the Neuromedin B peptide, dubbed the retrotrapezoid nucleus (RTN). RTN neurons directly stimulate the preBötC (thus breath rate and depth) with glutamate and neuropeptides when the G-protein coupled receptor (Gpr4) and a potassium channel (Task-2) are acidified3,27–29. Also, the RTN projects to the entire breathing control circuit, and plays an important role in promoting and stabilizing the regularity of basal breathing29.

Recently, the RTN has been demonstrated to increase breathing during exercise and locomotion (Fig. 3). Surprisingly, this function occurs at the onset of movement in “anticipation” to any exercise induced metabolic changes30,31. Clever in vitro studies have shown that pharmacological, electrical, and optogenetic stimulation of the spinal cord locomotor central pattern generator increases the speed of the brainstem generated breathing rhythm which depends upon the RTN32,33 (Fig. 3B). Consistently, chemogenetic inhibition of the RTN reduces the respiratory rate during locomotion30,34 (Fig. 3C). This phenomenon is established by lumbar neurons that ascend the spinal cord and synapse upon the RTN. It is likely that the powerful ability of the RTN to stimulate breathing will be used in other natural behavioral contexts, and a research area with an emerging connection is sleep29. Note, locomotion hyperpnea also emerges via excitatory drive from the cuneiform nucleus in the mesencephalic movement command region to the preBötC30.

Figure 3. The retrotrapezoid nucleus (RTN) is activated by the spinal cord locomotor system to stimulate breathing at movement onset.

Figure 3.

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A. The RTN is activated by glutamatergic spinal cord locomotor neurons to stimulate the breathing control circuit rhythm and motor output. VRG, ventral respiratory group; premotor neurons. MNs, breathing motor neurons. vglut2, vesicular glutamate transporter 2.

B. Schematic of brainstem / spinal cord in vitro studies to demonstrate the locomotor central pattern generators (CPGs) can stimulate breathing control circuits. Left, the breathing rhythm is recorded by the cervical rootlet (C4) and two lumbar rootlets (L2 and L5) show coordinated rhythmic activity at baseline. Isolated pharmacological stimulation of the lumbar locomotor CPG increases the speed of C4 activity32. Right, optogenetic stimulation of the brainstem vglut2 expressing breathing control circuit increases C4 activity without changes lumbar locomotor activity. Optogenetic stimulation of the lumbar vglut2 neurons induces a locomotor rhythm and increases the in vitro breathing rhythm33. ChR2, Channel Rhodopsin 2.

C. Animal running on a treadmill before and then after chemogenetic inhibition of the RTN30.

The pontine Kölliker-Fuse and Parabrachial nuclei are a hub for polymodal control of breathing and the forebrain.

The pontine region containing the parabrachial (PBN) and Kölliker-Fuse (KF) nuclei projects throughout the entire brainstem breathing control circuit and modulates it in many ways. For example, focal excitation of small compartments within the PBN/KF can increase or stop breathing, prolong inspiration, make a breath larger, or have no effect at all35. The KF is characterized as an “inspiratory off-switch” with an apparent role in generating the post-inspiration phase of the breath in reduced animal preparation36,37. But the PBN/KF is responsible for far more than breathing and is instead more broadly viewed as a hub to transform sensory signals from the body and transmit them throughout the brain. The PBN/KF contains 10 subdivisions based on cytoarchitectural criteria with primarily glutamatergic neurons, and recently, single cell sequencing, spatial transcriptomics, and transgenic/viral studies have identified 21 molecularly distinct neural clusters38.

Two portions of the PBN/KF coordinate the breathing and arousal from sleep that occurs from elevated CO2 (Fig. 4A). Such an event might arise during the slow and shallow breathing during sleep apnea. The PBN external lateral and adjacent KF contain neurons that express the neuropeptide Calcitonin gene-related peptide (Calca or CGRP) that promote arousal from sleep and the neurons in the dorsal and ventral lateral regions contain the transcription factor Forkhead box 2 (Foxp2) and increase the speed of breathing during sleep upon elevation of CO2. Foxp2 neurons project to the medullary breathing control circuit (NTS, preBötC)39, while Calca neurons induce arousal via connections to the basal forebrain, central amygdala (CeA), and lateral hypothalamus40. Thus, these two anatomically and molecularly distinct PBN groups are activated when CO2 is increased most likely via direct excitatory input from the RTN, and each contributes to the behavioral response to elevated CO2 during sleep39.

Figure 4. The parabrachial nucleus coordinates brain states and emotions with breathing via ascending and descending projections.

Figure 4.

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A. Left, subregions of the parabrachial nucleus where Calca neurons with ascending projections (blue) and Foxp2 neurons with descending projections (yellow) to the breathing control circuit reside. Combined, these two molecularly distinct cell types of parabrachial neurons are involved in the carbon dioxide induced breathing and arousal responses39,40. KF, Köllike Fuse nucleus. Parabrachial (PB) subnuclei: le, lateral external; ld, lateral dorsal; lv, lateral ventral. scvt, spinocerebellar ventral tract. II, lateral lemniscus. scp, superior cerebellar peduncle.

B. Two reciprocally connected μ-opioid receptor (Oprm1) expressing neurons coordinate elevations in breathing with pain and anxiety responses. Bottom, example data showing that optogenetic simulation of Oprm1 neurons with ascending projections to the central amygdala (CeA) increase breathing, pain, and have negative valence (red). Similarly, optogenetic stimulation of Oprm1 neurons with descending projections to the respiratory brainstem increase breathing, pain, and have a negative valence (purple). These two groups of neurons are reciprocally coupled and thereby coordinate breathing with emotion41.

Studies of the μ-opioid receptor (Oprm1) expressing PBN neurons have also characterized a role for distinct PBN neurons that coordinate a breathing response with a behavior, in this case, the hyperpnea that accompanies pain (Fig. 4B). This provides a link between the emotive components of pain and its accompanying physiological hyperpnea41. Some Oprm1 PBN/KF neurons project throughout the brainstem breathing control circuit (Oprm1 → breathing). Optogenetic and chemogenetic inhibition or excitation of them depresses basal breathing and ectopically speeds it up, respectively41. These neurons are reciprocally connected via glutamatergic synapses to nearby PBN/KF Oprm1 neurons that send ascending projections to brain regions such as the CeA. Experimental manipulation of the Oprm1 CeA neurons attenuates the affective but not perceptive components of pain and are necessary and sufficient for anxiety related behaviors. Thus, these two neural groups (Oprm1 → breathing and Oprm1 → CeA) simultaneously facilitate breathing and pain/anxiety. And, consistently, independent manipulation of either group modulates both breathing and pain/emotion.

These types of studies are the first-of-this-kind for the PBN/KF and are surely to spawn many future experiments to understand the interoceptive relationships between the physiology of breathing and behavior/emotion. A similar theme of ascending and descending projections has been shown for the PBN external lateral Tac1 expressing Calca non-expressing neurons42 and more like this are likely to be discovered.

Molecularly defined NTS neurons coordinate distinct respiratory reflexes

The brainstem nucleus of the solitary tract (NTS) serves as the point for airway and lung sensory afferents to enter the brain. The NTS then uses this information to adapt the breathing behavior via reflexes. These vagal afferents were classically categorized as slowly or rapidly adapting stretch receptors and bronchopulmonary C fibers, but recently, the vagal neurons have been extensively molecularly defined4 (PMID 35296859). Examples of this include distinct lung sensory neurons that express Transient receptor potential vanilloid 1 (Tprv1+), Parvalbumin+, or Piezo-type mechanosensitive ion channel component 2 (Piezo2+) that elicit cough, gasps, and shallower breaths / a lung stretch reflex43–46. It has become apparent that NTS interneurons can serve to integrate these sensory signals, in effect making a polymodal signature, and understanding how the breathing sensory information converges or diverges is an important next step.

Decades old electrophysiology recordings of NTS neurons demonstrated that certain neurons preferentially receive airway / lung sensory information. For example, neurons in the intermediate NTS dubbed pump-cells respond to airway stretch. These cells remain to be further characterized. Consistent with the physiology, recent studies have shown ~20 molecularly defined NTS neural types44–48 and that different NTS neurons in the caudal subregion receive unique sensory information and are involved in specific breathing behaviors. For example, Tachykinin 1 glutamatergic neurons respond to lung c-fiber tussive signals, they are necessary and sufficient for coughing, and they project upon brainstem regions that form the cough motor pattern44. And Gastrin releasing peptide neurons respond to carotid body hypoxia signals and induce sigh breaths via inputs to the brainstem breathing pacemaker43.

Note, the breathing control circuit receives other important sensory signals like those from the sensory trigeminal that have been shown to produce sneeze49,50 and the ammonia reflex51.

NTS feedforward hormone signaling increases breathing to maintain blood homeostasis when metabolism changes.

Beyond rapid reflexes, a recent example of hormone signaling within the NTS demonstrates a longer timescale feedforward regulation of breathing. The hormone Leptin is produced by white adipose fat tissue and Leptin-deficient obese mice hypoventilate and, as a result, have harmful acidic and increased carbon dioxide blood chemistry. When Leptin is present, the hormone depolarizes caudal Leptin receptor (LepR+) NTS neurons by increasing the conductance of the sodium leak channel Nalcn. LepR+ NTS neurons directly innervate the breathing premotor neurons and increase breathing and stabilize variability when active52. While there are many examples of the ability of the NTS to regulate respiratory reflexes (as described above), this new data demonstrates the importance of the NTS in regulating breathing physiology on longer timescales. Beyond the NTS, Leptin is proposed to also stimulate breathing via LepR+ dorsomedial hypothalamic neurons and the LepR+ carotid body oxygen sensitive cells53.

A “shortness-of-breath” sensation signal originates in the breathing control circuit.

Breathing is often subconscious, yet when stressed, it can become the only thing we are focused on. Shortness-of-breath or dyspnea is the feeling of running out of air or a sense of suffocation. This impacts millions of people, and beyond treating the underlying cause, there are limited therapeutics. The three substrates for this sensation are elevated blood CO2, chest tightness, and increased work of breathing54. The former two arise from chemosensory systems for CO2 and lung stretch. While the latter originates as an efferent copy signal from the breathing control circuit. This peripheral sensory signal is compared to the efferent copy and a mismatch creates the sensation of an increased “effort to breathe”. These three dyspnea substrates converge on the same higher order brain structures within the emotional circuits of the brain like the limbic system and insular cortex where it is believed the feeling of dyspnea is created55,56.

Recent studies in human neurosurgery / epilepsy patients have identified a region of the amygdala that upon stimulation produces prolonged apnea coupled with a significant drop in blood oxygen57,58. And, a seizure within this same region is thought to pause breathing. Surprisingly, the long pause in breathing from amygdala stimulation does not evoke dyspnea or air hunger. This contrasts with the breathlessness described for a protracted volitional breath hold. These observations have sparked a proposed mechanism whereby the subregion of the amygdala provides descending inhibition to the brainstem breathing control circuit that stops both breathing and CO2 stimulated shortness-of-breath59. Individuals with anxiety have altered amygdala activity and a hypersensitive response to elevated CO2, so characterization of an amygdala – CO2 relationship will result in important insights for the mechanism(s) of how interoceptive stimuli evoke arousal / anxiety / dyspnea. In one model, periodic amygdala activity pauses breathing resulting in hypercapnia, and this, coupled with CO2 hypersensitive emotional circuits, leads to episodes of anxiety / panic59.

Perspective on several puzzles.

The field of neural control of breathing is at a moment where the principles learned from the historical studies that exploited brain slice electrophysiology and whole animal in vitro physiology can now be re-explored in an awake behaving animal. The combination of multiunit neural recordings in the brainstem, mouse genetics and viral payloads, optogenetics, and the ability to measure breathing during complex behavioral assays has transformed the future. In the coming years, we will begin to understand how the brainstem breathing control circuit integrates with the body’s peripheral sensory signals and interacts with suprapontine structures like the amygdala, hypothalamus and cortical areas to directly or indirectly regulate emotions like calmness and anxiety and to be volitionally controlled. Other critical research avenues will be to understand the role of the many neuromodulators and hormones and the corresponding receptors that are expressed throughout the breathing control circuit. For example, progesterone in the early stages of pregnancy and the luteal phase of the menstrual cycle induces hyperventilation and a concomitant sensation of dyspnea60. Characterizing these modulators will undoubtedly result in new mechanistic pharmacological approaches to control breathing. And lastly, state-of-the-art mouse and human research can complement each other to provide deep insight into devastating breathing pathologies like sudden unexpected death, congenital hypoventilation, and opioid overdose.

Highlights: Recently identified properties of the breathing control circuit.

  • The breathing pacemaker is used to form complex sounds during vocalization.

  • The primary chemosensor is re-purposed to stimulate breathing during locomotion.

  • The parabrachial nucleus forms a hub to connect breathing and emotion.

  • The nucleus tractus solitarius coordinates breathing and metabolism.

Acknowledgments:

Funding:

This work was supported by the NINDS R01 NS126400, NIDA R01 DA054954–01A1, the Klingenstein Foundation.

Footnotes

Competing interests: Authors declare no competing interests.

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