Braintem Centres in Respiration

Introduction to Respiration

Respiration_(physiology) is the only behaviour present in mammals that requires the use of skeletal muscles continuously. At rest, it is responsible for the consumption of approximately 7% of total metabolic output of the body1. The longstanding hypothesis underlying the regulation of respiration was that a single rhythm generator was responsible for producing the two phases of respiration; inspiration, or inhalation, and expiration, or exhalation. In this system, the single oscillator with intrinsic activity times the cycle with appropriate output to various inspiratory and expiratory motoneurons. However with decades of experimentation and discoveries in the field of respiration neurobiology there has been movement towards a multi-centred model. In this model the intrinsic activity of the centres regulating respiration oscillate through phases and activate the appropriate inspiratory and expiratory motoneurons. This mutli-centred model offers that there exist a number of centres in the brainstem requiring mutual synaptic inhibition between to produce phasic breathing. The complexity in the neural regulation of phasic breathing has since been found to result not only from the eloquent relationships between higher function of centres in the lower brain, but is also due to the rich heterogeneity in types of the respiratory motoneurons, or motor_neurons that dominate in their sequence. Although much has been discovered, there still is no consensus on the true functionality of the Central Pattern Generator (CPG). As such, this neurowiki will attempt to outline the most likely theory with the most contemporary evidence.

A Few Definitions…

Unconscious breathing is produced and regulated by cells of the brainstem. It is a rhythmic motor behaviour organized by a CPG. This CPG is continuously modulating its output in response to gas exchange, but also the diversity in physiological and environmental restraints that can be imposed on the body. Thus far, oscillatory centres of the CPG are limited to the medulla with most residing in the Ventral Respiratory Column (VRC). The VRC can be anatomically divided into a number of regions including:

  • The Bötzinger Complex (BC)
  • The pre-Bötzinger Complex (pBC)
  • The Rostral Ventral Respiratory Group (rVRG)
  • The Caudal Ventral Respiratory Group (cVRG)

There are centres located outside of the column who provide both tonic and phasic drives to these columns and are also essential in rhythm and pattern formation, such as:

  • The paraFacial Respiratory Group (pFRG)
  • The Pontine Respiratory Group (PRG)

From this it is essential to note that there is a difference in the rhythm and pattern of respiration. The term rhythm will be used to refer to the intrinsic ability to produce respiration quantitatively, while pattern is the way in which respiration occurs qualitatively.

Functional Identifications:

In order to adequately cover this topic, each of the areas of the brainstem implicated in respiratory rhythm or pattern formation will be functionally identified with evidence from the literature.

The Breathing Brainstem
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Critical areas regulating the respiratory rhythm and pattern are outlined in this diagram.
The left structure shows an axial view of the brainstem with the pFRG, while the right
structure displays the PRG, BC, pBC, rVRG and cVRG in a coronal view.

The paraFacial Respiratory Group (pFRG)

The first of the distinct regions of the medulla named in rhythmogenesis is the pFRG also referred to as the Retro Trapezoidal Nucleus (RTN). A group of cells localized in the pFRG of an in-vitro brainstem was discovered to have properties as pre-inspiratory neurons firing milliseconds before respiration occurred, measured via the phrenic nerve2. The intrinsic activity of these neurons was then tested and confirmed3. As a critical centre controlling rhythmogenesis theory dictates that either lesion or blockade of such an area should produce apnea, or an outright arrest in breathing. In saporin-induced destruction of the pFRG, apnea resulted suggesting this area as having an essential role in the CPG4. However, as apnea, and not a complete cessation in breathing was found, this lends proof to the multi-centred model of the CPG. This is because in absence of the pFRG other areas in the brain are capable of producing a rhythm, albeit an ataxic one.

The pre-Bötzinger Complex

The second oscillator is the pBC, anatomically defined to the VRC. Using in-vitro methods, cells of this region were found to have endogenous properties as pacemakers. This means that they were capable, when isolated, of generating bursts of activity resembling a respiratory rhythm5. Predominately glutamateric in nature pBC cells facilitate excitation for generation of respiration. The pacemaker cells identified in the pBC have vary in their performance. The timing of their discharge differs; some active during inspiration and others expiration. One population of pBC pacemaker cells are considered pre-inspiratory in nature, like the pFRG, firing just before inspiration occurs6. Other neuronal types have been identified including three of the inspiratory variety and two that are expiratory cells7.
The presence of cell types within the pBC lends strong proof to this centre as an essential area for rhythmogenesis. Containing cells to stimulate both phases of respiration would be highly advantageous. These excitatory neurons of the pBC were found to have specific thresholds. Over and under these limitations of the cells dyspnea and apnea occurred8. Similarly to the pFRG destruction of the pBC by somatostatin resulted in apnea, a desirable response when hypothesising an area of the brain as a rhythmogenic centre9. Thus, the pBC appears to be another centre present in the brainstem having essential function within the CPG.

The Bötzinger Complex

Located in the medulla rostral to the pBC, the BC is yet another region of the VRC that has been found to have a role in the CPG. Containing bulbospinal neurons the BC makes direct widespread monosynaptic connections to various centres in the medullary respiratory network. These neurons provide inhibition of both inspiratory and expiratory neurons present in the VRC, specifically in the pBC, during specific phases of expiration10. Although this cell group lacks the intrinsic ability to regulate the breathing rhythm itself, its activity is more so identified with the modulation of the pattern. However, it will later be seen that the neurons of the BC have essential function in modulation of breathing rhythm in relation to the pBC.

The Rostral Ventral Respiratory Group

The rVRG is an area of the VRC just caudal to the pBC composed mainly of bulbospinal neurons. It is responsible for relaying the inspiratory drive to phrenic motoneurons which activate the diaphragm during inspiration11. This makes the rVRG a premotor inspiratory centre.

The Caudal Ventral Respiratory Group

The cVRG is a centre of the VRC located caudally to the rVRG. Is also contains predomiantly excitatory bulbospinal neurons but unlike the rVRG, they are active during expiration12. The cVRG is an integration centre; it receives synapses from the pRFG and pBC such that the pattern of expiration is modulated13.

Pontine Respiratory Group

The PRG has long been known as an apneuistic centre in the brain. This means, that rather than shaping the rhythm of respiration it, like the BC, contributes to its pattern. By extension a lesion or blockade of such a centre should produce apneusis and dyspnea rather than apnea; the effect of which was seen in-vitro14. More recently, evidence has emerged adding a level of intrigue to the pons. Specific regions in the pons have been implicated for a role in the CPG for respiration. As such, the pons is now being reconsidered in the scope of the respiratory network. Current studies have shown that both lesioning and blockade of pontine regions result in apnea, rather than apneusis, a trait of essential rhythm oscillators15. Of the implicated regions is the Pontine Kölliker-Fuse nucleus (PFK). Both blockade and lesioning of the PFK showed a functional disruption of the breathing rhythm such that apnea occurred16,17. A centre with responsibilities in facilitating eupnea, specific sites of the PRG may also be responsible for rhythmogenesis in the CPG.

Cortical and Motor Integrations

In addition to these areas there is integration from areas of the brain providing conscious regulation of respiration. Of these is the Primary_motor_cortex. Projections from the primary, or somatic motor cortex have been found to provide a so-called, ‘wakeful stimulus to breathe’. This is mediated by descending motoneurons of the corticospinal tract whose excitatory output enhances the response of motoneurons of the Phrenic_nerve, facilitating voluntary and constrained inspirations18. The Basal_ganglia is also known to have a role in regulating respiration. Depending on the specific location of the basal ganglia that is stimulated, respiration frequency may increase or decrease19.

Theories of the CPG

The formation of the CPG itself is a controversial topic for modern respiration neuroscientists. A number of models have been proposed, involving both the inhibition and pacemaker hypotheses to explain the series of events that lead to inspiration.

An Emerging Model For Respiration

In this section we will attempt to outline the architecture of interacting populations of neurons in the major respiratory centres, whose main function is to provide both stability and adaptability to rhythmogenesis. The most recent perspective is that there are centres located bilaterally in the medulla which control the CPG. While the activity is both rhythmic and patterned as described previously, this section will address primarily the formation of the rhythm.

The Respiratory Network
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The details of major synaptic connections addressed in this neurowiki are summarized in this image. There
are both inhibitory and excitatory connections in the brainstem that are essential for respiratory rhythmo-
genesis. Major cell nuclei are labelled as grey boxes. Note the "ring" of inhibition present between the BC
and pBC.

A Source of Inspiration

In terms of inspiration, the pBC has typically been held at its command. An example of these neurons are the rhythmically active pacemaker cells of the pBC. These type 1 inspiratory neurons have been shown to make many synaptic connections, within the pBC and outside of20,21. These neurons have critical function in rhythmogenesis; lesioning of only 18% of the inspiratory neurons present in the pBC created a fatal disolution of the breathing rhythm22. One theory states that the pBC is at the core of the CPG. In this view, the pBC is only attentive to the formation of the breathing rhythm, but is indirectly responsible for the qualitative details of the respiratory pattern23. The signals that originate from the pBC then through widespread glutamateric projections maintain the pattern by communication throughout the respiratory network24.
While the pBC was previously believed to be the sole source of signal output, advances in the field have now shown that this is not the case. The functional identification of the pFRG, whose activity takes precedence just before the beginning of inspiration, maintains that it is a secondary stimulator of inspiration 2. To wholly test the operation of inspiration, studies with the injection of opiates into the pBC were performed. The result was a loss of the inspiratory phase of respiration. At this time areas located rostrally to the pBC become mandatory25,26.

The Role of Inhibition

Interestingly, inhibitory post-synaptic potentials have been reported in respiration-modulating neurons in-vivo during the waking state27. From these experiments, a ring of inhibition was found in-vivo and is formed from three distinct populations of neurons that reside in the pBC and BC. These neurons project onto one another to facilitate the sequential activation of the appropriate cell group of the CPG in the correct temporal sequence for eupnea28. Each of the cell groups are believed to be excitatory in their outputs for inspiration29.

To explore the idea of group-inhibition a more recent study explored the effect of blockade of GABAA and glycine receptors in-vivo. Despite this blockade, an axtaxic breathing rhythm prevailed30. Although these results may be confusing to interpret what is essential to understand is that the pBC is just one of the proposed centres in the CPG. This study gives rise to what is known as the group-pacemaker hypothesis, where a number of centres in the brainstem, each with intrinsic activity, is capable of generating some fraction of the breathing rhythm. This means that when synaptic inhibition is disrupted between mutual groups, two other distinct regions are capable of maintaining respiration. However, this rhythm is in disarray, and may not produce a functional respiratory pattern in-vivo capable of sustaining life27. It is then evident that inhibition is crucial for respiratory motoneuron output and therefore pattern formation but not for rhythm formation itself.

The Emergence of Expiration

As the respiratory pattern is known to be active during inspiration and passive during expiration much of the focus have been on the source of inspiration while ignoring the complementary phase. Although the pBC has been identified as containing populations of expiratory neurons, the revelation of the existence of a back-up source of inspiration questioned the same for expiration7. Additional research indicated the pFRG in the generation of active expiration, where transection experimentations in the brainstem in the juncture of the pFRG found a cessation of active expiration. It was also found in this experiment that there were insignificant effects on the inspiratory phase when the pBC was in tact, further validating this centre for inspiration (Jancweski and Feldman, 2006)29. This region was then confirmed as an independent centre for rhythmogenesis when optogenetic-based stimulation of the pFRG facilitated the transformation of a breathing pattern indicative of the resting state to one owing of active expiration31.

One Last Circuit

The next essential component of the functional map is the connection present between the pBC and the pFRG. Excitatory, glutamate-expressing neurons of the pBC synapse onto the pFRG where glutamatergic, galanin-expressing cells project back to the pBC23,32. The role of these interconnecting neurons in rhythm generation have yet to be fully established but this connection seems promising.

The neural regulation of respiration is an interesting, yet highly complicated topic. In any case, it is evident that although much work has been done to better understand the breathing rhythm, there is much more which stands to be discovered.

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