By Dillon Lim - Medicine Student @ Brasenose College, Oxford
N.B. We use breathing, ventilation and respiration interchangeably here; respiration is definitely not the cellular respiration used to produce ATP!
Breathing is controlled by complex neural networks within the more primitive brain. The activity of these neurons controls the rate of ventilation based on signals coming from receptors in the brain, near blood vessels, and in the respiratory vessels themselves. These include chemoreceptors, which are sensitive to blood pH and gas concentrations, as well as mechanoreceptors, which detect stretch in pulmonary and respiratory tissues.
The basal rate of ventilation is around 12 breaths a minute. This control is conducted by specific areas of the pons and medulla in the brain. Neurons here often display consistent changes in their firing activity at different stages of the respiratory cycle (breathing in and out) and are therefore described as “respiratory-related”. The control of breathing is an incredibly complex activity for the brain to handle. A “central pattern generator” needs to be able to coordinate inputs from the rest of the body about its metabolic status and the concentrations of O2/CO2 in the blood, as well as be able to adjust breathing patterns to deal with things like speaking, eating and swallowing. It has been suggested it is possible that multiple such pattern generators exist which take over in different situations, but one structure that almost certainly plays a key role is called the pre-Bötzinger complex, which has many respiratory-related neurons.
Experimentally ablating it leads to loss of breathing rhythm and a decrease in the amplitude of breathing. Working out all the neural circuits and centres involved here requires more work.
Chemoreception (detection of chemical signals) to regulate breathing takes place both peripherally and centrally. Peripheral chemoreceptors are located at aortic and carotid bodies (i.e., small structures at the aorta and at the carotid arteries), to ensure that blood to the brain has gone through adequate gas exchange in the lungs. These bodies are made up of glomus cells and send sensory signals back towards the brain. Glomus cells are primarily sensitive to hypoxaemia (low O2 in the blood), although they may detect hypercapnia (high CO2) and acidosis as well; hypercapnia and acidosis may also further sensitise the hypoxic response. In response to these stimuli, the brainstem acts to increase ventilation to return to what we call a “normoxic” state. We’re not too sure how the glomus cells do this, but it might well be to do with changes in their metabolism that result from decreased oxygen levels.
Experimentation on dogs in the 1950s showed that even after denervation (cutting off the nerve supply) of the glomus cells, infusion of an acidic solution across the brain resulted in an increase in ventilation. This led us to realise that chemoreception takes place centrally too. Here it takes place via sensing of hypercapnia ‘via’ acidosis. Protons cannot easily diffuse across the blood brain barrier to the brain’s extracellular fluid, but CO2 can; CO2 dissolves and equilibrates releasing H+, causing a rapid drop in the ECF’s pH. This is especially marked since unlike the blood, the brain’s ECF is not well pH buffered.
Finally, there are also mechanoreceptors involved in the control of breathing – nerves which send information back to the brain about e.g. stretch or distention in the walls of bronchioles. Mechanoreception is particularly important in things like asthma or anaphylaxis, where bronchiolar constriction takes place before there is a change in blood gas levels. There are three types of fibres: slowly adapting, rapidly adapting, and juxtacapillary. Mechanoreceptors might really be a bit of a misnomer, because both rapidly adapting and juxtacapillary receptors appear to respond at least partially to chemical signals as well! The importance of the contribution of these fibres is still unclear, and their role has been less well studied than that of the chemoreceptors.
Further reading:
Respiration control. https://courses.lumenlearning.com/boundless-ap/chapter/respiration- control/
Chapter 9. Control of Breathing. https://accessmedicine.mhmedical.com/content.aspx?bookid=575§ionid=42512987
Physiology for practice: the mechanisms controlling respiration. https://www.nursingtimes.net/clinical-archive/respiratory-clinical-archive/physiology-for-practice-the-mechanisms-controlling-respiration-14-10-2003/