Tirumalai Kamala’s answer:
- Mammals primarily sense O2 and CO2 through specialized chemoreceptors located inside the (1, 2), a specialized tissue near the carotid artery bifurcation innervated by the glossopharyngeal nerve fibers (3, 4).
- won the Nobel Prize in Physiology and Medicine in 1938 for discovering the carotid body.
- Downstream brainstem neurons (5, 6, 7) sense local changes in pH when CO2 is converted to bicarbonate, this in mammals in general, i.e. in both mice and humans.
Do mice sense CO2 with their ears?
- Data from only one group so far suggests so.
- Two peer-reviewed papers (8, 9).
- Intra-tympanic gentamycin injections to induce inner ear damage.
- Such injections damage inner ear neurons and vestibular cells (authors refer to several older studies by others who developed this experimental procedure).
- 7 days after damage, authors exposed mice to 8% CO2 inhalation (5% in the 2nd study), and tested their respiratory response.
- When exposed to 8% CO2, respiratory response increased in control mice, and remained unchanged in inner-ear damaged mice.
- According to authors, brainstem is involved in this process
Problems with these two two mouse model studies
- Done by the same group; 2011 study cited 6 times; 2013 study not yet cited by others.
- Data need to be independently confirmed.
- Studies performed on mouse pups (babies): they were 17 days old at the time the researchers damaged their ears. Mice are usually weaned only at 21 to 27 days of age so these were pre-weaned babies. Presumably, researchers chose to test at such young age because they are trying to develop a mouse model for SIDS (Sudden Infant Death Syndrome). Can’t extrapolate these data to adults.
- The researchers chose to test respiratory response to 8% (or 5%) CO2. This is 400X (or 125X) higher than atmospheric CO2 (0.04%). Mice are much more sensitive to CO2 than humans, capable of sensing near-atmospheric levels while humans can’t smell CO2 concentrations as high as 30% (10). Why test at such high CO2 concentrations? Not clear. In any case, such a high CO2 concentration renders their studies non-physiological.
- Following mouse inner ear damage by intra-tympanic gentamycin, they found modest reduction in only one subset of ear neurons, the LVN, Lateral Vestibular Neurons. Is such modest neuronal damage necessary and sufficient for the reported difficulty of inner-ear damaged mice in sensing CO2? Maybe intra-tympanic gentamycin, at least the concentrations these authors used, damages other, deeper tissues as well? Open questions.
Human data: Some hints that ears are involved in respiratory rhythm but not much data on CO2 sensing
- Study (11) on 9 healthy young adults subjected to ‘buffeting’ inside cars. All breathed more frequently during buffeting.
- Follow-up study (12) on 5 normal elderly patients, 2 with bilateral loss of vestibular function and 5 with BPPV (Benign Paroxysmal Positional Vertigo; when patients with this condition move their head, they have hyperactive vestibular function). Hearing-impaired subjects were more anxious and breathed more frequently during buffeting.
- One study (13) compared the respiratory rhythm of acute vestibular neuritis patients and normal subjects in response to changes in posture. Switching from supine to sitting-up position reduced respiratory frequency and increased expiration time in normal subjects but not in acute vestibular neuritis patients.
- Another study (14) suggests that rotation (in a chair) activates the ear’s horizontal semicircular canals, which in turn increases breathing rate.
- A study (15) of 9 healthy, young adults; Compared role of semicircular canals versus otolith organs in breathing. Concluded former but not latter involved in breathing rate increase.
- 121 patients with dizziness (16). Arterial blood gas analysis showed abnormalities. Increase in bicarbonate (n = 57), increase in bicarbonate and arterial CO2 pressure (n = 8), low arterial O2 pressure (n = 22). Weakness of the study: Presumably blood gas numbers compared to historical, and not contemporaneous, data from normal subjects.
- 18 healthy subjects and 6 patients with bilateral loss of vestibular function (17). Subjects made to stand on a rotating platform and subjected to whole-body oscillation. Respiratory frequency increased in healthy, but not ear-damaged, subjects.
- Defective and/or abnormal response to O2 and CO2 implicated in cancer, neurodegeneration, panic attacks (18, 19, 20).
OTOH, there is much better substantiated data that, unlike humans (see caveat below), mice smell and taste atmospheric CO2. Data for possible biochemical pathways involved in mouse smelling and tasting CO2 also better worked out using gene knockout studies.
How do mice smell or taste CO2
- Compelling and better substantiated data (21) that a subset of olfactory neurons (GC-D+ neurons) are capable of sensing near-environmental concentrations of CO2.
- These neurons express CO2-catalyzing enzyme carbonic anhydrase II (CA II) and transmembrane receptor guanylate cyclases, responsive and modulated by bicarbonate.
- In this study, the fluorescent protein called EGFP (Enhanced Green Fluorescent Protein) was expressed under the control of guanylate cyclase promoter.
- EGFP+ GC-D neurons stimulated with CO2 induced rise in intracellular calcium.
- This rise in intracellular calcium was blocked by CA (Carbonic Anhydrase) inhibitors.
- Mice that lack CA II (Car2 knockout mice) have reduced behavioral responses to CO2 compared to wild-type mice.
- Working model for how mice can smell and taste CO2 (20).
Mouse nose receptors detect long-range, and taste receptors short-range, CO2. Caveat is similar receptors may be present in humans. For one thing, we know CO2-sensing taste receptors exist in humans. They are the ones that taste carbonated drinks.
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