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Hypoxemia from exposure to intermittent and/or acute environmental hypoxia (lower oxygen concentration) is a severe stressor for many animal species. The response to hypoxia of the hypothalamic-pituitary-adrenal axis (HPA-axis), which culminates in the release of glucocorticoids, has been well-studied in hypoxia-intolerant surface-dwelling mammals. Several group-living (social) subterranean species, including most African mole -rats, are hypoxia-tolerant, likely due to regular exposure to intermittent hypoxia in their underground bur-rows. Conversely, solitary mole-rat species, lack many adaptive mechanisms, making them less hypoxia-tolerant than the social genera. To date, the release of glucocorticoids in response to hypoxia has not been measured in hypoxia-tolerant mammalian species. Consequently, this study exposed three social African mole-rat species and two solitary mole-rat species to normoxia, or acute hypoxia and then measured their respective plasma gluco-corticoid (cortisol) concentrations. Social mole-rats had lower plasma cortisol concentrations under normoxia than the solitary genera. Furthermore, individuals of all three of the social mole-rat species exhibited signifi-cantly increased plasma cortisol concentrations after hypoxia, similar to those of hypoxia-intolerant surface -dwelling species. By contrast, individuals of the two solitary species had a reduced plasma cortisol response to acute hypoxia, possibly due to increased plasma cortisol under normoxia. If placed in perspective with other closely related surface-dwelling species, the regular exposure of the social African mole-rats to hypoxia may have reduced the basal levels of the components for the adaptive mechanisms associated with hypoxia exposure, including circulating cortisol levels. Similarly, the influence of body mass on plasma cortisol levels cannot be ignored. This study demonstrates that both hypoxia-tolerant rodents and hypoxia-intolerant terrestrial laboratory-bred rodents may possess similar HPA-axis responses from exposure to hypoxia. Further research is required to confirm the results from this pilot study and to further confirm how the cortisol concentrations may influence responses to hypoxia in African mole-rats.

At the onset of entrance into hibernation in many mammals, there is a reduction in the respiratory exchange ratio (RER) thought to result in a retention of CO2 that contributes to the ensuing metabolic suppression. In steady-state hibernation, the relative hypercapnic ventilatory response (HCVR; the % change in ventilation to CO2 exposure) is elevated. These two observations, paradoxically, suggest a transient decrease in CO2 sensitivity at the onset of entrance into hibernation, allowing the retention of CO2, then a subsequent increase in CO2 sensitivity giving rise to the elevated HCVR in steady-state hibernation. We examined the time course of the changes in ventilation, O2 consumption rates ([Formula: see text]o2), CO2 excretion rates, body temperature, and hence the RER and ACR (air convection ratio, ventilation/[Formula: see text]o2) and the HCVR throughout entrance and arousal into and out of hibernation in 13-lined ground squirrels to confirm this. We observed a significant drop (entrance) and rise (arousal) in the RER produced by hypo- and hyperventilation, respectively. CO2 chemo-sensitivity while the RER was reduced on entrance was blunted and rose late in entrance. On arousal, CO2 chemo-sensitivity was elevated when the RER was elevated and fell immediately after RER returned to normal values. At any given Tb, the HCVR was lower during entrance compared to arousal producing a significant hysteresis. The HCVR, however, was the same at any given [Formula: see text]o2 during entrance and arousal. These data suggest that both the changes in [Formula: see text]o2 and in the HCVR are associated with changes in central regulation of the effector limbs establishing steady-state hibernation.

This collection of research articles was put together in honour of respiratory physiologist Professor Peter Frappell’s (Frapps’s) academic achievements. It encompasses various topics relating to the oxygen transport cascade, which was central to Frapps’ career as a comparative physiologist. This issue highlights the diversity and outreach of his influence on the field and his pioneering spirit; promoting novel perspectives, methodologies and research techniques. This issue also demonstrates how Frapps’ knowledge and scientific findings answered some of the fundamental questions within the field of respiratory physiology while creating and fostering a rather unique work atmosphere in the laboratories he led. We thank Frapps for the contributions he has made and the friendships he has nurtured over his career. Cheers, Frapps – we love you mate!

Over the past decade, Peter Frappell, aka Frapps, has been an integral part of an international group studying birds that migrate or reside at altitude. This research has taken the extended group from Terkhiin Tsagaan Lake on the Mongolian plateau to Chilika Lake in eastern India, Koonthankulum bird sanctuary in southern India, Lake Qinghai in Chinese Tibet, Summer Lake Wildlife and Malheur National Wildlife Refuge in Oregon, and San Pedro a Marca, Vichaycocha and Lake Titicaca National Reserve in Peru. It has been a productive project producing over 30 manuscripts, 15 of which were based on research in the field. What has not been published are the stories behind the research and the critical lessons learned along the way. Some of these are chronicled here.

The ectothermic vertebrates are a diverse group that includes the Fishes (Agnatha, Chondrichthyes, and Osteichthyes), and the stem Tetrapods (Amphibians and Reptiles). From an evolutionary perspective, it is within this group that we see the origin of air-breathing and the transition from the use of water to air as a respiratory medium. This is accompanied by a switch from gills to lungs as the major respiratory organ and from oxygen to carbon dioxide as the primary respiratory stimulant. This transition first required the evolution of bimodal breathing (gas exchange with both water and air), the differential regulation of O2 and CO2 at multiple sites, periodic or intermittent ventilation, and unsteady states with wide oscillations in arterial blood gases. It also required changes in respiratory pump muscles (from buccopharyngeal muscles innervated by cranial nerves to axial muscles innervated by spinal nerves). The question of the extent to which common mechanisms of respiratory control accompany this progression is an intriguing one. While the ventilatory control systems seen in all extant vertebrates have been derived from common ancestors, the trends seen in respiratory control in the living members of each vertebrate class reflect both shared-derived features (ancestral traits) as well as unique specializations. In this overview article, we provide a comprehensive survey of the diversity that is seen in the afferent inputs (chemo and mechanoreceptor), the central respiratory rhythm generators, and the efferent outputs (drive to the respiratory pumps and valves) in this group.

We investigated the extent to which the facultative air-breathing fish, the striped catfish (Pangasianodon hypophthalmus), uses air-breathing to cope with aquatic hypercarbia, and how air-breathing is influenced by the experimental exposure protocol and level of hypercarbia. We exposed individuals to severe aquatic hypercarbia (up to PwCO2 = 81 mmHg) using step-wise and progressive exposure protocols while measuring gill ventilation rate, heart rate, mean arterial blood pressure, and air-breathing frequency, as well as arterial blood pH and PCO2. We confirm that P. hypophthalmus is tolerant of hypercarbia. Under both protocols gill ventilation rate, heart rate, and mean arterial blood pressure were maintained near control levels even at very high CO2 levels. We observed a marked amount of individual variation in the PwCO2 at which air-breathing was elicited, with some individuals not responding at all. The experimental protocol also influenced the onset of air-breathing. Air-breathing began at lower PwCO2 in the step-wise protocol (23 ± 4.1 mmHg) compared with the progressive protocol (46 ± 7.8 mmHg). Air-breathing was often followed by aquatic surface respiration, at higher PCO2 (71 ± 5.2 mmHg) levels. On average, the blood PCO2 was approximately 43% lower (46 ± 2.5 mmHg) than water PwCO2 (~81 mmHg) at our highest tested CO2 level. While this suggests that aerial CO2 elimination is an effective, and perhaps critical, respiratory strategy used by P. hypophthalmus to cope with severe hypercarbia, this observation may also be explained by a long lag time required for equilibration.

We examined the morphology of the lungs of five species of high‐altitude resident ducks from Lake Titicaca in the Peruvian Andes (yellow‐billed pintail [Anas georgica], cinnamon teal [Anas cyanoptera orinomus], puna teal [Anas puna], speckled teal [Anas flavirostris oxyptera], and ruddy duck [Oxyura jamaicensis ferruginea]) and compared them with those of the high‐altitude migratory bar‐headed goose (Anser indicus) and the low‐altitude migratory barnacle goose (Branta leucopsis). We then determined the relationship between mass‐specific lung volume, the volume densities of the component parts of the lung, and previously reported hypoxia‐induced increases in pulmonary O(2) extraction. We found that the mass‐specific lung volumes and the mass‐specific volume of the exchange tissue were larger in the lungs of high‐altitude resident birds. The bar‐headed goose had a mass‐specific lung volume that fell between those of the low‐altitude species and the high‐altitude residents, but a mass‐specific volume of exchange tissue that was not significantly different than that of the high‐altitude residents. The data suggest that the mass‐specific volume of the lung may increase with evolutionary time spent at altitude. We found an inverse relationship between the percentage increase in pulmonary O(2) extraction and the percentage increase in ventilation across species that was independent of the volume density of the exchange tissue, at least for the resident Andean birds.

The ability to respond rapidly to changes in oxygen tension is critical for many forms of life. Challenges to oxygen homeostasis, specifically in the contexts of evolutionary biology and biomedicine, provide important insights into mechanisms of hypoxia adaptation and tolerance. Here we synthesize findings across varying time domains of hypoxia in terms of oxygen delivery, ranging from early animal to modern human evolution and examine the potential impacts of environmental and clinical challenges through emerging multi-omics approaches. We discuss how diverse animal species have adapted to hypoxic environments, how humans vary in their responses to hypoxia (i.e., in the context of high-altitude exposure, cardiopulmonary disease, and sleep apnea), and how findings from each of these fields inform the other and lead to promising new directions in basic and clinical hypoxia research.

Background: Perfusion of intrapulmonary arteriovenous anastomoses (IPAVA) is increased during exercise and in hypoxia and is associated with variations in oxygen saturation (SPO2), resulting in blo...

At the onset of entrance into hibernation in many mammals, there is a reduction in the respiratory exchange ratio (RER) thought to result in a retention of CO

The aim of this study was to corroborate the presence of CO2/H+-sensitive arterial chemoreceptors involved in producing air-breathing responses to aquatic hypercarbia in the facultative air-breathing clown knifefish (Chitala ornata) and to explore their possible location. Progressively increasing levels of CO2 mixed with air were injected into the air-breathing organ (ABO) of one group of intact fish to elevate internal PCO2 and decrease blood pH. Another group of fish in which the gills were totally denervated was exposed to aquatic hypercarbia (pH ~ 6) or arterial hypercapnia in aquatic normocarbia (by injection of acetazolamide to increase arterial PCO2 and decrease blood pH). Air-breathing frequency, gill ventilation frequency, heart rate and arterial PCO2 and pH were recorded during all treatments. The CO2 injections into the ABO induced progressive increases in air-breathing frequency, but did not alter gill ventilation or heart rate. Exposure to both hypercarbia and acetazolamide post-denervation of the gills also produced significant air-breathing responses, but no changes in gill ventilation. While all treatments produced increases in arterial PCO2 and decreases in blood pH, the modest changes in arterial PCO2/pH in the acetazolamide treatment produced the greatest increases in air-breathing frequency. These results strengthen the evidence that internal CO2/H+ sensing is involved in the stimulation of air breathing in clown knifefish and suggest that it involves extra-branchial chemoreceptors possibly situated either centrally or in the air-breathing organ.

KEY POINTS For small mammals living in a cold, hypoxic environment, supplying enough O2 to sustain thermogenesis can be challenging. While heterothermic mammals are generally more tolerant of cold and hypoxia than homeothermic mammals, how they regulate O2 supply and demand during progressive cooling in hypoxia is largely unknown. We show that as ambient temperature is reduced in hypoxia, body temperature falls in both homeotherms and heterotherms. In the homeothermic rat, a decrease in O2 consumption rate and lung O2 extraction accompany this fall in body temperature, despite a relative hyperventilation. Paradoxically, in heterothermic mice, hamsters and ground squirrels, body temperature decreases more than in the homeothermic rat, even though they maintain ventilation, increase lung O2 extraction and maintain or elevate their O2 consumption rates. Variation in cold and hypoxia tolerance among homeotherms and heterotherms reflects divergent strategies in how O2 supply and demand are regulated under thermal and hypoxic challenges. ABSTRACT Compared to homeothermic mammals, heterothermic mammals are reported to be exceptionally tolerant of cold and hypoxia. We hypothesised that this variation in tolerance stems from divergent strategies in how homeotherms and heterotherms regulate O2 supply versus O2 demand when exposed to hypoxia during progressive cooling. To test this hypothesis, we exposed adult rodents ranging in their degree of heterothermic expression (homeotherm: rats, facultative heterotherms: mice and hamsters, and obligate heterotherm: ground squirrels) to either normoxia (21% O2 ) or environmental hypoxia (7% O2 ), while reducing ambient temperature from 38 to 5°C. We found that when ambient temperature was reduced in normoxia, all species increased their O2 consumption rate and ventilation in parallel, maintaining a constant ventilatory equivalent and level of lung O2 extraction. Surprisingly, body temperature fell in all species, significantly so in the heterotherms. When ambient temperature was reduced in hypoxia, however, the homeothermic rat decreased their O2 consumption rate and lung O2 extraction despite an increase in their ventilatory equivalent, indicative of a relative hyperventilation. Heterotherms (mice, hamsters and ground squirrels), on the other hand, decreased their ventilatory equivalent, but increased lung O2 extraction and maintained or elevated their O2 consumption rates, yet their body temperature fell even more than in the rat. These results are consistent with the idea that homeotherms and heterotherms diverge in the strategies they use to match O2 supply and O2 demand, and that enhanced cold and hypoxia tolerance in heterotherms may stem from an improved ability to extract O2 from the inspired air.

Burrowing rodents have a blunted ventilatory response to CO2 in comparison to non-burrowing rodents. Non-burrowing rats display a period during development where ventilatory responses to hypercarbia become transiently blunted. This study examined the ventilatory responses to CO2 of rats, hamsters and ground squirrels through neonatal development to determine whether the blunted adult response of burrowing species is a retention of the blunting period seen in rats or present from birth. All three species increased ventilation in response to hypercarbia on the day of birth (70–170% in response to 5% CO2; 100–250% in response to 7% CO2). Rats in our study exhibited the triphasic ventilatory response (when expressed as %Δ) to CO2 previously described. In golden-Syrian hamsters, the ventilatory response slowly and progressively waned to a blunted adult response while in the 13-lined ground squirrels, the early ventilatory response to CO2 decreased within days and remained attenuated through development. Our study shows three distinct developmental patterns in the hypercarbic ventilatory response.

The pre-Bötzinger complex (preBötC) of the ventral medulla generates the mammalian inspiratory breathing rhythm. When isolated in explants and deprived of synaptic inhibition, the preBötC continues to generate inspiratory-related rhythm. Mechanisms underlying burst generation have been investigated for decades, but cellular and synaptic mechanisms responsible for burst termination have received less attention. KCNQ-mediated K+ currents contribute to burst termination in other systems, and their transcripts are expressed in preBötC neurons. Therefore, we tested the hypothesis that KCNQ channels also contribute to burst termination in the preBötC. We recorded KCNQ-like currents in preBötC inspiratory neurons in neonatal rat slices that retain respiratory rhythmicity. Blocking KCNQ channels with XE991 or linopirdine (applied via superfusion or locally) increased inspiratory burst duration by 2- to 3-fold. By contrast, activation of KCNQ with retigabine decreased inspiratory burst duration by ~35%. These data from reduced preparations suggest that the KCNQ current in preBötC neurons contributes to inspiratory burst termination.

There was an error in Journal of Experimental Biology (2017) 220, [1079-1089][1] ([doi: 10.1242/jeb.151191][2]). In Fig. 2C,D, some of the symbols for the species were incorrect (although the colours were correct). The original and corrected figures are shown below. This does not change the

The effects of high external ammonia (HEA) exposure on breathing and the potential involvement of ammonia transporting Rh proteins in ammonia sensing were assessed in larval and adult zebrafish. Acute exposure of adults to either 250 or 500 μM (NH4)2SO4 caused increases in ventilation amplitude (AVENT) without affecting frequency (fVENT), resembling the ventilatory response to hypercapnia rather than hypoxia, during which fVENT was increased exclusively. The hyperventilatory response to HEA was prevented by hyperoxia, indicating that control of breathing through ammonia sensing is likely secondary to O2 chemoreception. Neuroepithelial cells (NECs) isolated from gill filaments exhibited a significant increase of intracellular [Ca2+] in response to 1 mM NH4Cl but this response was small (roughly 30%) compared to the response to hypercapnia (37.5 mmHg; ~800% increase). Immunohistochemistry (IHC) failed to reveal the presence of Rh proteins (Rhcgb, Rhbg or Rhag) in gill filament NECs. Knockout of rhcgb did not affect the ventilatory response of adults to HEA. Larvae at 4 days post fertilization (dpf) responded to HEA with increases in fVENT (AVENT was not measured). The hyperventilatory response of larvae to HEA was attenuated (60% reduction) after treatment from 0 to 4 dpf with the sympathetic neurotoxin 6-hydroxydopamine. In larvae, Rhcgb, Rhbg and Rhag were undetectable by IHC in cutaneous NECs yet the fVENT to HEA following Rhbg knockdown was slightly (22%) attenuated. Thus, the hyperventilatory response to external ammonia in adult zebrafish, while apparently initiated by activation of NECs, does not require Rhcgb, nor is the entry of ammonia into NECs reliant on other Rh proteins. The lack of colocalization of Rh proteins with NECs suggests that the entry of ammonia into NECs in larvae, also is not facilitated by this family of ammonia channels.

The cardiovascular system is critical for delivering O2 to tissues. Here we examine the cardiovascular responses to progressive hypoxia in four high-altitude Andean duck species compared to four related low-altitude populations in North America, tested at their native altitude. Ducks were exposed to stepwise decreases in inspired partial pressure of O2 while we monitored heart rate, O2 consumption rate, blood O2 saturation, haematocrit (Hct), and blood haemoglobin concentration [Hb]. We calculated O2 pulse (the product of stroke volume and the arterial-venous O2 content difference), blood O2 concentration, and heart rate variability. Regardless of altitude, all eight populations maintained O2 consumption rate with minimal change in heart rate or O2 pulse, indicating that O2 consumption was maintained by either a constant arterial-venous O2 content difference (an increase in the relative O2 extracted from arterial blood) or by a combination of changes in stroke volume and the arterial-venous O2 content difference. Three high-altitude taxa (yellow-billed pintails, cinnamon teal, and speckled teal) had higher Hct and [Hb], increasing the O2 content of arterial blood, and potentially providing a greater reserve for enhancing O2 delivery during hypoxia. Hct and [Hb] between low- and high-altitude populations of ruddy duck were similar, representing a potential adaptation to diving life. Heart rate variability was generally lower in high-altitude ducks, concurrent with similar or lower heart rates than low-altitude ducks, suggesting a reduction in vagal and sympathetic tone. These unique features of the Andean ducks differ from previous observations in both Andean geese and bar-headed geese, neither of which exhibit significant elevations in Hct or [Hb] compared to their low-altitude relatives, revealing yet another avian strategy for coping with high altitude.

Made available in DSpace on 2022-04-28T19:44:10Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-01-01 National Science Foundation Tracing the evolution of the central rhythm generators associated with ventilation in vertebrates is hindered by a lack of information surrounding key transitions. To begin with, central rhythm generation has been studied in detail in only a few species from four vertebrate groups, lamprey, anuran amphibians, turtles, and mammals (primarily rodents). Secondly, there is a lack of information regarding the transition from water breathing fish to air breathing amniotes (reptiles, birds, and mammals). Specifically, the respiratory rhythm generators of fish appear to be single oscillators capable of generating both phases of the respiratory cycle (expansion and compression) and projecting to motoneurons in cranial nerves innervating bucco-pharyngeal muscles. In the amniotes we find oscillators capable of independently generating separate phases of the respiratory cycle (expiration and inspiration) and projecting to pre-motoneurons in the ventrolateral medulla that in turn project to spinal motoneurons innervating thoracic and abdominal muscles (reptiles, birds, and mammals). Studies of the one group of amphibians that lie at this transition (the anurans), raise intriguing possibilities but, for a variety of reasons that we explore, also raise unanswered questions. In this review we summarize what is known about the rhythm generating circuits associated with breathing that arise from the different rhombomeric segments in each of the different vertebrate classes. Assuming oscillating circuits form in every pair of rhombomeres in every vertebrate during development, we trace what appears to be the evolutionary fate of each and highlight the questions that remain to be answered to properly understand the evolutionary transitions in vertebrate central respiratory rhythm generation. Department of Zoology University of British Columbia Département de Pédiatrie Université Laval Department of Biological Sciences California State University Department of Biology University of Ottawa Departamento de Morfologia e Fisiologia Animal UNESP Department of Zoophysiology Aarhus University Departamento de Morfologia e Fisiologia Animal UNESP

Hypoxia at high altitudes constrains O2supply to support metabolism, thermoregulation in the cold, and exercise. High-altitude natives that somehow overcome this challenge-who live, reproduce, and sometimes perform impressive feats of exercise at high altitudes-are a powerful group in which to study the evolution of physiological systems underlying hypoxia resistance. Here, we sought to determine whether a common pulse oximetry system for rodents (MouseOx Plus) can be used reliably in studies of high-altitude birds by examining the hypoxia responses of the Andean goose. We compared concurrent measurements of heart rate obtained using pulse oximetry versus electrocardiography. We also compared our measurements of peripheral arterial O2saturation (SaO2) in uncannulated birds with published data collected from blood samples in birds that were surgically implanted arterial cannulae. Responses to acute hypoxia were measured during stepwise reductions in inspired partial pressure of O2. Andean geese exhibited very modest breathing and heart rate responses to hypoxia but were nevertheless able to maintain normal O2consumption rates during severe hypoxia exposure down to 5 kPa O2. There were some minor quantitative differences between uncannulated and cannulated birds, which suggest that surgery, cannulation, and/or other sources of variability between studies had modest effects on the hypoxic ventilatory response, heart rate, blood hemoglobin, and hematocrit. Nevertheless, measurements of heart rate and SaO2by pulse oximetry had small standard errors and were generally concordant and well correlated with measurements using other techniques. We conclude that the MouseOx Plus pulse oximetry system can be a valuable tool for studying the cardiorespiratory physiology of waterfowl without the deleterious effects of surgery/cannulation.

The aim of the present study was to determine the roles of externally versus internally oriented CO2/H+-sensitive chemoreceptors in promoting cardiorespiratory responses to environmental hypercarbia in the facultative air-breathing fish, Chitala ornata (the clown knifefish). Fish were exposed to environmental acidosis (pH 6.0) or hypercarbia (ae 30 torr PCO2) that produced changes in water pH equal to the pH levels of the acidotic water to distinguish the relative roles of CO2 versus H+. We also injected acetazolamide to elevate arterial levels of PCO2 and [H+] in fish in normocarbic water to distinguish between internal and external stimuli. We measured changes in gill ventilation frequency, air breathing frequency, heart rate and arterial blood pressure in response to each treatment as well as the changes produced in arterial PCO2 and pH. Exposure to normocarbic water of pH 6.0 for 1 h did not produce significant changes in any measured variable. Exposure to hypercarbic water dramatically increased air breathing frequency, but had no effect on gill ventilation. Hypercarbia also produced a modest bradycardia and fall in arterial blood pressure. Injection of acetazolamide produced similar effects. Both hypercarbia and acetazolamide led to increases in arterial PCO2 and falls in arterial pH although the changes in arterial PCO2/pH were more modest following acetazolamide injection as were the increases in air breathing frequency. The acetazolamide results suggest that the stimulation of air breathing was due, at least in part, to stimulation of internally oriented CO2/H+ chemoreceptors monitoring blood gas changes.

Coordination of respiratory pump and valve muscle activity is essential for normal breathing. A hallmark respiratory response to hypercapnia and hypoxia is the emergence of active exhalation, characterized by abdominal muscle pumping during the late one-third of expiration (late-E phase). Late-E abdominal activity during hypercapnia has been attributed to the activation of expiratory neurons located within the parafacial respiratory group (pFRG). However, the mechanisms that control emergence of active exhalation, and its silencing in restful breathing, are not completely understood. We hypothesized that inputs from the Kölliker-Fuse nucleus (KF) control the emergence of late-E activity during hypercapnia. Previously, we reported that reversible inhibition of the KF reduced postinspiratory (post-I) motor output to laryngeal adductor muscles and brought forward the onset of hypercapnia-induced late-E abdominal activity. Here we explored the contribution of the KF for late-E abdominal recruitment during hypercapnia by pharmacologically disinhibiting the KF in in situ decerebrate arterially perfused rat preparations. These data were combined with previous results and incorporated into a computational model of the respiratory central pattern generator. Disinhibition of the KF through local parenchymal microinjections of gabazine (GABAA receptor antagonist) prolonged vagal post-I activity and inhibited late-E abdominal output during hypercapnia. In silico, we reproduced this behavior and predicted a mechanism in which the KF provides excitatory drive to post-I inhibitory neurons, which in turn inhibit late-E neurons of the pFRG. Although the exact mechanism proposed by the model requires testing, our data confirm that the KF modulates the formation of late-E abdominal activity during hypercapnia. NEW & NOTEWORTHY The pons is essential for the formation of the three-phase respiratory pattern, controlling the inspiratory-expiratory phase transition. We provide functional evidence of a novel role for the Kölliker-Fuse nucleus (KF) controlling the emergence of abdominal expiratory bursts during active expiration. A computational model of the respiratory central pattern generator predicts a possible mechanism by which the KF interacts indirectly with the parafacial respiratory group and exerts an inhibitory effect on the expiratory conditional oscillator.

Gulf toadfish (Opsanus beta) can switch from continuously excreting ammonia as their primary nitrogenous waste to excreting predominantly urea in distinct pulses. Previous studies have shown that the neurotransmitter serotonin (5-HT) is involved in controlling this process, but it is unknown if 5-HT availability is under central nervous control or if the 5-HT signal originates from a peripheral source. Following up on a previous study, cranial nerves IX (glossopharyngeal) and X (vagus) were sectioned to further characterize their role in controlling pulsatile urea excretion and 5-HT release within the gill. In contrast to an earlier study, nerve sectioning did not result in a change in urea pulse frequency. Total urea excretion, average pulse size, total nitrogen excretion, and percent ureotely were reduced the first day post-surgery in nerve-sectioned fish but recovered by 72 h post-surgery. Nerve sectioning also had no effect on toadfish urea transporter (tUT), 5-HT transporter (SERT), or 5-HT2A receptor mRNA expression or 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) abundance in the gill, all of which were found consistently across the three gill arches except 5-HIAA, which was undetectable in the first gill arch. Our findings indicate that the central nervous system does not directly control pulsatile urea excretion or local changes in gill 5-HT and 5-HIAA abundance.

Burrowing rodents have a blunted hypercapnic ventilatory response compared to non-burrowing rodents, but semi-fossorial ground squirrels and hamsters are not born with this blunted response when raised in room conditions. This study examined the hypercapnic ventilatory response of rats, hamsters, and ground squirrels raised in burrow-like hypercapnia (∼3 % CO2) through development (embryonic day 16–18 to postnatal day 30) to determine if chronic hypercapnia exerts any effect on the developing and adult semi-fossorial response. Chronic hypercapnia attenuated the ventilatory response to 5 % CO2 by 60 % (rats), 150 % (hamsters), and 70 % (squirrels) in newborns when compared to newborns raised in normal conditions. When raised in burrow conditions, squirrels and hamsters reached the blunted adult response ∼8−12 days sooner in development than their room air counterparts, while burrow-reared rats maintained a consistently blunted response until removal from chronic hypercapnia. Our study revealed no lasting effect of chronic hypercarbia on the ventilatory responses to CO2 in burrowing rodents, but rather a change in the developmental profile such that the blunted adult response was reached earlier in development.

During entrance into hibernation in golden-mantled ground squirrels (Callospermophilus lateralis), ventilation decreases as metabolic rate and body temperature fall. Two patterns of respiration occur during deep hibernation. At 7 °C body temperature (T b ), a breathing pattern characterized by episodes of multiple breaths (20.6 ± 1.9 breaths/episode) separated by long apneas or nonventilatory periods (T nvp ) (mean = 11.1 ± 1.2 min) occurs, while at 4 °C T b , a pattern in which breaths are evenly distributed and separated by a relatively short T nvp (0.5 ± 0.05 min) occurs. Squirrels exhibiting each pattern have similar metabolic rates and levels of total ventilation (0.2 and 0.23 ml O2/hr/kg and 0.11 and 0.16 ml air/min/kg, respectively). Squirrels at 7 °C T b exhibit a significant hypoxic ventilatory response, while squirrels at 4 °C T b do not respond to hypoxia at any level of O2 tested. Squirrels at both temperatures exhibit a significant hypercapnic ventilatory response, but the response is significantly reduced in the 4 °C T b squirrels. Carotid body denervation has little effect on the breathing patterns or on the hypercapnic ventilatory responses. It does reduce the magnitude and threshold for the hypoxic ventilatory response. Taken together the data suggest that (1) the fundamental rhythm generator remains functional at low temperatures; (2) the hypercapnic ventilatory response arises from central chemoreceptors that remain functional at very low temperatures; (3) the hypoxic ventilatory response arises from both carotid body and aortic chemoreceptors that are silenced at lower temperatures; and (4) there is a strong correlation between breathing pattern and chemosensitivity.

Aims Burrowing mammals tend to be more hypoxia tolerant than non-burrowing mammals and rely less on increases in ventilation and more on decreases in metabolic rate to tolerate hypoxia. Naked mole-rats (Heterocephalus glaber, NMRs), eusocial mammals that live in large colonies, are among the most hypoxia-tolerant mammals, and rely almost solely on decreases in metabolism with little change in ventilation during hypoxia. We hypothesized that the remarkable hypoxia tolerance of NMRs is an evolutionarily conserved trait derived from repeated exposure to severe hypoxia owing to their burrow environment and eusocial colony organization. Methods We used whole-body plethysmography and indirect calorimetry to measure the hypoxic ventilatory and metabolic responses of eight mole-rat species closely related to the NMR. Results We found that all eight species examined had a strong tolerance to hypoxia, with most species tolerating 3 kPa O2 , Heliophobius emini tolerating 2 kPa O2 and Bathyergus suillus tolerating 5 kPa O2 . All species examined employed a combination of increases in ventilation and decreases in metabolism in hypoxia, a response midway between that of the NMR and that of other fossorial species (larger ventilatory responses, lesser reductions in metabolism). We found that eusociality is not fundamental to the physiological response to hypoxia of NMRs as Fukomys damarensis, another eusocial species, was among this group. Conclusions Our data suggest that, while the NMR is unique in the pattern of their physiological response to hypoxia, eight closely related mole-rat species share the ability to tolerate hypoxia like the current "hypoxia-tolerant champion," the NMR.

The bar-headed goose is famed for migratory flight at extreme altitude. To better understand the physiology underlying this remarkable behavior, we imprinted and trained geese, collecting the first cardiorespiratory measurements of bar-headed geese flying at simulated altitude in a wind tunnel. Metabolic rate during flight increased 16-fold from rest, supported by an increase in the estimated amount of O2 transported per heartbeat and a modest increase in heart rate. The geese appear to have ample cardiac reserves, as heart rate during hypoxic flights was not higher than in normoxic flights. We conclude that flight in hypoxia is largely achieved via the reduction in metabolic rate compared to normoxia. Arterial Po2 was maintained throughout flights. Mixed venous PO2 decreased during the initial portion of flights in hypoxia, indicative of increased tissue O2 extraction. We also discovered that mixed venous temperature decreased during flight, which may significantly increase oxygen loading to hemoglobin., eLife digest The bar-headed goose is famous for reaching extreme altitudes during its twice-yearly migrations across the Himalayas. These geese have been tracked flying as high as 7,270 meters up, and mountaineers have anecdotally reported seeing them fly over summits around Mount Everest (that are over 8,000 meters tall). At these heights, the air is so thin that it contains only about 30–50% of the oxygen available at sea-level. Bar-headed geese have several adaptions that help them exercise in low oxygen conditions. For example, they have larger lungs than most other birds their size, and their red blood cells contain a version of hemoglobin that binds oxygen much more tightly. To date, however, there has been no work that has comprehensively measured how the bar-headed goose adapts its physiology to fly under low oxygen conditions. As such, it remains unclear whether these birds would even be able to fly where the oxygen is as limited as it is above the summits of the world’s highest mountains. This is partly because it is extremely challenging to make these kinds of recordings from flying geese, and partly because there are few wind tunnels in the world suitable to carry out such experiments. To better understand how the bar-headed goose accomplishes its remarkable, high altitude migration, Meir et al. raised bar-headed geese from eggs, with experimenters acting as the birds’ foster parents. The birds took their first flights either in a 30-meter wind tunnel at an engineering department in the University of British Columbia or, if the wind tunnel was unavailable, alongside a bicycle or a motor scooter. Once trained, the geese then flew in the wind tunnel wearing a backpack that contained the sensors needed to record their physiology. The birds also wore a breathing mask that could simulate the limited oxygen availability at altitudes of roughly 5,500 and 9,000 meters, and measure the oxygen consumed and the carbon dioxide produced by the geese. Meir et al. found that bar-headed geese could indeed fly at these simulated extreme altitudes in the wind tunnel, and that the birds largely achieved this by reducing their metabolism to match low oxygen conditions. The recordings show that the geese did not increase their heart rate when flying in reduced oxygen compared with normal flights, suggesting that their hearts were not working at maximum capacity despite the extreme conditions. Meir et al. also discovered that the blood in the birds’ veins cooled when flying, and in some cases by more than 2°C. Since hemoglobin’s affinity for oxygen changes with temperature, this may help increase the amount of oxygen that these birds can load into their blood at the lung when in flight. These measurements suggest that the anecdotes of bar-headed geese flying over some of the highest mountains in the world are indeed physiologically plausible. The findings will be valuable to researchers studying animals living at extreme altitudes. They may also be relevant to those looking to understand how humans respond to situations where oxygen is limited, such as during medical conditions like a heart attack or stroke, or procedures like organ transplants.

Birds migrating through extreme environments can experience a range of challenges while meeting the demands of flight, including highly variable ambient temperatures, humidity and oxygen levels. However, there has been limited research into avian thermoregulation during migration in extreme environments. This study aimed to investigate the effect of flight performance and high altitude on body temperature (Tb) of free-flying bar-headed geese (Anser indicus), a species that completes a high-altitude trans-Himalayan migration through very cold, hypoxic environments. We measured abdominal Tb, along with altitude (via changes in barometric pressure), heart rate and body acceleration of bar-headed geese during their migration across the Tibetan Plateau. Bar-headed geese vary the circadian rhythm of Tb in response to migration, with peak daily Tb during daytime hours outside of migration but early in the morning or overnight during migration, reflecting changes in body acceleration. However, during flight, changes in Tb were not consistent with changes in flight performance (as measured by heart rate or rate of ascent) or altitude. Overall, our results suggest that bar-headed geese are able to thermoregulate during high-altitude migration, maintaining Tb within a relatively narrow range despite appreciable variation in flight intensity and environmental conditions.

Carbon dioxide (CO2) and its hydration products hydrogen (H+), bicarbonate HCO 3 − and carbonate CO 3 2 − ions collectively contribute to the acid-base status of aqueous solutions, and have major effects on the physiology of organisms. Correspondingly, organisms have developed the ability to sense specific acid-base disturbances that routinely arise from metabolic and environmental sources, and to coordinate a variety of homeostatic responses. A common requirement for all homeostatic mechanisms is the ability to sense specific acid-base disturbances and to coordinate appropriate responses. This chapter synthetizes our knowledge concerning the sensory pathways that allow fish to sense acid-base disturbances of both metabolic and environmental origin and the ensuing downstream physiological responses that promote homeostasis in different organs. We focus largely on the peripheral, and to a lesser extent, the central sites of CO2/H+ detection, emphasizing the cellular sites and molecular mechanisms of acid-base sensing.

We examined the control of breathing and respiratory gas exchange in six species of high-altitude duck that independently colonized the high Andes. We compared ducks from high-altitude populations in Peru (Lake Titicaca at ∼3800 m above sea level; Chancay River at ∼3000–4100 m) with closely related populations or species from low altitude. Hypoxic ventilatory responses were measured shortly after capture at the native altitude. In general, ducks responded to acute hypoxia with robust increases in total ventilation and pulmonary O2 extraction. O2 consumption rates were maintained or increased slightly in acute hypoxia, despite ∼1–2°C reductions in body temperature in most species. Two high-altitude taxa – yellow-billed pintail and torrent duck – exhibited higher total ventilation than their low-altitude counterparts, and yellow-billed pintail exhibited greater increases in pulmonary O2 extraction in severe hypoxia. In contrast, three other high-altitude taxa – Andean ruddy duck, Andean cinnamon teal and speckled teal – had similar or slightly reduced total ventilation and pulmonary O2 extraction compared with low-altitude relatives. Arterial O2 saturation (SaO2) was elevated in yellow-billed pintails at moderate levels of hypoxia, but there were no differences in SaO2 in other high-altitude taxa compared with their close relatives. This finding suggests that improvements in SaO2 in hypoxia can require increases in both breathing and haemoglobin–O2 affinity, because the yellow-billed pintail was the only high-altitude duck with concurrent increases in both traits compared with its low-altitude relative. Overall, our results suggest that distinct physiological strategies for coping with hypoxia can exist across different high-altitude lineages, even among those inhabiting very similar high-altitude habitats.

We examined the control of breathing and respiratory gas exchange in six species of high-altitude duck that independently colonized the high Andes. We compared ducks from high-altitude populations in Peru (Lake Titicaca at ∼3800 m above sea level; Chancay River at ∼3000-4100 m) with closely related populations or species from low altitude. Hypoxic ventilatory responses were measured shortly after capture at the native altitude. In general, ducks responded to acute hypoxia with robust increases in total ventilation and pulmonary O

For illustrative purposes, in this article we use "Johansen Plots" as a graphical way of simultaneously visualizing the inter-connected variables that compose the convective steps of the gas transport cascade. These plots are used to reflect on some of the physiological characteristics seen in five species of birds, four of which sojourn to, or are native to, high altitudes (the barnacle goose, bar-headed goose, Andean goose, speckled teal and ruddy duck). These species were chosen to emphasize the diversity of responses to hypoxia that can exist within a single family. This diversity likely arose for many possible reasons, including local adaptation to hypoxia, differences in flight or diving abilities, or as a result of other phylogenetically-based differences across waterfowl in physiology, behaviour, and/or life style.

[Figure][1] Bill Milsom and Tobias Wang discuss the impact of Mogens Glass, Robert Boutilier and Norbert Heisler's classic paper ‘Ventilatory control of arterial P O2 in the turtle Chrysemys picta bellii : Effects of temperature and hypoxia’, published in Journal of Comparative

Neonatal animals are extremely tolerant of hypothermia. However, cooling will ultimately lead to ventilatory arrest, or cessation of respiratory movements. Upon rewarming, ventilation can recover spontaneously (autoresuscitation). This study examined the effect of age (P0-P5) and the pons on respiratory-related output during hypothermic ventilatory arrest and recovery using a brainstem-spinal cord preparation of neonatal rats. As temperature fell, burst frequency slowed, burst duration increased, burst shape became fragmented and eventually respiratory arrest occurred in all preparations. Removing the pons had little effect on younger preparations (P0-P2). Older preparations (P4-P5) with the pons removed continued to burst at cooler temperatures compared to pons-intact preparations and burst durations were significantly longer. Episodic breathing patterns were observed in all preparations (all ages, pons on or off) at lower temperatures. At 27 °C, however, episodic breathing was only observed in younger preparations with the pons on. These data suggest that developmental changes occurring at the level of the pons underlie the loss of hypothermic tolerance and episodic breathing.

Naked mole-rats (Heterocephalus glaber; NMRs) are among the most hypoxia-tolerant mammals described to date and exhibit plastic responses during hypoxia exposure. The goal of the present study was to determine if heart mitochondria from NMRs functionally differ from those of hypoxia-intolerant common laboratory mice (Mus musculus). We assessed heart mitochondrial respiratory flux, proton leak kinetics, responses to in vitro anoxia-recovery, and maximal complex enzyme activities. When investigated at their respective body temperatures (28 °C for NMR and 37 °C for mice), NMR heart mitochondria had lower respiratory fluxes relative to mice, particularly for state 2 and oligomycin-induced state 4 leak respiration rates. When leak respiration rates were standardized to the same membrane potential, NMR mitochondria had lower complex II-stimulated state 2 respiration rates than mice. Both mice and NMRs responded similarly to an in vitro anoxia-recovery challenge and decreased state 3 respiration rate post-anoxia. Finally, NMRs had overall lower maximal complex enzyme activities compared with mice, but the magnitude of the difference did not correspond with observed differences in respiratory fluxes. Overall, heart mitochondria from NMRs appear more coupled than those of mice, but in both species the heart appears equally susceptible to ischemic-reperfusion injury.

In rodents, the ventilatory responses to hypoxia (low O2) and hypercarbia (high CO2) change significantly over postnatal development. In hypoxia, most adult rodents increase ventilation and decrease metabolism to some degree. Hypercarbia, however, leads to an increase in ventilation with little, to no change in metabolism. Neonates, on the other hand, respond to hypoxia with a profound metabolic depression, and a severely attenuated ventilatory response. In hypercarbia, they exhibit a strong ventilatory response early in development that blunts, reaches a nadir, and then rises back to the adult-like response, thus, stabilizing postnatally. In this review we discuss how the O2 and CO2 ventilatory responses develop in rodents, the possible mechanisms that drive these postnatal changes, and how being raised in a burrow, an environment putatively low in O2 and high in CO2, may affect the development of O2 and CO2 sensitivity in rodents.

Naked mole rats (Heterocephalus glaber) are among the most hypoxia-tolerant mammals, but their physiological responses to acute and chronic sustained hypoxia (CSH), and the molecular underpinnings of these responses, are poorly understood. In the present study we evaluated the acute hypoxic ventilatory response and the occurrence of ventilatory acclimatization to hypoxia following CSH exposure (8-10 days in 8% O2) of naked mole rats. We also investigated the role of excitatory glutamatergic signaling in the control of ventilation and metabolism in these conditions. Animals acclimated to normoxia (control) or CSH and then exposed to acute hypoxia (7% O2 for 1 h) exhibited elevated tidal volume (VT), but decreased breathing frequency (fR). As a result, total ventilation ( V . E) remained unchanged. Conversely, VT was lower in CSH animals relative to controls, suggesting that there is ventilatory plasticity following acclimatization to chronic hypoxia. Both control and CSH-acclimated naked mole rats exhibited similar 60-65% decreases in O2 consumption rate during acute hypoxia, and as a result their air convection requirement (ACR) increased ∼2.4 to 3-fold. Glutamatergic receptor inhibition decreased fR, V . E, and the rate of O2 consumption in normoxia but did not alter these ventilatory or metabolic responses to acute hypoxia in either the control or CSH groups. Taken together, these findings indicate that ventilatory acclimatization to hypoxia is atypical in naked mole rats, and glutamatergic signaling is not involved in their hypoxic ventilatory or metabolic responses to acute or chronic hypoxia.

The structure and function of crocodilian lungs are unique compared with those of other reptiles. We examined the extent to which this and the semi-aquatic lifestyle of crocodilians affect their respiratory mechanics. We measured changes in intratracheal pressure in adult and juvenile caiman (

The diversity of sites and surfaces that are utilized for gas transfer from air to blood in fish is remarkable. While a few species do utilize their gills for gas exchange in air, this is a rare occurrence and most air-breathing fish utilize other surfaces including air-breathing organs and lungs. At present almost nothing is known about the central sites that initiate and regulate air breathing although hypotheses can be put forward based on our rudimentary understanding of the sites involved in water breathing in lampreys and teleost fishes, and those involved in air breathing in pre-metamorphic anuran ampibians. The pumps involved in producing both water and air breathing in fishes are highly conserved, a buccal pump, assisted by pharyngeal and/or parabranchial/opercular pumps, produce both forms of ventilation. What varies between species are the manner in which air breaths are produced (in two versus four phases), and the ‘valving’ involved in producing water flow over the gills versus air flow in and out of air-breathing organs. The latter suggests that a major step in the evolution of air breathing was the evolution of the mechanisms that control the flow of the respiratory medium. The neural matrix that underlies the co-ordination of the pump and the valving events remains enigmatic and in much need of further research.