Lowering heart rate while diving helps marine mammals regulate blood pressure while redistributing blood flow and conserving oxygen during extended dives. However, the classic characterization of this dive response—as a pronounced and abrupt reduction in heart rate observed during forced dives in laboratory settings—contrasts with the higher minimum heart rates and oscillatory patterns observed in freely diving marine mammals in the wild. To assess this apparent discrepancy in cardiovascular control, we measured the heart rates of three Steller sea lions (Eumetopias jubatus) using subcutaneous cardiac monitors during trained stationary dives (3–4 m) in an aquarium pool. During 12 of the longest dives (76–161 s), heart rates decreased from an average of 95 to 34 bpm within the first 26 s of submergence. However, while mean HR at depth eventually averaged around 31 bpm, it also oscillated between 27 and 39 bpm every 5–6 s (0.2 Hz) for much of the dive, before rising prior to surfacing. The observed relatively slow drops in heart rates were similar to those seen in other marine mammals, suggesting an optimal rate of decline that reflects the anticipated conditions of voluntary dives. We further hypothesize that the oscillating minimum heart rates of freely diving marine mammals reflect time delays in the baroreceptor reflex due to the prolongation of circulation time. Our findings suggest these delays shape the rate and pattern of heart rate decline, ultimately influencing cardiovascular control, gas management, and breath-hold duration in diving mammals.

In vertebrates, the basic respiratory rhythm is modified by both sensory feedback and input from higher centers to produce a broad range of breathing patterns. In carp (Cyprinus carpio L.), breathing is often episodic while in trout (Onchorhynchus mykiss) it is continuous and rhythmic except when water is hyperoxic. A previous study in carp revealed that stimulation of neurons at a site in the dorsal mesencephalic tegmentum (DMT) ventrolateral to the oculomotor nucleus, can terminate the apneas and initiate breathing episodes (Juch and Ballintijn, 1983). Such stimulation, however, did not eliminate the apneas or the breathing episodes. To determine whether this site also contains neurons involved in initiating periods of apnea that are intrinsic to episodic breathing, we attempted to lesion the DMT site in decerebrate, spinalectomized carp and trout using stereotaxic microinjections of 0.01 mM kainic acid. Following decerebration and spinalectomy, 93 % of carp and 33 % of trout breathed in episodes in hyperoxic water. Kainic acid injections initially stimulated breathing in all fish. As the excitotoxic effects progressed, breathing frequency and breath amplitude returned to normal levels suggesting that sites within the areas we lesioned are not involved in establishing the overall level of respiratory drive. The ensuing lesions, however, eliminated the episodic breathing in hyperoxia in over 50 % of the carp and 33 % of the trout. This suggests that sites within the midbrain tegmentum are involved in establishing breathing patterns and that there is a non-uniform distribution of neurons within the midbrain tegmentum involved in producing apneas and clustering breaths into episodes.

As mammals grow from developmentally immature neonates into adults, metabolic rate (V̇O2) has been hypothesized to scale isometrically with body mass until individuals reach a critical size, after which scaling becomes hypometric. This study aimed to determine when this occurs and gain insight into why this metabolic switch occurs in altricial thirteen-lined ground squirrels (Ictidomys tridecemlineatus). We hypothesized that the switch would be related to patterns of growth and development. We measured the mass and resting V̇O2 of I. tridecemlineatus pups using flow-through respirometry at postnatal days (P)0-P30 (inclusive), P60, P90, P120 and at over 1 year old and found repeated and asynchronous ontogenetic changes in growth rate and metabolic scaling. Following birth, pups grew 1.18±0.02 g day-1 and metabolism scaled isometrically as predicted (scaling exponent B=1.01±0.03). Surprisingly, B more than doubled to 2.64±0.13 at P18-P23 while growth rate remained constant. At P29, growth rate more than quadrupled to 4.87±0.03 g day-1 while between P35 and P43 the further increase in V̇O2 was proportionately less, and thus B fell to -0.27±0.43. Adult size was reached by P79, with final scaling and growth rate values maintained into adulthood (P465). The asynchronous changes in mass and resting V̇O2 appear to reflect metabolic trade-offs as pups allocated energy towards physiological development (P18-P35) versus growth (P35-P79): the period of hypermetabolic scaling (B=2.64±0.13) coincided with the time when pups became weaned and sufficiently physiologically and morphologically developed to live independently.

During hibernation, golden-mantled ground squirrels (Spermophilus lateralis) breathe in distinct multi-breath episodes separated by prolonged periods of apnea. We hypothesized that vagal afferent feedback from pulmonary stretch receptors, and N-methyl-D-aspartate (NMDA) type glutamate receptor-mediated processes in the pons are instrumental in the production of this breathing pattern and analyzed the effects of disrupting vagal feedback, and blockade of NMDA type receptors by the non-competitive antagonist (+)-5-methyl-10,11-dihydro-5 H-dibenzo[a, d]-cyclohepten-5,10-imine maleate (MK-801), on breathing pattern and ventilatory responses to hypoxia and hypercapnia in ground squirrels during natural hibernation. The hibernating squirrels breathed episodically and exhibited a robust ventilatory response to hypercapnia but not hypoxia. The breathing episode (not the individual breath) was the major regulated variable in the breathing pattern. Vagal blockade did not alter breathing on a breath-by-breath basis but did decrease the breaths per episode decreasing overall ventilation and abolished the hypercapnic ventilatory response. MK-801 increased the number of breaths per episode and the frequency of breathing during episodes but did not alter overall ventilation nor the hypercapnic ventilatory response. Combined treatment with MK-801 and vagal blockade abolished episodic breathing but also initiated arousal from hibernation. The data suggest that in golden-mantled ground squirrels hibernating at 5°C body temperature, vagal feedback and NMDA receptor mediated processes still modulate breathing. Whether they are responsible for clustering breaths into episodes is suggested but remains equivocal.

High-altitude life poses physiological challenges to all animals due to decreased environmental oxygen (O2) availability (hypoxia) and cold. Supporting high metabolic rates and body temperatures with limited O2 is challenging. Many birds, however, thrive at high altitudes. The O2-transport cascade describes the pathway involved in moving O2 from the environment to the tissues encompassing: (i) ventilation, (ii) pulmonary O2 diffusion, (iii) circulation, (iv) tissue O2 diffusion, and (v) mitochondrial O2 use for ATP production. Shared avian traits such as rigid lungs with cross-current gas exchange and unidirectional airflow aid in O2 acquisition and transport in all birds. Many high-altitude birds, however, have evolved enhancements to some or all steps in the cascade. In this review, we summarize the current literature on gas exchange and O2 transport in high-altitude birds, providing an overview of the O2-transport cascade that principally draws on the literature from high-altitude waterfowl, the most well-studied group of high-altitude birds. We close by discussing two important avenues for future research: distinguishing between the influences of plasticity and evolution and investigating whether the morphological and physiological differences discussed contribute to enhanced locomotor or thermogenic performance, a potential critical link to fitness.This article is part of the theme issue 'The biology of the avian respiratory system'.

Peripheral arterial chemoreceptors monitor the levels of arterial blood gases and adjust ventilation and perfusion to meet metabolic demands. These chemoreceptors are present in all vertebrates studied to date but have not been described fully in reptiles other than turtles. The goals of this study were to (1) identify functional chemosensory areas in the South American rattlesnake (Crotalus durissus), (2) determine the neurochemical content of putative chemosensory cells in these areas and (3) determine the role each area plays in ventilatory and cardiovascular control. To this end, rattlesnakes were instrumented with transonic flow probes, arterial catheters and subcutaneous impedance electrodes to measure shunt fraction, heart rate, blood pressure and ventilation. The catheters were placed at three putative chemosensory sites, the bases of the aortic arch and pulmonary artery, and the carotid bifurcation, for site-specific activation with sodium cyanide (NaCN). These same sites were subsequently examined using immunohistochemical markers for acetylcholine, tyrosine hydroxylase (the rate-limiting enzyme in catecholamine synthesis) and serotonin to identify putative oxygen-sensing cells. All three sites were chemosensory and stimulating each led to cardiovascular (shunt fraction and heart rate) and respiratory adjustments although not in an identical fashion. All three chemosensory areas contained cells positive for serotonin; however, cells positive for vesicular acetylcholine transporter (VAChT) were found only in the aorta and pulmonary artery. We found no labelling for tyrosine hydroxylase at any site.

Hypoxia and cold temperatures create unique physiological challenges for high-altitude organisms that can vary depending on lifestyle. While nearly all studies of air-breathing animals at high altitude are from terrestrial species, species that breath-hold dive underwater at high altitude encounter a very different set of selective pressures influencing their phenotype. The goal of this publication is to highlight the changes in O2 transport and utilization in high-altitude diving birds relative to divers at sea level, and the extent to which these changes are qualitatively distinct from phenotypic changes in non-diving species at high altitude. For example, while high capacities for sustained O2 transport may be required for sustained flight and thermogenesis (particularly in small endotherms), high-altitude breath-hold diving is a form of intense exercise uniquely defined by transient and sometimes severe O2 depletion (hypoxemia) and CO2 accumulation (hypercapnia), interspersed by recovery between dives when O2 stores must be rapidly replenished despite the hypoxic environment at high altitude. Given this, diving behavior may preclude or constrain the physiology of divers, such that high-altitude divers are predicted to exhibit qualitatively distinct phenotypic changes compared to non-divers, as each likely experience unique signals for phenotypic plasticity and selective pressures driving their evolution. Here, we reanalyze and synthesize new and recent findings describing O2 transport for two high-altitude breath-hold divers in the Andes of South America, the ruddy duck (Oxyura jamaicensis) and the torrent duck (Merganetta armata). Analysis across the O2-transport cascade including (1) ventilation, (2) pulmonary O2 diffusion, (3) circulatory O2 delivery, (4) tissue O2 diffusion, and (5) tissue O2 utilization reveals that different routes to functional adaptation have emerged between diving and non-diving birds in the high Andes. While ruddy ducks and torrent ducks differed in numerous ways, we found that these two high-altitude divers had generally much higher blood-O2 carrying capacity relative to non-divers. Furthermore, unlike non-diving high-altitude waterfowl, these highaltitude divers did not increase Hb-O2 affinity at high altitude, because Hb-O2 affinity was already high in the low-altitude diving ancestor. Due to these factors, these divers always had higher arterial O2 content (CaO2) than non-divers, but unlike the non-divers, there was never any difference in CaO2 between high- and low-altitude populations among the divers. Finally, high-altitude divers exhibited greater magnitudes of body temperature (Tb) suppression during hypoxia than their corresponding low-altitude populations, whereas hypoxic Tb suppression was similar between high- and lowaltitude taxa among non-divers. In fact, the ruddy duck had the lowest Tb of all species under extreme hypoxia. Such changes may be beneficial by reducing the metabolic cost of thermogenesis during dives in cold alpine waters. Further insight into the unique physiology of high-altitude divers would benefit from future study of cardiorespiratory control and pulmonary function during the recovery phase between dives, as well as mitochondrial bioenergetics, reactive oxygen species (ROS) production, and antioxidant defense.

Many animal species do not breathe in a continuous, rhythmic fashion, but rather display a variety of breathing patterns characterized by prolonged periods between breaths (inter-breath intervals), during which the heart continues to beat. Examples of intermittent breathing abound across the animal kingdom, from crustaceans to cetaceans. With respect to human physiology, intermittent breathing-also termed 'periodic' or 'episodic' breathing-is associated with a variety of pathologies. Cardiovascular phenomena associated with intermittent breathing in diving species have been termed 'diving bradycardia', 'submersion bradycardia', 'immersion bradycardia', 'ventilation tachycardia', 'respiratory sinus arrhythmia' and so forth. An examination across the literature of terminology applied to these physiological phenomena indicates, unfortunately, no attempt at standardization. This might be viewed as an esoteric semantic problem except for the fact that many of the terms variously used by different authors carry with them implicit or explicit suggestions of underlying physiological mechanisms and even human-associated pathologies. In this article, we review several phenomena associated with diving and intermittent breathing, indicate the semantic issues arising from the use of each term, and make recommendations for best practice when applying specific terms to particular cardiorespiratory patterns. Ultimately, we emphasize that the biology-not the semantics-is what is important, but also stress that confusion surrounding underlying mechanisms can be avoided by more careful attention to terms describing physiological changes during intermittent breathing and diving.

The dive response involves three main components - breath holding, reduced heart rate and increased peripheral vasoconstriction - and is ubiquitous during forced dives in air-breathing vertebrates; however, numerous studies in free-diving animals have shown that the heart rate response to diving varies considerably in a manner that suggests cognitive control. Furthermore, studies on free-diving animals and controlled experiments in trained animals both indicate that the dive response can be conditioned, such that the reduction in heart rate begins before submergence and the extent of the reduction is set early in the dive. In addition, numerous species also experience an increase in heart rate and blood flow during ascent at the end of a dive, a phenomenon commonly called 'ascent tachycardia'. Collectively, these data suggest that although the dive response is under autonomic control, many species can vary its magnitude depending on the length and type of the planned dive - an indication of a role for cognition in the overall physiological responses associated with diving. Here, we provide examples of the conditioned cardiac responses - including anticipatory changes in heart rate - in several diving species and propose potential underlying mechanisms. We also discuss how the anticipatory cardiovascular responses not only improve diving capacity, but also prevent diving-related problems, such as decompression sickness or barotrauma, through a mechanism described by the selective gas exchange hypothesis.

Common tenrecs (Tenrec ecaudatus) are fossorial mammals that use burrows during both active and hibernating seasons in Madagascar and its neighboring islands. Prevailing thought was that tenrecs hibernate for 8–9 months individually, but 13 tenrecs were removed from the same sealed burrow 1 m deep from the surface. Such group hibernation in sealed burrows presumably creates a hypoxic and/or hypercapnic environment and suggests that this placental mammal may have an increased tolerance to hypoxia and hypercapnia. Higher tolerances to hypoxia and hypercapnia have been documented for other mammals capable of hibernation and to determine if this is the case for tenrecs, we exposed them to acute hypoxia (4 h of 16 or 7 V̇O_2 ), body temperature (Tb), and heart rate (HR) were highly variable between individuals. This inter-individual variation was greatly reduced in animals held at 28 °C for oxygen consumption rate and body temperature. Both hypoxia (acute and progressive) and progressive hypercapnia led to decreases in V̇O_2 as well as the variation in V̇O_2 between animals held at 16 °C. The fall in oxygen consumption rate in 7 V̇O_2 , HR, or Tb, indicative of high tolerance to both hypoxia and hypercapnia. High variation in heart rate remained between individuals in all gas compositions and at all temperatures. Tenrec Hb–O2 affinity was similar to other homeothermic placental mammals and likely does not contribute to the increased hypoxia tolerance. Ultimately, our results suggest changes in Ta dictate physiological responses to hypoxia or hypercapnia in tenrecs, responses more characteristic of reptiles than of most placental mammals. Given that numerous anatomical and physiological characteristics of tenrecs suggest that they may be representative of an ancestral placental mammal, our findings suggest the typical hypoxic metabolic response evolved later in mammalian evolution.

In this review, we explore the inconsistencies in the data and gaps in our knowledge that exist in what is currently known regarding gill chemosensors which drive the cardiorespiratory reflexes in fish. Although putative serotonergic neuroepithelial cells (NEC) dominate the literature, it is clear that other neurotransmitters are involved (adrenaline, noradrenaline, acetylcholine, purines, and dopamine). And although we assume that these agents act on neurons synapsing with the NECs or in the afferent or efferent limbs of the paths between chemosensors and central integration sites, this process remains elusive and may explain current discrepancies or species differences in the literature. To date it has been impossible to link the distribution of NECs to species sensitivity to different stimuli or fish lifestyles and while the gills have been shown to be the primary sensing site for respiratory gases, the location (gills, oro-branchial cavity or elsewhere) and orientation (external/water or internal/blood sensing) of the NECs are highly variable between species of water and air breathing fish. Much of what has been described so far comes from studies of hypoxic responses in fish, however, changes in CO2, ammonia and lactate have all been shown to elicit cardio-respiratory responses and all have been suggested to arise from stimulation of gill NECs. Our view of the role of NECs is broadening as we begin to understand the polymodal nature of these cells. We begin by presenting the fundamental picture of gill chemosensing that has developed, followed by some key unanswered questions about gill chemosensing in general.

Arterial pressure (Pa) regulation is essential to adequately distribute nutrients to metabolizing tissues, remove wastes and avoid lesions associated with hypertension. In vertebrates, short-term Pa regulation is achieved through the baroreflex, which elicits inversely proportional changes in heart rate (fH) and vascular resistance to restore Pa. The cardiac limb of this reflex has been reported in all vertebrate groups studied to date: teleosts, amphibians, snakes, lizards, crocodiles, birds and mammals - which led to the suggestion that the baroreflex is an ancient trait present in all vertebrate species. However, it is not clear whether more basal groups of vertebrates, such as cyclostomes, elasmobranchs and chondrosteans, manifest baroreflex regulation of fH. Thus, the aim of this study was to determine whether the white sturgeon (Acipenser transmontanus; Chondrostei: Acipenseridae) exhibits a cardiac baroreflex. To do so, we induced Pa perturbations through injections of phenylephrine, sodium nitroprusside (SNP) and saline solution (hypervolemia), and examined possible fH baroreflex responses. We also investigated whether fH responses triggered by fright and chemoreflex were present in this species, in order to confirm the potential of sturgeon to perform reflexive cardiac adjustments. The findings indicate that A. transmontanus exhibits reflex bradycardia in response to fright and chemoreceptor stimulation, illustrating its capacity for short-term cardiac regulation. However, this species does not display baroreflex control of fH across its physiological range. This dissociation suggests that while the nervous and cardiovascular systems of A. transmontanus are primed for rapid reflex responses, a cardiac baroreflex mechanism remains absent.

Introduction-Little is known about the epidemiology of emergency medical search and rescue in-cidents globally. The purpose of this study was to describe the epidemiology of emergency medical search and rescue incidents in the North Shore Mountains of Vancouver, British Columbia, Canada.Methods-This was a retrospective review and descriptive analysis of search and rescue incident re-ports created by North Shore Rescue over a 25 y period from 1995 to 2019, inclusive. Incident reports were screened for inclusion against a priori criteria defining a medical callout. The National Advisory Committee of Aeronautics (NACA) severity score was used as a method to grade medical acuity of included subjects.Results-We included 906 subjects. Their median age was 35 y (interquartile range, 24-53), and 65% of subjects were men. Forty-one percent (n=371) of subjects were classified as non-trauma and 54% (n=489) as trauma. The top 3 activities were hiking (53%), biking (10%), and snow sports (10%). Forty-nine percent of incidents were classified as having a NACA score of >= 3. For subjects with trauma, the top 3 body regions were lower limb (52%), head (18%), and torso (12%). For subjects with non-traumatic conditions, the top 3 causes were mental health crises (25%), exposure (25%), and cardiovascular incidents (11%).Conclusions-Half of the incidents were serious enough to require medical assessment at a hospital (NACA score >= 3). Given this medical acuity, there is a need for evidence-based guidelines and core training competencies for mountain medical search and rescue. Standardized core data sets and out-comes are needed to monitor quality of care over time.

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.

Mammalian hibernation initiates dramatic changes in physiology that include large reductions in ventilation (V̇E), heart rate, oxygen consumption rate (V̇o2), and body temperature (Tb) upon entrance into torpor, effects that reverse upon arousal. Several physiologic processes must maintain function throughout a wide range of temperatures. Recent evidence indicates that neuronal synapses loosen and retract in regions of the brain that are silenced during a torpor bout, although little is understood yet about how these connections are regulated during hibernation. Microglia, brain resident immune cells, are potential facilitators of these essential neural homeostatic activities due to their critical roles in neuronal support and synaptic strengthening and pruning. Thus, we hypothesized that microglia are required for maintaining normal ventilatory neural control during hibernation. To test this, we treated 13‐lined ground squirrels with either vehicle or colony‐stimulating factor receptor‐1 (CSF1R) antagonist, PLX3397 (80mg/kg, po), a receptor whose activation is necessary for microglial survival in the adult nervous system, and measured V̇E, V̇o2, and Tb throughout a torpor bout. During entrance, PLX‐treated squirrels took ~1.5 hours longer to reach their minimum torpor temperature (Tb; 12°C) compared to control animals (Tb; 9.3°C) (ambient temperature; 5‐6°C). Similarly, arousal time in microglia‐depleted animals was as much as 1 hour longer relative to controls, despite starting at a higher minimum Tb. In both treatment groups, V̇o2 during entrance fell and spiked periodically. However, in PLX‐treated animals, these spikes were much greater and more frequent. Minimum V̇o2 in torpor was ~3 times greater in PLX‐treated animals compared to control animals. Upon arousal from torpor, V̇o2 remained elevated, longer, in PLX‐treated squirrels. Total V̇E tended to be elevated in PLX‐treated animals through entrance, steady state torpor, and arousal, but it was most striking during steady state torpor, where V̇E in PLX‐treated animals was 15‐fold higher than control animals. The net result in torpor was an elevated air convection requirement, thus microglia‐depleted animals hyperventilated throughout the torpor bout. Together, these results suggest that microglia play an important regulatory role in normal ventilatory and temperature control throughout torpor and influence the rate at which animals enter into and arouse from torpor. Mechanisms whereby microglia contribute to hibernation neurophysiology are currently under investigation.

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.

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. © 2022 American Physiological Society. Compr Physiol 12: 1-120, 2022.

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.

Mammals entering hibernation undergo drastic reductions in metabolic rate and body temperature (Tb; to as low as ∼2% of euthermic metabolic rate and 1°C to −2°C). Although ventilation (V˙E) is also greatly reduced in hibernating ground squirrels, their relative ventilatory response (%ΔV˙E) to increases in inspired CO2 (∼400% increase to 7% CO2) dwarfs that of euthermic squirrels (∼60% increase). On the basis of data from earlier studies on hypothermic animals, we hypothesized that this switch in apparent ventilatory sensitivity was the result of the change in state (from euthermic to hibernating) and not due to the change in core Tb. Thus, we used whole-body plethysmography to assess the hypercapnic ventilatory response (HCVR) in thirteen-lined ground squirrels in steady-state hibernation at 20°C, 15°C, 10°C, 7°C, and 5°C. With the transition into hibernation as Tb fell, the breathing pattern became irregular and then episodic. Total V˙E and the oxygen consumption rate (V˙O2) decreased progressively as Tb fell. Hibernating squirrels with a core Tb of 20°C increased V˙E by 150% from normocapnic levels when given 7% CO2 to breathe, while squirrels with a Tb of 7°C increased V˙E by 650% when exposed to the same inspired CO2. When Tb was cooled from 7°C to 5°C, however, the increase in the HCVR fell to 450% and was associated with a rise in V˙O2 and total V˙E. These results reveal progressive changes in breathing pattern and the HCVR with decreasing Tb and suggest that the effects of hibernation state may be Tb dependent. V˙E did not fall in proportion to metabolic rate, and the HCVR increased progressively in both absolute terms and relative terms until a Tb of 7°C, both of which potentially constrain the extent of the metabolic suppression.