Modeling Post Stroke Respiratory Dysfunction, Apneas and Cognitive Decline

Modeling Post Stroke Respiratory Dysfunction, Apneas and Cognitive Decline Anthony Patrizz, B.A. Advisory Professor: Louise McCullough M.D., Ph.D. Stroke is a major cause of mortality and the leading cause of long-term disability in the US. More than 60% of individuals suffering a first time stroke develop respiratory dysfunction, prolonging recovery and increasing mortality. Post-stroke cognitive decline is a major contributor to disability and nursing home placement, therefore the cognitive consequences of Stroke Induced Respiratory Dysfunction (SIRD) need to be explored if we hope to enhance functional recovery. The first step towards treatment of the negative consequences of SIRD is the development of appropriate animal models that will allow us to explore the pathophysiology of SIRD and provide the opportunity to test potential pharmacological agents. We developed and characterized an animal model of stroke induced respiratory dysfunction recapitulating the respiratory phenotype witnessed in the clinical population, characterized by incidences of apnea and hypoventilation. Interestingly, mice with high incidence of apneas display signs of progressive cognitive decline compared to those with low/no incidence of apneas. Histological analysis of vital brainstem respiratory control sites unveiled reactive astrocytosis, an important cell type in the neurovascular unit and an essential component of chemoreception. Respiratory dysfunction and brainstem astrocytosis was reproduced in mice that underwent intracerebroventricular injections of TGF-b. Suggesting the TGF-b signaling pathway contributes to the onset of astrogliosis and respiratory dysfunction. Our data suggests that stroke disrupts basal breathing rather than increasing chemoreceptor gain. Therefore, we predict treatments designed to stimulate breathing independent of chemoreceptor gain will improve respiratory instability, behavior, cognition and mortality. Systemic application of acetazolamide eliminated apneas while preventing further cognitive decline. This work not only developed a model of stroke induced respiratory dysfunction that recapitulates the respiratory phenotype witnessed in the clinical population, but also providing translational relevance to the field of stroke, aging, and cognitive decline. Successful treatment of SIRD may lead to significant improvements in post-stroke recovery and cognition

Time domains of hypoxia responses and -omics insights

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

Circadian Modulation Of Breathing Stability And Respiratory Plasticity

Purpose: Our project was designed to determine the effect of time of day on multiple mechanisms influencing breathing stability and respiratory plasticity. We investigated if the number and duration of breathing events coupled to upper airway collapsibility, as well as the carbon dioxide reserve, chemoreflex sensitivity and arousal threshold during non-rapid eye movement (NREM) sleep were affected by the time of day. In addition, we examined if mild intermittent hypoxia (IH) initiates long-term facilitation of upper airway muscle activity leading to a reduction in the therapeutic continuous positive airway pressure required to eliminate breathing events. Methods: Male participants with obstructive sleep apnea completed a constant routine protocol that consisted of sleep sessions in the evening (10 PM to 1 AM), morning (6 AM to 9 AM), and afternoon (2 PM to 5 PM). On one occasion the number and duration of breathing events was ascertained for each sleep session. For breathing events detected during these sessions the rate of change of respiratory effort, maximum respiratory effort immediately prior to termination of an event, and the maximum tidal volume and the minimum partial pressure of end-tidal carbon dioxide (PETCO2) immediately following an event were measured Participants then completed the same protocol on two additional occasions, where the critical closing pressure that demarcated upper airway collapsibility was determined on one, and baseline levels of carbon dioxide PET(CO2) and minute ventilation, as well as the PET(CO2) that demarcated the apneic threshold and hypocapnic ventilatory response were measured on the other (the order of these 2 visits was randomized). In the second aim of the study, male participants with obstructive sleep apnea were treated with twelve 2-minute episodes of hypoxia (PETO2 ≈ 50 mmHg) separated by 2-minute intervals of normoxia in the presence of PETCO2 that was sustained 3 mmHg above baseline. During recovery from the last episode the positive airway pressure was reduced in a step-wise fashion until flow limitation was evident. The participants also completed a sham protocol under normocapnic conditions, which mimicked the timeframe of the IH protocol. Results: The duration of breathing events was consistently greater in the morning compared with the evening and afternoon during N1 and N2, while an increase in event frequency was evident during N1. The critical closing pressure was increased in the morning (2.68 ± 0.98 cmH2O) compared with the evening (1.29 ± 0.91 cmH2O; P ≤ 0.02) and afternoon (1.25 ± 0.79; P ≤ 0.01). The increase in the critical closing pressure was correlated to the decrease in the baseline partial pressure of carbon dioxide in the morning compared with the afternoon and evening (r = −0.73, P ≤ 0.005).. The nadir of core body temperature during sleep occurred in the morning and was accompanied by reductions in minute ventilation and PETCO2 compared with the evening and afternoon (minute ventilation: 5.3 ± 0.3 vs. 6.2 ± 0.2 vs. 6.1 ± 0.2 l/min, P lt; 0.02; PET(CO2): 39.7 ± 0.4 vs. 41.4 ± 0.6 vs. 40.4 ± 0.6 Torr, P \u3c 0.02). The carbon dioxide reserve was reduced, and the hypocapnic ventilatory response increased in the morning compared with the evening and afternoon (carbon dioxide reserve: 2.1 ± 0.3 vs. 3.6 ± 0.5 vs. 3.5 ± 0.3 Torr, P \u3c 0.002; hypocapnic ventilatory response: 2.3 ± 0.3 vs. 1.6 ± 0.2 vs. 1.8 ± 0.2 l·min(-1)·mmHg(-1), P \u3c 0.001). The rate of change of respiratory effort was similar in N2 compared to N1 but the maximum respiratory effort immediately prior to event termination was greater (-10.7 ± 1.2 vs. -9.6 ± 1.0 cmH2O/s, P \u3c 0.05). Likewise, tidal volume was increased (1169 ± 105 vs. 1082 ± 100 ml, P \u3c 0.05) and PETCO2 was decreased (37.0 ± 0.8 vs. 37.7 ± 0.8 mmHg P \u3c 0.05) following events in N2 compared to N1. A similar tidal volume and PETCO2 response was evident following events in the morning compared to the evening independent of sleep stage. After exposure to IH the therapeutic pressure was significantly reduced (Δ CPAP = - 4.95 ± 0.5 cmH2O, p \u3c 0.001) without evidence of flow limitation (P \u3e 0.2) or increases in upper airway resistance (P \u3e 0.4). In contrast, a similar decrease in pressure was accompanied by significant flow limitation (P \u3c 0.003) and an increase in upper airway resistance (P \u3c 0.01) following completion of the sham protocol. Conclusion: Our findings indicate that time of day affects the duration and frequency of events, coupled with alterations in upper airway collapsibility and chemoreflex properties during sleep, which may contribute to increases in breathing instability in the morning compared with other periods throughout the day/night cycle in individuals with sleep apnea. We propose that increases in airway collapsibility in the morning may be linked to an endogenous modulation of baseline carbon dioxide levels and chemoreflex sensitivity, which are independent of the consequences of sleep apnea. We also conclude that alterations in the arousal threshold, reflected by an increase in respiratory effort at event termination, coupled to increases in tidal volume and reductions in PETCO2 contribute to modifications in event duration and frequency associated with variations in sleep state or time of night. In addition, Exposure to IH decreases the therapeutic pressure required to eliminate apneic events which could improve treatment compliance. This possibility coupled with the direct beneficial effects of IH on co-morbidities linked to sleep apnea suggests that IH may have a multipronged therapeutic effect on sleep apnea

Sleep and Breathing at High Altitude

This thesis describes the work carried out during four treks, each over 10-11 days, from 1400m to 5000m in the Nepal Himalaya and further work performed during several two-night sojourns at the Barcroft Laboratory at 3800m on White Mountain in California, USA. Nineteen volunteers were studied during the treks in Nepal and seven volunteers were studied at White Mountain. All subjects were normal, healthy individuals who had not travelled to altitudes higher than 1000m in the previous twelve months. The aims of this research were to examine the effects on sleep, and the ventilatory patterns during sleep, of incremental increases in altitude by employing portable polysomnography to measure and record physiological signals. A further aim of this research was to examine the relationship between the ventilatory responses to hypoxia and hypercapnia, measured at sea level, and the development of periodic breathing during sleep at high altitude. In the final part of this thesis the possibility of preventing and treating Acute Mountain Sickness with non-invasive positive pressure ventilation while sleeping at high altitude was tested. Chapter 1 describes the background information on sleep, and breathing during sleep, at high altitudes. Most of these studies were performed in hypobaric chambers to simulate various high altitudes. One study measured sleep at high altitude after trekking, but there are no studies which systematically measure sleep and breathing throughout the whole trek. Breathing during sleep at high altitude and the physiological elements of the control of breathing (under normal/sea level conditions and under the hypobaric, hypoxic conditions present at high altitude) are described in this Chapter. The occurrence of Acute Mountain Sickness (AMS) in subjects who travel form near sea level to altitudes above 3000m is common but its pathophysiology not well understood. The background research into AMS and its treatment and prevention are also covered in Chapter 1. Chapter 2 describes the equipment and methods used in this research, including the polysomnographic equipment used to record sleep and breathing at sea level and the high altitude locations, the portable blood gas analyser used in Nepal and the equipment and methodology used to measure each individual’s ventilatory response to hypoxia and hypercapnia at sea level before ascent to the high altitude locations. Chapter 3 reports the findings on the changes to sleep at high altitude, with particular focus on changes in the amounts of total sleep, the duration of each sleep stage and its percentage of total sleep, and the number and causes of arousals from sleep that occurred during sleep at increasing altitudes. The lightest stage of sleep, Stage 1 non-rapid eye movement (NREM) sleep, was increased, as expected with increases in altitude, while the deeper stages of sleep (Stages 3 and 4 NREM sleep, also called slow wave sleep), were decreased. The increase in Stage 1 NREM in this research is in agreement with all previous findings. However, slow wave sleep, although decreased, was present in most of our subjects at all altitudes in Nepal; this finding is in contrast to most previous work, which has found a very marked reduction, even absence, of slow wave sleep at high altitude. Surprisingly, unlike experimental animal studies of chronic hypoxia, REM sleep was well maintained at all altitudes. Stage 2 NREM and REM sleep, total sleep time, sleep efficiency and spontaneous arousals were maintained at near sea level values. The total arousal index was increased with increasing altitude and this was due to the increasing severity of periodic breathing as altitude increased. An interesting finding of this research was that fewer than half the periodic breathing apneas and hypopneas resulted in arousal from sleep. There was a minor degree of upper airway obstruction in some subjects at sea level but this was almost resolved by 3500m. Chapter 4 reports the findings on the effects on breathing during sleep of the progressive increase of altitude, in particular the occurrence of periodic breathing. This Chapter also reports the results of changes to arterial blood gases as subjects ascended to higher altitudes. As expected, arterial blood gases were markedly altered at even the lowest altitude in Nepal (1400m) and this change became more pronounced at each new, higher altitude. Most subjects developed periodic breathing at high altitude but there was a wide variability between subjects as well as variability in the degree of periodic breathing that individual subjects developed at different altitudes. Some subjects developed periodic breathing at even the lowest altitude and this increased with increasing altitude; other subjects developed periodic breathing at one or two altitudes, while four subjects did not develop periodic breathing at any altitude. Ventilatory responses to hypoxia and hypercapnia, measured at sea level before departure to high altitude, was not significantly related to the development of periodic breathing when the group was analysed as a whole. However, when the subjects were grouped according to the steepness of their ventilatory response slopes, there was a pattern of higher amounts of periodic breathing in subjects with steeper ventilatory responses. Chapter 5 reports the findings of an experimental study carried out in the University of California, San Diego, Barcroft Laboratory on White Mountain in California. Seven subjects drove from sea level to 3800m in one day and stayed at this altitude for two nights. On one of the nights the subjects slept using a non-invasive positive pressure device via a face mask and this was found to significantly improve the sleeping oxyhemoglobin saturation. The use of the device was also found to eliminate the symptoms of Acute Mountain Sickness, as measured by the Lake Louise scoring system. This finding appears to confirm the hypothesis that lower oxygen saturation, particularly during sleep, is strongly correlated to the development of Acute Mountain Sickness and may represent a new treatment and prevention strategy for this very common high altitude disorder

The impact of two different dosing courses of acetazolamide on ventilatory sensitivity to hypoxia and hypercapnia in a young and old Cohort – a comparison study

Introduction – Acetazolamide (Az) is a carbonic anhydrase (CA) inhibitor used to treat acute mountain sickness (AMS). Current dose recommendations are to take 250mg of Az twice daily (BD) for 48 hours. However, evidence indicates that, due to impaired renal function, older people may require less to get the same protective effect. The present study aimed to assess this hypothesis by testing the hypoxic ventilatory response (HVR) and hypercapnic ventilatory response (HCVR) following the administration of Az at two different doses in young and older individuals. Methods – 13 participants were recruited (7 young, M = 24.3 ± 3.1 and 6 old, M = 71 ± 2) and performed a HVR and HCVR using a steady state method on 3 occasions: a no drug control, after 125mg Az BD for 48 hours and after 250mg Az BD for 48 hours. Az-induced alterations in acid-base balance were confirmed via blood gas sampling on each visit. Results – Both doses of Az caused significant reductions in bicarbonate (HCO3-), pH and base excess whilst also stimulating resting ventilation in both groups (p<0.001 for all). Hypoxic sensitivity was significantly blunted in the older group on Az (p=0.031). In contrast it was the young group that developed a blunted hypercapnic hypoxic response on Az, with a significant reduction in the slope (-0.013x ± 0.007x vs -0.0098x ± 0.006x, p=0.025) and intercept (1.01 ± 0.5 vs 0.77 ± 0.4, p=0.019) of the ventilation line of best fit. Estimated glomerular filtration rate (eGFR) was significantly lower in the older group (125.2 ± 17.8ml/min/1.73m2 vs 87.7 ± 8.1ml/min/1.73m2, p=0.001). Discussion – Alterations to acid-base balance were caused by 125mg Az BD in both cohorts, indicating the effectiveness of Az at inhibiting renal CA at 125mg BD. The lower eGFR recorded in the older participants would reduce the clearance of Az of the older participants. The impaired clearance of Az most likely caused the blunting effect of the HVR seen within the older group, as Az would accumulate in the circulation and inhibit off-target CA isoforms within the peripheral chemoreceptors (PCR), reducing the ventilatory drive. In contrast, it was the young cohort who experienced a blunted HCVR after using Az. Inhibition of CA in the red blood cells (RBC) causes CO2 retention and so may reduce the offloading of CO2 at the blood brain barrier (BBB) causing this blunting effect. Compensation for this action may arise through a separate mechanism in the older participants

Relationship between Baseline Inflammation and Peak Erythropoietin Levels in People Undergoing Carbon Monoxide Inhalation and Hot Water Immersion

35 pagesErythropoietin (EPO) is a hormone produced by the kidneys that is responsible for stimulating red blood cell (RBC) production. The stimulus for EPO production is a reduction in oxygen delivery to the kidneys, which can occur by reducing either the rate of blood flow or the oxygen content of the blood being delivered to the kidneys. However, EPO is not the only protein that can regulate RBCs. High levels of circulating inflammatory proteins can negatively impact RBC mass, and one of the pathways by which this can occur is by inhibiting EPO production. Recently, carbon monoxide (CO) inhalation and heat have been used as ways to reduce renal oxygen delivery, yet no studies have examined these treatments in combination nor the effects of inflammation on the EPO response in humans. The purpose of this study was twofold: 1) to determine whether combining CO inhalation and heat via hot water immersion has an additive effect on circulating EPO concentration, and 2) to examine the association between baseline inflammatory protein concentrations and EPO concentrations. It was hypothesized that 1) CO and heat will have an additive effect on circulating EPO concentrations, and 2) higher baseline levels of circulating inflammation will result in reduced EPO concentration in response to heat and CO stimuli. By inducing a hypoxic response through the interventions of CO inhalation, hot water immersion, and combined CO inhalation and heat, the mechanism(s) by which EPO is released can be better understood. Research on this topic also has important implications in treating high circulating inflammation in chronic diseases and female athletes. Male and female subjects underwent three treatments: inhalation of CO, hot-water immersion (HWI), and a combination of CO inhalation and HWI. On the CO inhalation visits, the volume of CO administered was 1.0mL/kg body weight for men and 0.8mL/kg body weight for women, and subjects breathed that volume twice, each bout lasting 10 minutes. This volume of CO was intended to raise blood carbon monoxide saturation to 10-15% and reduce functional oxygen saturation to 85-90% to simulate a moderate altitude. On the heat visits, subjects sat in a hot tub heated to 40°C for 45 minutes. An intravenous (IV) catheter was placed for all study visits to collect venous blood at baseline and every hour after treatment for six hours. Whole blood was spun and the serum stored at -80°C until analysis. The serum was analyzed for EPO concentration at all time points using an ELISA kit. Baseline inflammation was analyzed using a multi-plex flow cytometry assay (Human Inflammation Panel 1, BioLegend) that measures the following inflammatory proteins: interleukins (IL)-1β, -6, -8, -10, -12p70, -17A, -18, -23, and -33; interferons (IFN)-α2, -γ; tumor necrosis factor (TNF)-α; and monocyte chemoattractant protein (MCP)-1. All interventions were found to increase concentrations of EPO. Contrary to our hypothesis, there were no additive effects of CO inhalation and hot water immersion. A positive linear relationship was found between peak EPO concentration and baseline IL-18 concentration, although the reasoning for this relationship must be explored further

Unstable Ventilatory Control During Sleep After High Spinal Cord Injury: The Contribution Of Chemosensitivity And Hypoventilation

ABSTRACT UNSTABLE VENTILATORY CONTROL DURING SLEEP AFTER HIGH SPINAL CORD INJURY: THE CONTRIBUTION OF CHEMOSENSITIVITY AND HYPOVENTILATION by Amy T. Bascom May 2015 Advisor: Dr. Harry G. Goshgarian Major: Anatomy and Cell Biology Degree: Doctor of Philosophy A high prevalence of sleep-disordered breathing (SDB) after spinal cord injury (SCI) has been reported in the literature; however, the underlying mechanisms are not well understood. My studies had 2 aims: 1) to determine the effect of the withdrawal of the wakefulness drive to breathe on the degree of hypoventilation in SCI patients and able-bodied controls and 2) to determine the response of the peripheral chemoreceptors to brief hyperoxia (60 seconds of \u3e60% FiO2) and hypercapnia (a single breath of elevated CO2). I studied subjects with chronic cervical and high thoracic SCI and matched able-bodied subjects. For the first aim subjects underwent polysomnography, which included quantitative measurement of ventilation, timing, and upper airway resistance (RUA) on a breath-by-breath basis during transitions from wake to stage N1 sleep. Compared to able-bodied controls, SCI subjects had a significantly greater reduction in tidal volume during the transition from wake to N1sleep (from 0.51±0.21 L to 0.32±0.10 L vs. 0.47±0.13 L to 0.43±0.12 L; respectively, p\u3c0.05). Moreover, end-tidal CO2 and O2 were significantly altered from wake to sleep in SCI (38.9±2.7 vs. 40.6±3.4 mmHg; 94.1±7.1 vs. 91.2±8.3 mmHg; respectively, p˂0.05), but not in able-bodied controls (39.5±3.2 vs. 39.9±3.2 mmHg; 99.4±5.4 vs. 98.9±6.1 mmHg; respectively, p=ns). RUA was not significantly altered in either group. In aim 2 SCI subjects had a greater reduction in ventilation with hyperoxia administration (63.9±23.0 % of baseline VE) compared to able-bodied subjects (91.4±15.1 % of baseline VE, p\u3c0.05) and a higher ventilatory response to a single breath of CO2 (SCI: 0.78±0.4 L/min/mmHg vs. able-bodied: 0.26±0.1 L/min/mmHg, p\u3c0.05). In conclusion, individuals with SCI experience hypoventilation at sleep onset, which cannot be explained by upper airway mechanics and a high peripheral chemoreflex response to O2 and CO2. Sleep onset hypoventilation and high peripheral chemoresponsiveness may contribute to the development SDB in the SCI population

The influence of environmental hypoxia in the physiological responses of laboratory rats and mice during postnatal life and adulthood

Il existe chez les différentes espèces de rongeurs une importante variabilité dans les capacités à établir des colonies stables en haute altitude (HA). Par exemple, on trouve des souris (Mus) jusqu'à 4000m alors qu’il n’y a pas de rats (Rattus). La capacité des animaux à survivre et réaliser des activités physiques en HA dépend d’adaptations biologiques physiologiques (plasticité phénotypique) et génétiques ou épigénétiques. Des rats Sprague Dawley (SD) maintenus en HA dans des conditions de laboratoire survivent pendant plusieurs générations (La Paz, Bolivia – 3600m) mais présentent des signes de maladaptations physiologiques (érythrocytose excessive, hypertrophie ventriculaire droite – signe d’hypertension artérielle pulmonaire – et altération des structures alvéolaires avec élargissements des espaces pulmonaires). Ces réponses sont principalement liées à une hypersensibilité au niveau d’oxygène (O2) ambient au cours de la période postnatale et élever les rats de HA à une pression d’O2 reproduisant celle du niveau de la mer (NM) au cours de cette période améliore significativement leur adaptation physiologique1,2. Actuellement, aucune adaptation génétique n’a été mise en évidence chez des souris (Mus musculus) sauvages capturées en HA. Notre hypothèse générale est que les souris possèdent des caractéristiques physiologiques spécifiques qui assurent leur survie en HA. Pour répondre à cette hypothèse, nous avons réalisé 4 études comparant les réponses physiologiques (ventilation, métabolisme, hématologie, saturation artérielle en O2 et rythme cardiaque) entre des souris FVB et des rats SD élevés au NM (Québec, Canada) ou en HA (La Paz, Bolivie – 3600m). Nos principaux résultats démontrent que, par rapport aux rats, les souris adultes de HA présentent une surface alvéolaire augmentée associée avec une meilleure extraction d’O2 sans augmentation excessive de l’érythrocytose ni hypertrophie ventriculaire. Au NM, en conditions ambiantes, les deux espèces présentent des réponses physiologiques similaires. Par contre, après 6h d’exposition en hypoxie (12% d’O2), par rapport aux rats, les souris augmentent leur ventilation minute et diminuent leur métabolisme. Les souris augmentent également l’expression de l’hypoxia inducible factor 1 (HIF-1 – molécule principale de régulation des réponses cellulaires en hypoxie) dans le tronc cérébral après 6h d’hypoxie (15% d’O2) ; cet effet n’est pas présent chez les rats. Au NM, l’hypoxie postnatale induit une augmentation du volume pulmonaire et de la réponse ventilatoire à l’hypoxie chez les souris mais pas chez les rats. Cependant, chez les jeunes rats de HA, l’architecture pulmonaire est préservée comparée aux rats exposés en hypoxie postnatale au NM. En conclusion, les rats vivant en HA depuis plusieurs générations présentent des stratégies physiologiques pour faire face au manque d’O2 ambient leur permettant de survivre dans des conditions de laboratoire mais qui ne sont pas suffisantes pour assurer leur survie en milieu sauvage. Nos résultats confirment également que les souris possèdent des prédispositions physiologiques permettant la survie en altitude.Different rodent species present divergent abilities to colonize and establish stable colonies at high altitude (HA). Ecological studies show that mice (Mus) can be found at HA (up to 4000m) while rats (Rattus) are absent. The ability of an animal to survive and do physical activities at HA depends upon biological adaptations that can include physiological (phenotypical plasticity) and genetic, or epigenetic modifications. Adult Sprague Dawley (SD) rats can live under laboratory conditions at HA for several generations (La Paz, Bolivia – 3600m), but they display signs of physiological maladaptation such as excessive erythrocytosis, right ventricular hypertrophy (a sign of pulmonary hypertension) and altered alveolar structure with enlarged airspace in the lungs. These responses are mainly linked to an excessive sensibility to the oxygen (O2) ambient level during postnatal life. Indeed, raising the HA rats under sea level (SL) O2 pressure during early postnatal life significantly improved the physiological adaptation1,2. Furthermore, in HA wild mice (Mus musculus) living at HA, there is no signs of genetic adaptation to this environment. Accordingly, our general hypothesis is that mice possess specific physiological traits ensuring survival at HA. To assess this hypothesis, we conducted 4 studies to compare physiological responses (including ventilation, metabolic rate, hematology, lung morphology, arterial O2 saturation and heart rate) between FVB mice and SD rats raised at SL (Quebec, Canada) or HA (La Paz, Bolivia – 3600m). Our main results show that compared with rats, HA adult mice display enhanced alveolar surface area associated with increased O2 extraction, and avoid excessive erythrocytosis and right ventricular hypertrophy. At SL, under ambient conditions, mice and rats display similar physiological variables. However, after 6 hours of sustained hypoxia (12% O2), mice have higher minute ventilation and lower metabolic rate than rats. Mice also had an increased expression of the hypoxia inducible factor 1 (HIF-1 – the principal mediator of the cellular responses in hypoxia) in the brainstem after 6 hours of hypoxia (15% O2), while this response was not observed in rats. Hypoxic exposure during postnatal life at SL increased the lung volume and the hypoxic ventilatory response in mice but not rats. However, young HA rats preserve their lung architecture compared with young SL rats exposed to postnatal hypoxia. We conclude that rats living at HA for several generations display physiological strategies to cope with the ambient hypoxia that allow them to survive in laboratory conditions but are not sufficient to establish stables colonies in the wild. Also, our results confirm that mice are predisposed to withstand hypoxic environment