The recent Journal of Physiological Anthropology article on polycythemia among Tibetan highlanders (Arima et al., J Physiol Anthropol 43:25, 2024) piqued our interest because we collected similar data in the same Nepali village in Upper Mustang two years later with notably different results (Cho et al., Evol Med Public Health 2017:82–96, 2017; Ye et al., Proc Natl Acad Sci U S A 121:e2403309121, 2024). Arima et al report high prevalences of chronic disease and conclude that Tsarang villagers have poor health. Here, we describe our relevant findings to show that authors' definitions and other research design elements can yield different population health implications. Our study sampled ethnic Tibetan Upper Mustang women 39 Years and older in 2012 who had been married or pregnant and were lifelong residents of this village at 3500m. At our 2019 follow-up study, the women were 46 Years and older. Fifty-five of the 64 eligible Tsarang residents (85

Highland groups have adapted to the extreme selective pressures of hypoxia at high altitude via alterations in the oxygen-transport cascade. PRKAA1, which encodes the catalytic subunit of the AMP-activated protein kinase (AMPK), is a notable target of natural selection in Andeans and has been associated with protective fetal phenotypes in this population. AMPK is a universal cellular energy sensor involved in a multitude of physiological processes, including ventilation and the hypoxic ventilatory response (HVR) in animal models. We localized a signal of positive selection and identified a regulatory promoter variant (rs10035235, C>T) of adaptive significance that is associated with ventilatory and sleep phenotypes in male Andean highlanders as well as sleep phenotypes in publicly available lowland cohorts. This work identifies a functional, adaptive, and likely pleiotropic regulatory variant in PRKAA1 in Andeans that may accentuate hypoxia-induced ventilation and provide protection from sleep-disordered breathing in both high- and lowland populations.

We chose the “natural laboratory” provided by high-altitude native ethnic Tibetan women who had completed childbearing to examine the hypothesis that multiple oxygen delivery traits were associated with lifetime reproductive success and had genomic associations. Four hundred seventeen (417) women aged 46 to 86 y residing at ≥3,500 m in Upper Mustang, Nepal, provided information on reproductive histories, sociocultural factors, physiological measurements, and DNA samples for this observational cohort study. Simultaneously assessing multiple traits identified combinations associated with lifetime reproductive success measured as the number of livebirths. Women with the most livebirths had distinctive hematological and cardiovascular traits. A hemoglobin concentration near the sample mode and a high percent of oxygen saturation of hemoglobin raised arterial oxygen concentration without risking elevated blood viscosity. We propose ongoing stabilizing selection on hemoglobin concentration because extreme values predicted fewer livebirths and directional selection favoring higher oxygen saturation because higher values had more predicted livebirths. EPAS1, an oxygen homeostasis locus with strong signals of positive natural selection and a high frequency of variants occurring only among populations indigenous to the Tibetan Plateau, associated with hemoglobin concentration. High blood flow into the lungs, wide left ventricles, and low hypoxic heart rate responses aided effective convective oxygen transport to tissues. Women with physiologies closer to unstressed, low altitude values had the highest lifetime reproductive success. This example of ethnic Tibetan women residing at high altitudes in Nepal links reproductive fitness with trait combinations increasing oxygen delivery under severe hypoxic stress and demonstrates ongoing natural selection.

Biosynthesis and storage of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is under dietary and genetic control in Atlantic salmon (Salmo salar). Enhanced EPA and DHA biosynthesis and storage may improve utilization, and thus reduce marine forage fish oil use in aquafeeds. To determine phenotypic variability in EPA and DHA tissue content and growth performance, 50 families (n = 30 salmon/family, 48 g/fish initial weight) of Atlantic salmon (Saint John River strain) were reared in freshwater and fed either a fish oil (FO) control diet or FO-free diet. After 16 weeks, body size was recorded. Salmon fed the FO-free diet overall showed significantly lower growth performance compared to salmon fed the FO control diet, regardless of family. To determine the relationship between growth and FA content, the five families with the highest and the five families with the lowest weight gain were sampled for tissue and liver FA analysis. There was a significant interaction between growth and diet. The family x diet interaction was significant for final weight, final length, weight gain, growth rate and feed conversion ratio. Among the five fastest growing families, there was a significant family effect for EPA and DHA storage in the liver but not for muscle. Among the five slowest growing families, by comparison salmon had similar liver DHA and EPA content, independent of diet treatment. Family and diet were interacting factors that determine EPA and DHA storage in liver. Certain fast-growing families also had significantly higher DHA content in liver and muscle. This study demonstrates the potential for selecting families that can better utilize a diet without marine forage fish oil.

Populations living at high altitudes exhibit distinct cardiovascular and ventilatory responses to hypoxia, which may result from exposure to the selective pressure of chronic hypoxia throughout hundreds of generations at high altitude. Compared to Andean highlanders and some acclimatized lowlanders, many Tibetans show an increased hypoxic ventilatory response (HVR) and lower hemoglobin concentration ([Hb]). While the effects of menopause on [Hb] have been well studied, its effects on HVR and heart rate responses to hypoxia (HHRR) in Tibetan women residing at high altitude have not been elucidated. We hypothesized that hypoxic ventilatory and heart rate responses to hypoxia decrease with menopausal status in Tibetan women, suggesting a change of adaptation during post-reproductive years in women. We measured minute ventilation (V I ) and heart rate (HR) during room air and acute hypoxia in 376 Tibetan women (age range 46-86 years old) living in in Mustang, Nepal (>11,482ft / 3,500m) and compared responses between pre- and post-menopausal groups (mean ± SEM). Using a rebreathing system, we induced hypoxia to produce events of at least 10% desaturation (from 91 ± 0.2% to 78 ± 0.2%), expressed HVR and HRR as -ΔV I / ΔSpO 2 and -ΔHR / ΔSpO 2 , respectively, and tested for associations between HVR and HHRR with age and [Hb]. HVR, HHRR, and [Hb] associated negatively with age in the post- but not pre-menopausal group. During hypoxia, post-menopausal women had lower V I (14.2 ± 0.2 L/min) and HR (80 ± 1 BPM) when compared (p<0.01) to pre-menopausal women (16.9 ± 0.4 L/min for V I and 85 ± 1 BPM for HR). V I was also lower in room air conditions (p<0.01) for post-menopausal (11.5 ± 0.1 L/min) versus pre-menopausal women (12.6 ± 0.2 L/min). HVR and HHRR was lower in post- (0.21 ± 0.01 L/%O2 and 0.65 ± 0.02 BPM/%O2 respectively) versus pre-menopausal women (HVR: 0.34 ± 0.03 L/%O2 and HHRR: 0.92 ± 0.05 BPM/%O2). Pre-menopausal women also exhibited negative correlations with HVR and HHRR with increasing [Hb]; however, these correlations were not significant in the post-menopausal group. A non-blunted HVR is a hallmark of adaptation in Tibetans, and physiological changes observed in Tibetan women during later life stages may result in a loss of such traits. These data suggest a hypothesis of menopause-related loss, or change, of adaptation to high-altitude hypoxia among middle-aged to elderly Tibetan women. Supported by NSF award 1831530 to CMB and NIH 1R01HL145470 to TSS. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The hypoxic ventilatory response (HVR) is the increase in breathing in response to reduced arterial oxygen pressure. Over several decades, studies have revealed substantial population-level differences in the magnitude of the HVR as well as significant inter-individual variation. In particular, low HVRs occur frequently in Andean high-altitude native populations. However, our group conducted hundreds of HVR measures over several years and commonly observed low responses in sea-level populations as well. As a result, we aimed to determine the normal HVR distribution, whether low responses were common, and to what extent variation in study protocols influence these findings. We conducted a comprehensive search of the literature and examined the distributions of HVR values across 78 studies that utilized step-down/steady-state or progressive hypoxia methods in untreated, healthy human subjects. Several studies included multiple datasets across different populations or experimental conditions. In the final analysis, 72 datasets reported mean HVR values and 60 datasets provided raw HVR datasets. Of the 60 datasets reporting raw HVR values, 35 (58.3%) were at least moderately positively skewed (skew > 0.5), and 21 (35%) were significantly positively skewed (skew > 1), indicating that lower HVR values are common. The skewness of HVR distributions does not appear to be an artifact of methodology or the unit with which the HVR is reported. Further analysis demonstrated that the use of step-down hypoxia versus progressive hypoxia methods did not have a significant impact on average HVR values, but that isocapnic protocols produced higher HVRs than poikilocapnic protocols. This work provides a reference for expected HVR values and illustrates substantial inter-individual variation in this key reflex. Finally, the prevalence of low HVRs in the general population provides insight into our understanding of blunted HVRs in high-altitude adapted groups.

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.

INTRODUCTION Faults or errors during use of closed-circuit rebreathers (CCRs) can cause hypoxia. Military aviators face a similar risk of hypoxia and undergo awareness training to determine their 'hypoxia signature', a personalised, reproducible set of symptoms. We aimed to establish a hypoxia signature among divers, and to investigate their ability to detect hypoxia and self-rescue while cognitively overloaded. METHODS Eight CCR divers and 12 scuba divers underwent an initial unblinded hypoxia exposure followed by three trials; a second hypoxic trial and two normoxic trials in randomised order. Hypoxia was induced by breathing on a CCR with no oxygen supply. Subjects pedalled on a cycle ergometer while playing a neurocognitive computer game to simulate real world task loading. Subjects identified hypoxia symptoms by pointing to a board listing common hypoxia symptoms, and were instructed to perform a 'bailout' procedure to mimic self-rescue if they perceived hypoxia. Divers were prompted to bailout if peripheral oxygen saturation fell to 75%, or after six minutes during normoxic trials. Subsequently we interviewed subjects to determine their ability to distinguish hypoxia from normoxia. RESULTS Ninety-five percent of subjects (19/20) showed agreement between unblinded and blinded hypoxia symptoms. Subjects correctly identified the gas mixture in 85% of the trials. During unblinded hypoxia, only 25% (5/20) of subjects performed unprompted bailout. Fifty-five percent of subjects (11/20) correctly performed the bailout but only when prompted, while 15% (3/20) were unable to bailout despite prompting. During blinded hypoxia 45% of subjects (9/20) performed the bailout unprompted while 15% (3/20) remained unable to bailout despite prompting. CONCLUSIONS Although our data support a normobaric hypoxia signature among both CCR and scuba divers under experimental conditions, most subjects were unable to recognise hypoxia in real time and perform a self-rescue unprompted, although this improved in the second hypoxia trial. These results do not support hypoxia exposure training for CCR divers.

People with high-altitude ancestry exhibit distinct cellular, respiratory, and cardiovascular adaptive phenotypes relative to individuals with lowland ancestry. For example, Tibetans at high altitude exhibit higher ventilatory responses to hypoxia relative to Han Chinese at comparable altitude. We hypothesize Tibetans living at intermediate altitude maintain responses similar to those at high altitude. We measured levels of total hemoglobin ([Hb]), carboxyhemoglobin saturation (SpCO), and methemoglobin (MetHb), as well as the hypoxic and heart rate responses to acute hypoxia (HVR and HHR, respectively) under isocapnic and poikilocapnic conditions, in 21 individuals of Tibetan (n = 21) and Han Chinese (n = 16) ancestry residing at ~1300 m (~4327 ft) in Salt Lake City, Utah. To study ventilatory and heart rate responses to changes of CO2 during hypoxia (ΔVI /ΔEtCO2 and ΔHR/ΔEtCO2 respectively), we measured the difference in ventilation and heart rate between isocapnic (constant End-tidal CO2) and poikilocapnic (with decreased End-tidal CO2 due to hyperventilation) hypoxic conditions. Tibetans had lower [Hb] (p < 0.002), higher SpCO (p < 0.004), and higher MetHb (p < 0.02) levels compared to Han Chinese. [Hb] is negatively correlated with HHR in the Han Chinese (p < 0.05), but this was not observed in Tibetans. We did not find significant differences in HVR between Tibetans and Han Chinese, in contrast to previous reports at high altitude; however, we found that Tibetans exhibited a blunted HHR during poikilocapnic hypoxia (p < 0.03) relative to Han Chinese. We did not find differences in the ΔVI /ΔEtCO2 between the two groups, but Tibetans had lower ΔHR/ΔEtCO2 with more negative values compared to Han Chinese (p < 0.01). We also found that the correlation between HVR and HHR is similar for both groups during isocapnia, but the slopes of these correlations are significantly different in poikilocapnia (p < 0.003) with a positive relationship observed only in Tibetans (p < 0.006). Our results show that, at intermediate altitude, individuals with Tibetan ancestry have lower levels of [Hb], higher levels of Hb metabolites, and exhibit an attenuated heart rate response to hypoxia. The correlation between ventilatory and heart rate responses to hypoxia is similar between groups during isocapnia but is decreased during poikilocapnic hypoxia (with lower levels of CO2 due to hyperventilation) in Han Chinese but not Tibetans, suggesting a CO2-dependent effect on HR in Han Chinese but not in Tibetans. Therefore, Hb levels and metabolism but not the HVR to hypoxia may be maintained in individuals with Tibetan ancestry at intermediate altitudes. Correlations in poikilocapnic vs. isocapnic hypoxia may suggest an attenuated effect of CO2 on heart rate during hypoxia in people with Tibetan ancestry.

Concern is often voiced over the ongoing loss of atmospheric O-2. This loss, which is caused by fossil-fuel burning but also influenced by other processes, is likely to continue at least for the next few centuries. We argue that this loss is quite well understood, and the eventual decrease is bounded by the fossil-fuel resource base. Because the atmospheric O-2 reservoir is so large, the predicted relative drop in O-2 is very small even for extreme scenarios of future fossil-fuel usage which produce increases in atmospheric CO2 sufficient to cause catastrophic climate changes. At sea level, the ultimate drop in oxygen partial pressure will be less than 2.5 mm Hg out of a baseline of 159 mmHg. The drop by year 2300 is likely to be between 0.5 and 1.3 mmHg. The implications for normal human health is negligible because respiratory O-2 consumption in healthy individuals is only weakly dependent on ambient partial pressure, especially at sea level. The impacts on top athlete performance, on disease, on reproduction, and on cognition, will also be very small. For people living at higher elevations, the implications of this loss will be even smaller, because of a counteracting increase in barometric pressure at higher elevations due to global warming.

Population living at high altitudes for hundreds of generations exhibit distinct respiratory and cardiovascular responses to hypoxia relative to other populations. The extent of these differences at intermediate altitude is less understood and could provide important insight into ancestry specific physiological responses in the absence of hypoxia. We hypothesized that Tibetans living at intermediate altitude (1300 m, 4327 ft) exhibit an increased hypoxic ventilatory response (HVR) and an elevated hypoxic heart rate response (HHR) compared to Han Chinese examined at the same altitude. To estimate O2 sensitivity, we measured ventilation (VI), heart rate (HR) and O2 saturation (Sat) under hyperoxic conditions (30% O2) and then during a hypoxic stimulus (10% minimum desaturation) keeping end‐tidal CO2 (EtCO2) levels constant (isocapnia) or allowing changes in the EtCO2 (poikilocapnia). We quantified HVR and HHR as change in VI and HR between hyperoxia and hypoxia standardized per the change in O2 Sat (ΔVI/ΔSat and ΔHR/ΔSat respectively). To estimate CO2 sensitivity, we measured changes in VI and HR responses between poikilocapnic and isocapnic hypoxia and standardized these changes per change in EtCO2 (ΔVI/ΔEtCO2 and ΔHR/ΔEtCO2 respectively). We did not find significant differences in ΔVI/ΔSat and ΔVI/ΔEtCO2 between Tibetan and Han Chinese during isocapnic and poikilocapnic hypoxia. The ΔHR/ΔSat between populations during isocapnic hypoxia was also not significantly different. However, Tibetans exhibited a blunted ΔHR/ΔSat during poikilocapnic hypoxia compared to Han Chinese (35.8% decrease, p < 0.02) with a significant ancestry effect in women (37.6% decrease, p < 0.009). The mean value of ΔHR/ΔEtCO2 was positive in the Han Chinese group but negative in Tibetan (169% difference, p < 0.02), indicating that Tibetans had a blunted HR response when CO2 is not controlled. Our results show that HVR responses in Tibetan individuals with high‐altitude ancestry is not different than Han Chinese residents at comparable intermediate altitude, but the HHR to hypoxia during poikilocapnia is blunted in individuals with Tibetan ancestry. These results suggest that, at intermediate altitude, individuals with Tibetan ancestry exhibit an attenuated heart rate response to hypoxia due to an increased contribution of the CO2 chemosensory response.Support or Funding InformationSupported by NIH 1RO1HL145470 and R01 HL‐081823.

Andean highlanders are challenged by chronic hypoxia and many exhibit elevated hematocrit (Hct) and blunted ventilation compared to other high-altitude populations. While many Andeans develop Chronic Mountain Sickness (CMS) and excessive erythrocytosis, Hct varies markedly within Andean men and women and may be driven by individual differences in ventilatory control and/or sleep events which exacerbate hypoxemia. To test this hypothesis, we quantified relationships between resting ventilation and ventilatory chemoreflexes, sleep desaturation, breathing disturbance, and Hct in Andean men and women. Ventilatory measures were made in 109 individuals (n = 63 men; n = 46 women), and sleep measures in 45 of these participants (n = 22 men; n = 23 women). In both men and women, high Hct was associated with low daytime SpO2 (p < 0.001 and p < 0.002, respectively) and decreased sleep SpO2 (mean, nadir, and time <80%; all p < 0.02). In men, high Hct was also associated with increased end-tidal PCO2 (p < 0.009). While ventilatory responses to hypoxia and hypercapnia did not predict Hct, decreased hypoxic ventilatory responses were associated with lower daytime SpO2 in men (p < 0.01) and women (p < 0.009) and with lower nadir sleep SpO2 in women (p < 0.02). Decreased ventilatory responses to CO2 were associated with more time below 80% SpO2 during sleep in men (p < 0.05). The obstructive apnea index and apnea-hypopnea index also predicted Hct and CMS scores in men after accounting for age, BMI, and SpO2 during sleep. Finally, heart rate response to hypoxia was lower in men with higher Hct (p < 0.0001). These data support the idea that hypoventilation and decreased ventilatory sensitivity to hypoxia are associated with decreased day time and nighttime SpO2 levels that may exacerbate the stimulus for erythropoiesis in Andean men and women. However, interventional and longitudinal studies are required to establish the causal relationships between these associations.

We hypothesized that hypoxia inducible factor 1α (HIF‐1α) in CNS respiratory centres is necessary for ventilatory acclimatization to hypoxia (VAH); VAH is a time‐dependent increase in baseline ventilation and the hypoxic ventilatory response (HVR) occurring over days to weeks of chronic sustained hypoxia (CH). Constitutive deletion of HIF‐1α in CNS neurons in transgenic mice tended to blunt the increase in HVR that occurs in wild‐type mice with CH. Conditional deletion of HIF‐1α in glutamatergic neurons of the nucleus tractus solitarius during CH significantly decreased ventilation in acute hypoxia but not normoxia in CH mice. These effects are not explained by changes in metabolic rate, nor CO2, and there were no changes in the HVR in normoxic mice. HIF‐1α mediated changes in gene expression in CNS respiratory centres are necessary in addition to plasticity of arterial chemoreceptors for normal VAH.

Ventilatory acclimatization to hypoxia (VAH) is defined as the time‐dependent increase in ventilation which occurs with chronic sustained hypoxia (CSH) of several hours to months. Previous research has shown that astrocytes and microglia undergo a morphology shift, indicating a possible change in activity, upon exposure to hypoxic conditions and may contribute to VAH. Understanding when and how the different cell types in respiratory control regions are activated is pertinent to understanding ventilatory control during hypoxic conditions. The first part of this study aimed to optimize the Sholl analysis method to detect morphological changes in microglia. Two different microglia antibodies, Iba‐1 and CD11b[Ox42], were compared using Sholl analysis to determine which antibody best represents the branching pattern of the individual microglia. Analysis indicated that neither antibody was statistically different from the other in terms of microglia branching (p>0.05), so CD11b[Ox42] was chosen to simplify the immunohistochemistry protocol. The second part of this study assessed the morphology shift of microglia in the nucleus tractus solitarius (NTS) and Pre‐Bötzinger Complex (PBC) following CSH exposure. Based on previous research, we hypothesized that microglia in the NTS and PBC would be activated following CSH exposure, as assessed via a morphology shift to a more amoeboid state indicated by less microglia branch crossings of the Sholl brackets. To address this hypothesis, rats were exposed to either normoxic, 60‐minutes of CSH, or 12‐hours of CSH. Microglia morphology was assessed in perfused brainstem tissue via immunohistochemistry, confocal imaging, and image analysis. In the NTS, microglia branching analysis revealed a trend towards a more amoeboid morphology at the 60‐minute CSH time point, but only one of the Sholl analysis brackets, 21–30μM, was statistically significant from normoxic conditions (p<0.05). In the PBC, microglia branching analysis also revealed a trend towards a more amoeboid morphology at the 60‐minute CSH time point with statistically significant (p<0.05) branch patterns at the 11–20μM, 21–30μM, and 31–40 μM Sholl brackets. A morphology shift of microglia to a more amoeboid state could indicate their localized response to neurotransmitters or cytokines. In a follow‐up study we investigated the expression of IL‐1β in the NTS region using immunofluorescent labeling. Rat brainstem tissue from normoxic conditions, 15‐minute CSH, and 60‐minute CSH was labeled with antibodies against IL‐1β, GFAP, and Cd11b[Ox42]. IL‐1β positive cells were counted in the NTS region. This preliminary set of cell counts (n=2) suggests that there is an increase in IL‐1β positive cells with CHS exposure (normoxic 17 ± 2 IL‐1β positive cells, 15‐minute CSH 31.5 ± 0.5 IL‐1β positive cells, 60‐minute CSH 29.5 ± 9.5 IL‐1β positive cells). Taken together these data provide a great starting point in assessing the activation profiles of glial cells and cytokine activity in select respiratory control regions in the brainstem.Support or Funding InformationCentenary College Student‐Faculty Summer Research Award 2018 and 2019 (JRF and JAS); NIH R01HL081823 (FLP)

Infectious salmon anaemia (ISA) is a highly virulent viral disease of Atlantic salmon that causes massive economic losses to infected aquaculture operations. Our goal was to detect and map quantitative trait loci (QTL) that confer resistance to ISA in an admixed commercial strain of Atlantic salmon that was largely founded from the Saint John River (SJR) in North America. Full-sibling families were challenged with a virulent strain of ISA virus. Mortality was tracked during two annual trials with individual fish that survived to the end of the trial being classified as ‘resistant’, and those that died were classified as ‘susceptible’. Ten families with intermediate levels of mortality and an average size of 54.2 individuals were chosen for genotyping with a 50K SNP array designed for the SJR strain. Single nucleotide polymorphisms that were segregating within families were first used to make a composite 11K female linkage map that was then used to find the positions of QTL for ISA resistance using a half-sib model. The dam-based HS model detected a total of three QTL for ISA resistance including an experiment-wide significant QTL on Ssa25 that accounted for 8.3% of the phenotypic variance and chromosome-wide significant QTL on Ssa03 and on Ssa04 that accounted for 6.0% and 6.6% respectively. We conclude that classic linkage mapping within families continues to be an important method of detecting QTL for oligogenic traits in strains founded from multiple populations. Single nucleotide polymorphisms with moderate trait effects are being used to select within families for more ISA-resistant strains of Atlantic salmon.

Chronic sustained hypoxia (CH) occurs in populations living at high altitude and in patients with chronic pulmonary disease. Exposure to CH produces ventilatory acclimatization to hypoxia (VAH) and increases the hypoxic ventilatory response (HVR) by mechanisms that involve areas of the brainstem that control breathing. The nucleus tractus solitarius (NTS) is a sensory integrative center in the medulla receiving carotid body afferents and known to be crucial for VAH. Our previous results demonstrated that glia cells in the rat NTS contribute to VAH but these mechanisms have not been studied in mice exposed to CH beyond 24 hours. We hypothesized that CH produces an early transient activation of astrocytes and microglia in the mouse brainstem as observed in rats. To study the activation of glial cells with CH, we exposed mice to normobaric hypoxia (10% FiO2) for 0.5, 1 and 4 hours and 1 and 7 days. Mice were perfused with 4% paraformaldehyde and brainstem sections were obtained. We quantified astrocyte activation by measuring glial fibrillary acidic protein (GFAP) intensity with immunofluorescence, and microglial activation by measuring branch morphology using Iba‐1 marker. Exposure to CH significantly increased GFAP intensity after 30 minutes and 1day while microglia morphology did not change significantly. The results differ from those in rats (J. Neurophysiol.117: 1625–1635, 2017) and suggest that time‐dependent astrocyte activation in the NTS may contribute to VAH.Support or Funding InformationSupported by NIH RO1 HL‐081823