Brain stem serotonin protects blood pressure in neonatal rats exposed to episodic anoxia

In neonatal rodents, a loss of brain stem serotonin [5-hydroxytryptamine (5-HT)] in utero or at birth compromises anoxia-induced gasping and the recovery of heart rate (HR) and breathing with reoxygenation (i.e., autoresuscitation). How mean arterial pressure (MAP) is influenced after an acute loss of brain stem 5-HT content is unknown. We hypothesized that a loss of 5-HT for ∼1 day would compromise MAP during episodic anoxia. We injected 6-fluorotryptophan (20 mg/kg ip) into rat pups (postnatal days 9–10 or 11–13, n = 22 treated, 24 control), causing a ∼70% loss of brain stem 5-HT. Pups were exposed to a maximum of 15 anoxic episodes, separated by 5 min of room air to allow autoresuscitation. In younger pups, we measured breathing frequency and tidal volume using “head-out” plethysmography and HR from the electrocardiogram. In older pups, we used whole body plethysmography to detect gasping, while monitoring MAP. Gasp latency and the time required for respiratory, HR, and MAP recovery following each episode were determined. Despite normal gasp latency, breathing frequency and a larger tidal volume ( P < 0.001), 5-HT-deficient pups survived one-half the number of episodes as controls ( P < 0.001). The anoxia-induced decrease in MAP experienced by 5-HT-deficient pups was double that of controls ( P = 0.017), despite the same drop in HR ( P = 0.48). MAP recovery was delayed ∼10 s by 5-HT deficiency ( P = 0.001). Our data suggest a loss of brain stem 5-HT leads to a pronounced, premature loss of MAP in response to episodic anoxia. These data may help explain why some sudden infant death syndrome cases die from what appears to be cardiovascular collapse during apparent severe hypoxia.

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Vulnerability of neonatal respiratory neural control to sustained hypoxia during a uniquely sensitive window of development

Journal of Applied Physiology ◽

10.1152/japplphysiol.00976.2013 ◽

2014 ◽

Vol 116 (5) ◽

pp. 514-521 ◽

Cited By ~ 17

Author(s):

C. A. Mayer ◽

J. M. Di Fiore ◽

R. J. Martin ◽

P. M. MacFarlane

Keyword(s):

Critical Period ◽

Neural Control ◽

Sudden Infant Death ◽

Whole Body ◽

Sudden Infant ◽

Environmental Stressor ◽

Rat Pups ◽

Comparable Effect ◽

Whole Body Plethysmography ◽

Sustained Hypoxia

The first postnatal weeks represent a period of development in the rat during which the respiratory neural control system may be vulnerable to aberrant environmental stressors. In the present study, we investigated whether sustained hypoxia (SH; 11% O2) exposure starting at different postnatal ages differentially modifies the acute hypoxic (HVR) and hypercapnic ventilatory response (HCVR). Three different groups of rat pups were exposed to 5 days of SH, starting at either postnatal age 1 (SH1–5), 11 (SH11–15), or 21 (SH21–25) days. Whole body plethysmography was used to assess the HVR and HCVR the day after SH exposure ended. The primary results indicated that 1) the HVR and HCVR of SH11–15 rats were absent or attenuated (respectively) compared with age-matched rats raised in normoxia; 2) there was a profoundly high (∼84% of pups) incidence of unexplained mortality in the SH11–15 rats; and 3) these phenomena were unique to the SH11–15 group with no comparable effect of the SH exposure on the HVR, HCVR, or mortality in the younger (SH1–5) or older (SH21–25) rats. These results share several commonalities with the risk factors thought to underlie the etiology of sudden infant death syndrome, including 1) a vulnerable neonate; 2) a critical period of development; and 3) an environmental stressor.

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Maturation of baseline breathing and of hypercapnic and hypoxic ventilatory responses in newborn mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.281.5.r1746 ◽

2001 ◽

Vol 281 (5) ◽

pp. R1746-R1753 ◽

Cited By ~ 23

Author(s):

Sylvain Renolleau ◽

Stéphane Dauger ◽

Fanny Autret ◽

Guy Vardon ◽

Claude Gaultier ◽

...

Keyword(s):

Cesarean Section ◽

Tidal Volume ◽

Mammalian Species ◽

Whole Body ◽

Body Plethysmography ◽

Genetic Studies ◽

Newborn Mice ◽

Ventilatory Responses ◽

Neuronal Mechanisms ◽

Whole Body Plethysmography

Breathing during the first postnatal hours has not been examined in mice, the preferred mammalian species for genetic studies. We used whole body plethysmography to measure ventilation (V˙e), breath duration (TTOT), and tidal volume (Vt) in mice delivered vaginally (VD) or by cesarean section (CS). In experiment 1, 101 VD and 100 CS pups aged 1, 6, 12, 24, or 48 h were exposed to 8% CO2 or 10% O2for 90 s. In experiment 2, 31 VD pups aged 1, 12, or 24 h were exposed to 10% O2 for 5 min. Baseline breathing maturation was delayed in CS pups, but V˙eresponses to hypercapnia and hypoxia were not significantly different between VD and CS pups [at postnatal age of 1 h (H1): 48 ± 44 and 18 ± 32%, respectively, in VD and CS pups combined]. TheV˙e increase induced by hypoxia was greater at H12 (46 ± 27%) because of TTOT response maturation. At all ages, hypoxic decline was ascribable mainly to a Vtdecrease, and posthypoxic decline was ascribable to a TTOTincrease with apneas, suggesting different underlying neuronal mechanisms.

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Maternal dietary tryptophan deficiency alters cardiorespiratory control in rat pups

Journal of Applied Physiology ◽

10.1152/japplphysiol.00788.2010 ◽

2011 ◽

Vol 110 (2) ◽

pp. 318-328 ◽

Cited By ~ 13

Author(s):

Eliana M. Penatti ◽

Alexis E. Barina ◽

Sharat Raju ◽

Aihua Li ◽

Hannah C. Kinney ◽

...

Keyword(s):

Brain Stem ◽

Sudden Infant Death ◽

Normal Weight ◽

Sudden Infant ◽

Postnatal Life ◽

Cardiorespiratory Control ◽

Cardiorespiratory Function ◽

Rat Pups ◽

Neuronal Number

Malnutrition during pregnancy adversely affects postnatal forebrain development; its effect upon brain stem development is less certain. To evaluate the role of tryptophan [critical for serotonin (5-HT) synthesis] on brain stem 5-HT and the development of cardiorespiratory function, we fed dams a diet ∼45% deficient in tryptophan during gestation and early postnatal life and studied cardiorespiratory variables in the developing pups. Deficient pups were of normal weight at postnatal day (P)5 but weighed less than control pups at P15 and P25 ( P < 0.001) and had lower body temperatures at P15 ( P < 0.001) and P25 ( P < 0.05; females only). Oxygen consumption (V̇o2) was unaffected. At P15, deficient pups had an altered breathing pattern and slower heart rates. At P25, they had significantly lower ventilation (V̇e) and V̇e-to-V̇o2 ratios in both air and 7% CO2. The ventilatory response to CO2 (% increase in V̇e/V̇o2) was significantly increased at P5 (males) and reduced at P15 and P25 (males and females). Deficient pups had 41–56% less medullary 5-HT ( P < 0.01) compared with control pups, without a difference in 5-HT neuronal number. These data indicate important interactions between nutrition, brain stem physiology, and age that are potentially relevant to understanding 5-HT deficiency in the sudden infant death syndrome.

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Aerodynamic factors affecting rebreathing in infants

Journal of Applied Physiology ◽

10.1152/japplphysiol.00784.2018 ◽

2019 ◽

Vol 126 (4) ◽

pp. 952-964

Author(s):

Nadav Itzhak ◽

David Greenblatt

Keyword(s):

Tidal Volume ◽

Strouhal Number ◽

Prone Position ◽

Sudden Infant Death Syndrome ◽

Infant Death ◽

Sudden Infant Death ◽

Sudden Infant ◽

Breathing Frequency ◽

Aerodynamic Parameters ◽

Expired Air

The rebreathing of expire air, with high carbon dioxide and low oxygen concentrations, has long been implicated in unexplained Sudden Infant Death Syndrome (SIDS) when infants are placed to sleep in a prone (facedown) position. This study elucidates the effect of the aerodynamic parameters Reynolds number, Strouhal number, and Froude number on the percentage of expired air that is reinspired (rebreathed). A nasal module was designed that served as a simplified geometric representation of infant nostrils and placed above a hard, flat surface. Quantitative and flow visualization experiments were performed to measure rebreathing, using water as the working medium, under conditions of dynamic similarity. Different anatomic (e.g., tidal volume, nostril diameter), physiological (e.g., breathing frequency), and environmental (e.g., temperature, distance from the surface) factors were considered. Increases in Strouhal number (simultaneously faster and shallower breathing) always produced higher rebreathed percentages, because rolled-up vortices in the vicinity of the nostrils had less time to move away by self-induction. Positively and negatively buoyant flows resulted in significant rebreathing. In the latter case, consistent with a warm environment and a high percentage of rebreathed CO2, denser gas pooled in the vicinity of the nostrils. Reynolds numbers below 200 also dramatically increased rebreathing because the expired gas pooled much closer to the nostrils. These results clearly elucidated how the prone position dramatically increases rebreathing by a number of different mechanisms. Furthermore, the results offer plausible explanations of why a high-temperature environment and low birthweight are SIDS risk factors. NEW & NOTEWORTHY A fundamentally new aerodynamics-based approach to the study of rebreathing of expired air in infants is presented. Rebreathing is implicated in unexplained Sudden Infant Death Syndrome (SIDS) when infants sleep in a prone position. This is the first time that aerodynamic parameters are systematically varied and their effects on rebreathing quantified. The study provides us with a deeper understanding of the effects of breathing frequency, tidal volume (birthweight) and environmental conditions.

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Novel whole body plethysmography system for the continuous characterization of sleep and breathing in a mouse

Journal of Applied Physiology ◽

10.1152/japplphysiol.00818.2011 ◽

2012 ◽

Vol 112 (4) ◽

pp. 671-680 ◽

Cited By ~ 24

Author(s):

A. B. Hernandez ◽

J. P. Kirkness ◽

P. L. Smith ◽

H. Schneider ◽

M. Polotsky ◽

...

Keyword(s):

Tidal Volume ◽

Gold Standard ◽

Inbred Mouse ◽

Respiratory Movement ◽

Whole Body ◽

Mouse Strains ◽

Obese Mouse ◽

Body Plethysmography ◽

Breathing Patterns ◽

Whole Body Plethysmography

Sleep is associated with marked alterations in ventilatory control that lead to perturbations in respiratory timing, breathing pattern, ventilation, pharyngeal collapsibility, and sleep-related breathing disorders (SRBD). Mouse models offer powerful insight into the pathogenesis of SRBD; however, methods for obtaining the full complement of continuous, high-fidelity respiratory, electroencephalographic (EEG), and electromyographic (EMG) signals in unrestrained mice during sleep and wake have not been developed. We adapted whole body plethysmography to record EEG, EMG, and respiratory signals continuously in unrestrained, unanesthetized mice. Whole body plethysmography tidal volume and airflow signals and a novel noninvasive surrogate for respiratory effort (respiratory movement signal) were validated against simultaneously measured gold standard signals. Compared with the gold standard, we validated 1) tidal volume (correlation, R2 = 0.87, P < 0.001; and agreement within 1%, P < 0.001); 2) inspiratory airflow (correlation, R2 = 0.92, P < 0.001; agreement within 4%, P < 0.001); 3) expiratory airflow (correlation, R2 = 0.83, P < 0.001); and 4) respiratory movement signal (correlation, R2 = 0.79–0.84, P < 0.001). The expiratory airflow signal, however, demonstrated a decrease in amplitude compared with the gold standard. Integrating respiratory and EEG/EMG signals, we fully characterized sleep and breathing patterns in conscious, unrestrained mice and demonstrated inspiratory flow limitation in a New Zealand Obese mouse. Our approach will facilitate studies of SRBD mechanisms in inbred mouse strains and offer a powerful platform to investigate the effects of environmental and pharmacological exposures on breathing disturbances during sleep and wakefulness.

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Modified control of breathing in genetically obese (ob/ob) mice

Journal of Applied Physiology ◽

10.1152/jappl.1996.81.2.716 ◽

1996 ◽

Vol 81 (2) ◽

pp. 716-723 ◽

Cited By ~ 88

Author(s):

C. Tankersley ◽

S. Kleeberger ◽

B. Russ ◽

A. Schwartz ◽

P. Smith

Keyword(s):

Tidal Volume ◽

Minute Ventilation ◽

Whole Body ◽

Breathing Frequency ◽

Wild Type ◽

Genetic Determinants ◽

Human Obesity ◽

Ventilatory Control ◽

Age Dependent ◽

Whole Body Plethysmography

Attenuated hypercapnic chemosensitivity and hypoventilation are characteristics periodically associated with human obesity. We tested the hypothesis that ventilatory control is altered by genetic determinants and age-dependent factors that influence the obese phenotype. To this end, the magnitude and pattern of breathing were examined before and associated with the development of obesity in C57BL/6J mice homozygous and heterozygous at the ob gene locus. Breathing frequency and tidal volume were measured using whole body plethysmography, and minute ventilation was assessed during acute hypoxic and hypercapnic challenges with intermittent room air exposures. In age- and weight-matched mice before pronounced obesity, significant (P < 0.05) reductions in hypercapnic ventilatory sensitivity occurred in mutant (ob/ob) mice relative to wild-type (+/+) homozygotes primarily because of an attenuated tidal volume. Longitudinal studies indicated that mutant ob mice developed rapid baseline breathing relative to the wild type, accompanying a twofold greater increase in body mass. Early differences between homozygotes in hypercapnic ventilatory sensitivity were maintained through 230 days. These data demonstrate that genetic determinants at or closely linked to the ob locus influence hypercapnic ventilation before the emergence of pronounced obesity, whereas changes in baseline breathing appear due to age-dependent increases in body weight.

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