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Gordon S Mitchell

Publications and source records attributed to Gordon S Mitchell.

At least 19 recordsLinked to original sources
PubMed2006

Is there a link between intermittent hypoxia-induced respiratory plasticity and obstructive sleep apnoea?

Although neuroplasticity is an important property of the respiratory motor control system, its existence has been appreciated only in recent years and, as a result, its functional significance is not completely understood. The most frequently studied models of respiratory plasticity is respiratory long-term facilitation (LTF) following acute intermittent hypoxia and enhanced LTF following chronic intermittent hypoxia. Since intermittent hypoxia is a prominent feature of sleep-disordered breathing, LTF and/or enhanced LTF may compensate for factors that predispose to sleep-disordered breathing, particularly during obstructive sleep apnoea (OSA). Long-term facilitation has been studied most frequently in rats, and exhibits interesting properties consistent with a role in stabilizing breathing during sleep. Specifically, LTF: (1) is prominent in upper airway respiratory motor activity, suggesting that it stabilizes upper airways and maintains airway patency; (2) is most prominent during sleep in unanaesthetized rats; and (3) exhibits sexual dimorphism (greatest in young male and middle-aged female rats; smallest in middle-aged male and young female rats). Although these features are consistent with the hypothesis that upper airway LTF minimizes the prevalence of OSA in humans, there is little direct evidence for such an effect. Here we review advances in our understanding of LTF and its underlying mechanisms and present evidence concerning a potential role for LTF in maintaining upper airway patency, stabilizing breathing and preventing OSA in humans. Regardless of the relationship between LTF and OSA, a detailed understanding of cellular and synaptic mechanisms that underlie LTF may guide the development of new drugs to regulate upper airway tone, thereby offsetting the tendency for upper airway collapse characteristic of heavy snoring and OSA.

Animals↗
PubMed2006

Layers of exercise hyperpnea: modulation and plasticity.

Despite the fundamental biological significance of the ventilatory response to mild or moderate physical activity (the exercise hyperpnea), we still know remarkably little concerning its underlying mechanisms. Part of the difficulty in revealing those mechanisms may arise due to confusion between multiple mechanistic layers, each contributing to the impressive degree of regulation achieved. The primary, feedforward exercise stimulus or stimuli increase ventilation in approximate proportion to changes in metabolic rate. Chemoreceptor feedback then minimizes deviations from optimal blood gas regulation, most often preventing excessive hypocapnia in non-human mammals. Recent evidence has accumulated, suggesting that adaptive control strategies including modulation and plasticity may adjust the feedforward and/or feedback contributions when blood gas homeostasis proves inadequate. In this review, we present evidence from a goat model of exercise hyperpnea concerning the existence of modulation and plasticity, and specifically mechanisms known as short-term and long-term modulation of the exercise ventilatory response. Throughout the review, we consider available evidence concerning the relevance of these mechanisms to humans. Plasticity is a property only recently recognized in the neural system subserving respiratory control, and the application of these concepts to the exercise ventilatory response in humans is in its infancy. Modulation and plasticity may confer an ability of individuals to adapt their exercise ventilatory response so that it remains appropriate in the face of life-long changes in endogenous (e.g. development, aging, onset of disease) or exogenous (e.g. altitude, wearing a breathing apparatus during physical exertion) physiological conditions.

Adaptation, Physiological↗
PubMed2006

Early postnatal chronic intermittent hypoxia modifies hypoxic respiratory responses and long-term phrenic facilitation in adult rats.

Acute isocapnic intermittent hypoxia elicits time-dependent, serotonin-dependent enhancement of phrenic motor output in anesthetized rats (phrenic long-term facilitation, pLTF). In adult rats, pLTF is enhanced by chronic intermittent hypoxia (CIH). To test the hypothesis that early postnatal CIH induces persistent modifications of ventilation and pLTF, we exposed male Sprague-Dawley rat pups on their first day of life to a CIH profile consisting of alternating room air and 10% oxygen every 90 s for 30 days during daylight hours (RAIH) or to comparable exposures consisting of room air throughout (RARA). One month after cessation of CIH, respiratory responses were recorded using whole body plethysmography, and integrated phrenic nerve activity was recorded in urethane-anesthetized, vagotomized, paralyzed, and ventilated rats at baseline and after exposures to three 5-min hypoxic episodes [inspired O2 fraction (FiO2)=0.11] separated by 5 min of hyperoxia (FiO2=0.5). RAIH rats displayed greater normoxic ventilation and also increased burst frequency compared with RARA rats (P<0.01). Ventilatory responses to hypoxia and short-term phrenic responses during acute hypoxic challenges were reduced in RAIH rats (P<0.01). Although pLTF was present in both RAIH and RARA rats, it was diminished in RAIH rats (minute activity: 74+/-2% in RARA vs. 55+/-5% in RAIH at 60 min; P<0.01). Thus we conclude that early postnatal CIH modifies normoxic and hypoxic ventilatory and phrenic responses that persist at 1 mo after cessation of CIH (i.e., metaplasticity) and markedly differ from previously reported increased neural plasticity changes induced by CIH in adult rats.

Animals↗
PubMed2005

Respiratory plasticity after perinatal hypercapnia in rats.

Environmental conditions during early life may have profound effects on respiratory control development. We hypothesized that perinatal hypercapnia would exert lasting effects on the mammalian hypercapnic ventilatory response, but that these effects would differ between males and females. Rats were exposed to 5% CO2 from 1 to 3 days before birth through postnatal week 2 and ventilation was subsequently measured by whole-body plethysmography. In both male and female rats exposed to perinatal hypercapnia, a rapid, shallow breathing pattern was observed for the first 2 weeks after return to normocapnia, but ventilation was unchanged. Acute hypercapnic ventilatory responses (3% and 5% CO2) were reduced 27% immediately following perinatal hypercapnia, but these responses were normal after 2 weeks of recovery in both sexes and remained normal as adults. Collectively, these data suggest that perinatal hypercapnia elicits only transient respiratory plasticity in both male and female rats. This plasticity appears similar to that observed after chronic hypercapnia in adult animals and, therefore, is not unique to development.

Age Factors↗
PubMed2005

Recovery of phrenic activity and ventilation after cervical spinal hemisection in rats.

We tested two hypotheses: 1) that the spontaneous enhancement of phrenic motor output below a C2 spinal hemisection (C2HS) is associated with plasticity in ventrolateral spinal inputs to phrenic motoneurons; and 2) that phrenic motor recovery in anesthetized rats after C2HS correlates with increased capacity to generate inspiratory volume during hypercapnia in unanesthetized rats. At 2 and 4 wk post-C2HS, ipsilateral phrenic nerve activity was recorded in anesthetized, paralyzed, vagotomized, and ventilated rats. Electrical stimulation of the ventrolateral funiculus contralateral to C2HS was used to activate crossed spinal synaptic pathway phrenic motoneurons. Inspiratory phrenic burst amplitudes ipsilateral to C2HS were larger in the 4- vs. 2-wk groups (P<0.05); however, no differences in spinally evoked compound phrenic action potentials could be detected. In unanesthetized rats, inspiratory volume and frequency were quantified using barometric plethysmography at inspired CO2 fractions between 0.0 and 0.07 (inspired O2 fraction 0.21, balance N2) before and 2, 3, and 5 wk post-C2HS. Inspiratory volume was diminished, and frequency enhanced, at 0.0 inspired CO2 fraction (P<0.05) 2-wk post-C2HS; further changes were not observed in the 3- and 5-wk groups. Inspiratory frequency during hypercapnia was unaffected by C2HS. Hypercapnic inspiratory volumes were similarly attenuated at all time points post-C2HS (P<0.05), thereby decreasing hypercapnic minute ventilation (P<0.05). Thus increases in ipsilateral phrenic activity during 4 wk post-C2HS have little impact on the capacity to generate inspiratory volume in unanesthetized rats. Enhanced crossed phrenic activity post-C2HS may reflect plasticity associated with spinal axons not activated by our ventrolateral spinal stimulation.

Action Potentials↗
PubMed2005

Carotid sinus nerve responses and ventilatory acclimatization to hypoxia in adult rats following 2 weeks of postnatal hyperoxia.

Adult rats have decreased carotid body volume and reduced carotid sinus nerve, phrenic nerve, and ventilatory responses to acute hypoxic stimulation after exposure to postnatal hyperoxia (60% O2, PNH) during the first 4 weeks of life. Moreover, sustained hypoxic exposure (12%, 7 days) partially reverses functional impairment of the acute hypoxic phrenic nerve response in these rats. Similarly, 2 weeks of PNH results in the same phenomena as above except that ventilatory responses to acute hypoxia have not been measured in awake rats. Thus, we hypothesized that 2-week PNH-treated rats would also exhibit blunted chemoafferent responses to acute hypoxia, but would exhibit ventilatory acclimatization to sustained hypoxia. Rats were born into, and exposed to PNH for 2 weeks, followed by chronic room-air exposure. At 3-4 months of age, two studies were performed to assess: (1) carotid sinus nerve responses to asphyxia and sodium cyanide in anesthetized rats and (2) ventilatory and blood gas responses in awake rats before (d0), during (d1 and d7), and 1 day following (d8) sustained hypoxia. Carotid sinus nerve responses to i.v. NaCN and asphyxia (10 s) were significantly reduced in PNH-treated versus control rats; however, neither the acute hypoxic ventilatory response nor the time course or magnitude of ventilatory acclimatization differed between PNH and control rats despite similar levels of PaO2 . Although carotid body volume was reduced in PNH rats, carotid body volumes increased during sustained hypoxia in both PNH and control rats. We conclude that normal acute and chronic ventilatory responses are related to retained (though impaired) carotid body chemoafferent function combined with central neural mechanisms which may include brainstem hypoxia-sensitive neurons and/or brainstem integrative plasticity relating both central and peripheral inputs.

Acclimatization↗
PubMed2005

Spinal synaptic enhancement with acute intermittent hypoxia improves respiratory function after chronic cervical spinal cord injury.

Respiratory insufficiency is the leading cause of death after high-cervical spinal cord injuries (SCIs). Although respiratory motor recovery can occur with time after injury, the magnitude of spontaneous recovery is limited. We hypothesized that partial respiratory motor recovery after chronic cervical SCI could be strengthened using a known stimulus for spinal synaptic enhancement, intermittent hypoxia. Phrenic motor output was recorded before and after intermittent hypoxia from anesthetized, vagotomized, and pump-ventilated control and C2 spinally hemisected rats at 2, 4, and 8 weeks after injury. Weak spontaneous phrenic motor recovery was present in all C2-injured rats via crossed spinal synaptic pathways that convey bulbospinal inspiratory premotor drive to phrenic motoneurons on the side of injury. Intermittent hypoxia augmented crossed spinal synaptic pathways [phrenic long-term facilitation; pLTF] for up to 60 min after hypoxia at 8 weeks, but not 2 weeks, after injury. Ketanserin, a serotonin 2A receptor antagonist, administered before intermittent hypoxia at 8 weeks after injury prevented pLTF. Serotonergic innervation near phrenic motoneurons was assessed after injury. The limited magnitude of pLTF at 2 weeks was associated with an injury-induced reduction in serotonin-containing nerve terminals in the vicinity of phrenic motoneurons ipsilateral to C2 hemisection. Thereafter, pLTF magnitude progressively increased with the recovery of serotonergic innervation in the phrenic motor nucleus. Intermittent hypoxia (or pLTF) has intriguing possibilities as a therapeutic tool, because its greatest efficacy may be in patients with chronic SCI, a time when most patients have already achieved maximal spontaneous functional recovery.

Animals↗
PubMed2005

Carotid chemoafferent plasticity in adult rats following developmental hyperoxia.

Developmental hyperoxia impairs carotid chemoreceptor development and induces long-lasting reduction in carotid sinus nerve (CSN) responses to hypoxia in adult rats. Studies were carried out to determine if CSN responses to acute hypoxia would exhibit hypoxia-induced plasticity in adult 3-5-months-old rats previously treated with postnatal hyperoxia (60% O2, PNH) of 1, 2, or 4 weeks duration. CSN responses to acute hypoxia were assessed in adult rats exposed to 1 week of sustained hypoxia (12% O2, SH). In normal adult rats and adult rats treated with 1 week of PNH, CSN responses to acute hypoxia were significantly increased in urethane-anesthetized rats when studied 3-5 h after SH. Apparent increases in CSN responses to hypoxia were not significant in rats treated with 2 weeks of PNH and were clearly absent after 4 weeks of PNH, but exponential analysis suggests a PNH duration-dependent plasticity of the CSN response to acute hypoxia after SH. In a second study rats exposed to 2 weeks of PNH were treated with SH for 1 week as adults and acute hypoxic responses were tested 4-5 months later. CSN responses in these rats were unaffected by SH suggesting a lack of persistent SH-induced functional plasticity. We conclude that rats treated with 1 week of PNH retain the capacity for hypoxia-induced plasticity of carotid chemoafferent function and some potential for plasticity may be present after 2 weeks of PNH, whereas 4 weeks of PNH impairs the capability of rats to exhibit plasticity following 1 week of SH.

Animals↗
PubMed2005

Cervical spinal cord injury upregulates ventral spinal 5-HT2A receptors.

Following chronic C2 spinal hemisection (C2HS), crossed spinal pathways to phrenic motoneurons exhibit a slow, spontaneous increase in efficacy by a serotonin (5-HT)-dependent mechanism associated with 5-HT2A receptor activation. Further, the spontaneous appearance of cross-phrenic activity following C2HS is accelerated and enhanced by exposure to chronic intermittent hypoxia (CIH). We hypothesized that chronic C2HS would increase 5-HT and 5-HT2A receptor expression in ventral cervical spinal segments containing phrenic motoneurons. In addition, we hypothesized that CIH exposure would further increase 5-HT and 5-HT2A receptor density in this region. Control, sham-operated, and C2HS Sprague-Dawley rats were studied following normoxia or CIH (11% O2-air; 5-min intervals; nights 7-14 post-surgery). At 2 weeks post-surgery, ventral spinal gray matter extending from C4 and C5 was isolated ipsilateral and contralateral to C2HS. Neither C2HS nor CIH altered 5-HT concentration measured with an ELISA on either side of the spinal cord. However, 5-HT2A receptor expression assessed with immunoblots increased in ipsilateral gray matter following C2HS, an effect independent of CIH. Immunocytochemistry revealed increased 5-HT2A receptor expression on identified phrenic motoneurons (p<0.05), as well as in the surrounding gray matter. Contralateral to injury, 5-HT2A receptor expression was elevated in CIH, but not normoxic C2HS rats (p<0.05). Our data are consistent with the hypothesis that spontaneous increase in 5-HT2A receptor expression on or near phrenic motoneurons contributes to strengthened crossed-spinal synaptic pathways to phrenic motoneurons following C2HS.

Animals↗
PubMed2004

Breathing in thin air: acclimatization to altitude in ducks.

We measured ventilation (VI) and arterial blood gases in Pekin ducks during acclimatization to 3800 m altitude for 1-90 days. Four experimental series were conducted over 4 years using both natural altitude and a hypobaric chamber. PaCO2 decreased to 3.5 Torr, relative to the value measured during acute hypoxia after 1 day and remained at this level for up to 90 days. However, PaO2 did not increase. Arterial pH showed an unexpected metabolic alkalosis during the first hours at altitude but after 3 days, a metabolic acidosis partially compensated the respiratory alkalosis and pHa was constant thereafter. When normoxia was restored after hypoxia, PaCO2 was 5.5 Torr less than the original normoxic control value, but PaO2 was not increased. VI showed variable changes during acclimatization but if metabolic rate was constant in our study, as reported by others, then effective parabronchial V(VP) increased during acclimatization. Increased VP tends to restore PaO2 toward normoxic levels and decreases adverse effects of gas exchange limitation, which apparently increased during acclimatization in ducks.

Acclimatization↗
PubMed2004

Differences in time-dependent hypoxic phrenic responses among inbred rat strains.

Hypoxic ventilatory responses differ between rodent strains, suggesting a genetic contribution to interindividual variability. However, hypoxic ventilatory responses consist of multiple time-dependent mechanisms that can be observed in different respiratory motor outputs. We hypothesized that strain differences would exist in discrete time-dependent mechanisms of the hypoxic response and, furthermore, that there may be differences between hypoglossal and phrenic nerve responses to hypoxia. Hypoglossal and phrenic nerve responses were assessed during and after a 5-min hypoxic episode in anesthetized, vagotomized, and ventilated rats from four inbred strains: Brown Norway (BN), Fischer 344 (FS), Lewis (LW), and Piebald-viral-Glaxo (PVG). During baseline, burst frequency was higher in PVG than LW rats (P < 0.05), phrenic burst amplitude was higher in PVG vs. other strains (P < 0.05), and hypoglossal burst amplitude was higher in PVG and BN vs. FS and LW (P < 0.05). During hypoxia, burst frequency did not change in BN or LW rats, but it increased in PVG and FS rats. The phrenic amplitude response was smallest in PVG vs. other strains (P < 0.05), and the hypoglossal response was similar among strains. Short-term potentiation posthypoxia was slowest in FS and fastest in LW rats (P < 0.05). Posthypoxia frequency decline was absent in PVG, but it was observed in all other strains. Augmented breaths were observed during hypoxia in FS rats only. Thus genetic differences exist in the time domains of the hypoxic response, and these are differentially expressed in hypoglossal and phrenic nerves. Furthermore, genetic diversity observed in hypoxic ventilatory responses in unanesthetized rats may arise from multiple neural mechanisms.

Adaptation, Physiological↗
PubMed2003

BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia.

Intermittent hypoxia causes a form of serotonin-dependent synaptic plasticity in the spinal cord known as phrenic long-term facilitation (pLTF). Here we show that increased synthesis of brain-derived neurotrophic factor (BDNF) in the spinal cord is necessary and sufficient for pLTF in adult rats. We found that intermittent hypoxia elicited serotonin-dependent increases in BDNF synthesis in ventral spinal segments containing the phrenic nucleus, and the magnitude of these BDNF increases correlated with pLTF magnitude. We used RNA interference (RNAi) to interfere with BDNF expression, and tyrosine kinase receptor inhibition to block BDNF signaling. These disruptions blocked pLTF, whereas intrathecal injection of BDNF elicited an effect similar to pLTF. Our findings demonstrate new roles and regulatory mechanisms for BDNF in the spinal cord and suggest new therapeutic strategies for treating breathing disorders such as respiratory insufficiency after spinal injury. These experiments also illustrate the potential use of RNAi to investigate functional consequences of gene expression in the mammalian nervous system in vivo.

Animals↗
PubMed2003

Exercise-induced changes in hippocampal brain-derived neurotrophic factor and neurotrophin-3: effects of rat strain.

We tested the hypothesis that exercise-induced changes in hippocampal brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) differ among rat strains exhibiting a range of voluntary wheel running activity. Four strains (Sprague-Dawley, Brown Norway, Dark Agouti and PVG) were given access to running wheels (1 or 7 nights). Over 7 nights, the average distance run per night was higher in PVG versus other strains, and higher in Brown Norway versus Sprague-Dawley rats. Hippocampal BDNF concentrations in sedentary rats were higher in PVG versus Sprague-Dawley rats. When data from all strains were combined, BDNF levels increased with 7 nights of wheel running and were positively correlated to the previous night distance run. Sedentary hippocampal NT-3 levels were not different between rat strains, but decreased with 7 nights of wheel access; NT-3 was negatively correlated with previous night distance run. There were no differences between strains in the correlation between distance run and BDNF or NT-3 levels. Although exercise decreases hippocampal NT-3, strain does not alter NT-3 levels. In contrast, BDNF levels increase with exercise and basal levels differ between strains, possibly due to strain differences in spontaneous activity.

Animals↗
PubMed2003

Sex steroid hormones and the neural control of breathing.

We review evidence that sex steroid hormones including estrogen, progesterone and testosterone are involved in the central neural control of breathing. Sex hormones may exert their effects on respiratory motoneurons via neuromodulators, in particular, the serotonergic system. Recent studies have shown that levels of serotonin (5HT) in the hypoglossal and phrenic nuclei are greater in female than in male rats. Serotonin-dependent plasticity in hypoglossal and phrenic motor output also differs in male and female rats. Changing levels of gonadal hormones throughout the estrus cycle coincide with changing levels of 5HT in respiratory motor nuclei, and gonadectomy in male rats results in a decrease in 5HT-dependent plasticity in respiratory motor output. We speculate that sex steroid hormones are critically involved in adaptations in the neural control of breathing throughout life, and that decreasing levels of these hormones with increasing age may have a negative influence on the respiratory control system in response to challenge.

Animals↗
PubMed2003

Synaptic pathways to phrenic motoneurons are enhanced by chronic intermittent hypoxia after cervical spinal cord injury.

Spinal hemisection at C2 reveals caudal synaptic pathways that cross the spinal midline (crossed phrenic pathways) and can restore inspiratory activity in ipsilateral phrenic motoneurons. Intermittent hypoxia induces plasticity in the cervical spinal cord, resulting in enhanced inspiratory phrenic motor output. We hypothesized that chronic intermittent hypoxia (CIH) (alternating 11% O(2) and air; 5 min periods; 12 hr per night; 7 nights) would strengthen crossed phrenic pathways. Experiments were performed on anesthetized, vagotomized, paralyzed, ventilated, and spinally injured (C2 hemisection) rats that were exposed to either normoxia or CIH before acute injury (preconditioning) or after chronic injury (postconditioning). Spontaneous inspiratory bursts or compound action potentials evoked via stimulation of the ventrolateral funiculus (contralateral to injury) were recorded in both phrenic nerves. Spontaneous or evoked activity in crossed phrenic pathways were minimal or absent in all acutely injured rats regardless of preconditioning. In rats postconditioned with normoxia, crossed phrenic inspiratory bursts were observed occasionally during baseline conditions and always during chemoreceptor stimulation (hypoxia and hypercapnia). However, CIH postconditioned rats had substantially larger crossed phrenic inspiratory bursts during baseline, hypoxia, and hypercapnia (all p < 0.05 vs normoxic group). Short-latency (0.7 msec) evoked crossed phrenic potentials were also enhanced by CIH conditioning in chronically injured rats (p < 0.05). We conclude that CIH induced spinal cord plasticity-enhanced phrenic motor output. This plasticity required preconditions established by chronic spinal injury.

Animals↗
PubMed2003

Breathing: rhythmicity, plasticity, chemosensitivity.

Breathing is a vital behavior that is particularly amenable to experimental investigation. We review recent progress on three problems of broad interest. (i) Where and how is respiratory rhythm generated? The preBötzinger Complex is a critical site, whereas pacemaker neurons may not be essential. The possibility that coupled oscillators are involved is considered. (ii) What are the mechanisms that underlie the plasticity necessary for adaptive changes in breathing? Serotonin-dependent long-term facilitation following intermittent hypoxia is an important example of such plasticity, and a model that can account for this adaptive behavior is discussed. (iii) Where and how are the regulated variables CO2 and pH sensed? These sensors are essential if breathing is to be appropriate for metabolism. Neurons with appropriate chemosensitivity are spread throughout the brainstem; their individual properties and collective role are just beginning to be understood.

Adaptation, Physiological↗
PubMed2003

Exercise increases hippocampal neurogenesis to high levels but does not improve spatial learning in mice bred for increased voluntary wheel running.

The hippocampus is important for the acquisition of new memories. It is also one of the few regions in the adult mammalian brain that can generate new nerve cells. The authors tested the hypothesis that voluntary exercise increases neurogenesis and enhances spatial learning in mice selectively bred for high levels of wheel running (S mice). Female S mice and outbred control (C) mice were housed with and without running wheels for 40 days. 5-Bromodeoxyuridine was used to label dividing cells. The Morris water maze was used to measure spatial learning. C runners showed a strong positive correlation between running distance and new cell number, as well as improved learning. In S runners, neurogenesis increased to high levels that reached a plateau, but no improvement in learning occurred. This is the first evidence that neurogenesis can occur without learning enhancement. The authors propose an alternative function of neurogenesis in the control of motor behavior.

Animals↗