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Eugene E Nattie - One of the best experts on this subject based on the ideXlab platform.
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central chemoreceptors locations and functions
Comprehensive Physiology, 2012Co-Authors: Eugene E NattieAbstract:Central Chemoreception traditionally refers to a change in ventilation attributable to changes in CO2/H(+) detected within the brain. Interest in central Chemoreception has grown substantially since the previous Handbook of Physiology published in 1986. Initially, central Chemoreception was localized to areas on the ventral medullary surface, a hypothesis complemented by the recent identification of neurons with specific phenotypes near one of these areas as putative chemoreceptor cells. However, there is substantial evidence that many sites participate in central Chemoreception some located at a distance from the ventral medulla. Functionally, central Chemoreception, via the sensing of brain interstitial fluid H(+), serves to detect and integrate information on (i) alveolar ventilation (arterial PCO2), (ii) brain blood flow and metabolism, and (iii) acid-base balance, and, in response, can affect breathing, airway resistance, blood pressure (sympathetic tone), and arousal. In addition, central Chemoreception provides a tonic "drive" (source of excitation) at the normal, baseline PCO2 level that maintains a degree of functional connectivity among brainstem respiratory neurons necessary to produce eupneic breathing. Central Chemoreception responds to small variations in PCO2 to regulate normal gas exchange and to large changes in PCO2 to minimize acid-base changes. Central chemoreceptor sites vary in function with sex and with development. From an evolutionary perspective, central Chemoreception grew out of the demands posed by air versus water breathing, homeothermy, sleep, optimization of the work of breathing with the "ideal" arterial PCO2, and the maintenance of the appropriate pH at 37°C for optimal protein structure and function.
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julius h comroe jr distinguished lecture central Chemoreception then and now
Journal of Applied Physiology, 2011Co-Authors: Eugene E NattieAbstract:The 2010 Julius H. Comroe, Jr., Lecture of the American Physiological Society focuses on evolving ideas in Chemoreception for CO2/pH in terms of what is “sensed,” where it is sensed, and how the sensed information is used physiologically. Chemoreception is viewed as involving neurons (and glia) at many sites within the hindbrain, including, but not limited to, the retrotrapezoid nucleus, the medullary raphe, the locus ceruleus, the nucleus tractus solitarius, the lateral hypothalamus (orexin neurons), and the caudal ventrolateral medulla. Central Chemoreception also has an important nonadditive interaction with afferent information arising at the carotid body. While ventilation has been viewed as the primary output variable, it appears that airway resistance, arousal, and blood pressure can also be significantly affected. Emphasis is placed on the importance of data derived from studies performed in the absence of anesthesia.
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State-dependent central Chemoreception: a role of orexin
Respiratory physiology & neurobiology, 2010Co-Authors: Tomoyuki Kuwaki, Eugene E NattieAbstract:Sites involved in central Chemoreception (CCR) are widely distributed in the brain. One possible explanation for the existence of multiple central chemoreceptor sites is the vigilance state-dependent hypothesis, that some sites are of greater importance in wakefulness others in sleep. We briefly summarize the evidence for a distributed network of central chemoreceptor sites and a vigilance state-dependent differentiation among them. We then discuss the role of orexin in vigilance state-dependent CCR based on our recent studies using orexin knockout mice and focal microdialysis of an orexin receptor antagonist at the retrotrapezoid nucleus and medullary raphe in rats. Orexin affects CCR in a vigilance state-dependent manner that varies with circadian time. Orexin also contributes to emotional stress- and other state-dependent related regulation of ventilation, e.g., the defense response. Diversity in central Chemoreception including orexin neurons and the synaptic control of respiratory and cardiovascular output neurons appears to be necessary for animals to adapt themselves to constantly changing situations and behavioral states.
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central Chemoreception is a complex system function that involves multiple brain stem sites
Journal of Applied Physiology, 2009Co-Authors: Eugene E NattieAbstract:central Chemoreception refers to detection of CO2/pH within the brain and the subsequent reflex effects on breathing. It involves multiple sites within the hindbrain ([9][1], [12][2], [19][3]) as focal acidification in vivo uniquely at these sites stimulates breathing, indicating detection and
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medullary serotonergic neurones and adjacent neurones that express neurokinin 1 receptors are both involved in Chemoreception in vivo
The Journal of Physiology, 2004Co-Authors: Eugene E Nattie, George B Richerson, Douglas A LappiAbstract:Neurokinin-1 receptor (NK1R)-expressing neurones that are involved in Chemoreception at the retrotrapezoid nucleus (Nattie & Li, 2002b) are also prominent at locations that contain medullary serotonergic neurones, which are chemosensitive in vitro. In medullary regions containing both types, we evaluated their role in central Chemoreception by specific cell killing. We injected (2×100 nl) (a) substance P–saporin (SP-SAP; 1μm) to kill NK1R-expressing neurones, (b) a novel conjugate of a monoclonal antibody to the serotonin transporter (SERT) and saporin (anti-SERT-SAP; 1μm) to kill serotonergic neurones, or (c) SP-SAP and anti-SERT-SAP together to kill both types. Controls received IgG-SAP injections (1μm). There was no double-labelling of NK1R-immunoreactive (ir) and tryptophan-hydroxylase (TPOH)-ir neurones. Cell (somatic profile) counts showed that NK1R-ir neurones in the SP-SAP group were reduced by 31%; TPOH-ir neurones in the anti-SERT-SAP group by 28%; and NK1R-ir and TPOH-ir neurones, respectively, in the combined lesion group by 55% and 31% (P < 0.001; two-way ANOVA; P < 0.05, Tukey's post hoc test). The treatments had no significant effect on sleep/wake time, body temperature, or oxygen consumption but all three reduced the ventilatory response to 7% inspired CO2 in wakefulness and sleep by a similar amount. SP-SAP treatment decreased the averaged CO2 responses (3, 7 and 14 days after lesions) in wakefulness and sleep by 21% and 16%, anti-SERT-SAP decreased the responses by 15% and 18%, and the combined treatment decreased the responses by 12% and 12% (P < 0.001; two-way ANOVA; P < 0.05, Tukey's post hoc test). We conclude that separate populations of serotonergic and adjacent NK1R-expressing neurones in the medulla are both involved in central Chemoreception in vivo.
Daniel K. Mulkey - One of the best experts on this subject based on the ideXlab platform.
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Purinergic signaling contributes to CO2-sensitivity of neurons in the retrotrapezoid nucleus but not nucleus of the solitary tract or medullary raphe (872.6)
The FASEB Journal, 2014Co-Authors: Ian C Wenker, Cleyton R Sobrinho, Erin M Poss, Thiago S Moreira, Takakura Ana, Daniel K. MulkeyAbstract:Central Chemoreception is the mechanism by which the brain controls breathing in response to changes in tissue CO2/H+. Several brainstem regions are thought to contribute to Chemoreception including the caudal nucleus of the solitary tract (cNTS), medullary raphe and retrotrapezoid nucleus (RTN). Although the molecular basis of Chemoreception remains unclear, evidence suggests that RTN Chemoreception involves intrinsic H+ sensing by an unidentified K+ channel and purinergic signaling possibly from CO2-sensitive astrocytes. However, it is not clear whether purinergic signaling influences CO2-responsiveness of other putative chemoreceptors. The goal of this study is to determine whether purinergic signaling modulates basal activity or CO2-responsivness of neurons in the cNTS or medullary raphe. We use cell-attached current clamp techniques to characterize firing rate responses to 15% CO2 and focal application of ATP (1mM) under control conditions and in the presence of a P2-receptor blocker (PPADS, 100 µM)....
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purinergic signalling contributes to Chemoreception in the retrotrapezoid nucleus but not the nucleus of the solitary tract or medullary raphe
The Journal of Physiology, 2014Co-Authors: Cleyton R Sobrinho, Ian C Wenker, Erin M Poss, Ana C Takakura, Thiago S Moreira, Daniel K. MulkeyAbstract:Key points Several brain regions are thought to sense changes in tissue CO2/H+ to regulate breathing (i.e. central chemoreceptors) including the nucleus of the solitary tract (NTS), medullary raphe and retrotrapezoid nucleus (RTN). Mechanism(s) underlying RTN Chemoreception involve direct activation of RTN neurons by H+-mediated inhibition of a resting K+ conductance and indirect activation of RTN neurons by purinergic signalling, most likely from CO2/H+-sensitive astrocytes. Here, we confirm that activation of P2 receptors in the RTN stimulates cardiorespiratory activity, and we show at the cellular and systems level that purinergic signalling is not essential for CO2/H+ sensing in the NTS or medullary raphe. These results support the possibility that purinergic signalling is a unique feature of RTN Chemoreception. Abstract Several brain regions are thought to function as important sites of Chemoreception including the nucleus of the solitary tract (NTS), medullary raphe and retrotrapezoid nucleus (RTN). In the RTN, mechanisms of Chemoreception involve direct H+-mediated activation of chemosensitive neurons and indirect modulation of chemosensitive neurons by purinergic signalling. Evidence suggests that RTN astrocytes are the source of CO2-evoked ATP release. However, it is not clear whether purinergic signalling also influences CO2/H+ responsiveness of other putative chemoreceptors. The goals of this study are to determine if CO2/H+-sensitive neurons in the NTS and medullary raphe respond to ATP, and whether purinergic signalling in these regions influences CO2 responsiveness in vitro and in vivo. In brain slices, cell-attached recordings of membrane potential show that CO2/H+-sensitive NTS neurons are activated by focal ATP application; however, purinergic P2-receptor blockade did not affect their CO2/H+ responsiveness. CO2/H+-sensitive raphe neurons were unaffected by ATP or P2-receptor blockade. In vivo, ATP injection into the NTS increased cardiorespiratory activity; however, injection of a P2-receptor blocker into this region had no effect on baseline breathing or CO2/H+ responsiveness. Injections of ATP or a P2-receptor blocker into the medullary raphe had no effect on cardiorespiratory activity or the chemoreflex. As a positive control we confirmed that ATP injection into the RTN increased breathing and blood pressure by a P2-receptor-dependent mechanism. These results suggest that purinergic signalling is a unique feature of RTN Chemoreception.
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purinergic signalling contributes to Chemoreception in the retrotrapezoid nucleus but not the nucleus of the solitary tract or medullary raphe
The Journal of Physiology, 2014Co-Authors: Cleyton R Sobrinho, Ian C Wenker, Erin M Poss, Ana C Takakura, Thiago S Moreira, Daniel K. MulkeyAbstract:Several brain regions are thought to function as important sites of Chemoreception including the nucleus of the solitary tract (NTS), medullary raphe and retrotrapezoid nucleus (RTN). In the RTN, mechanisms of Chemoreception involve direct H(+)-mediated activation of chemosensitive neurons and indirect modulation of chemosensitive neurons by purinergic signalling. Evidence suggests that RTN astrocytes are the source of CO2-evoked ATP release. However, it is not clear whether purinergic signalling also influences CO2/H(+) responsiveness of other putative chemoreceptors. The goals of this study are to determine if CO2/H(+)-sensitive neurons in the NTS and medullary raphe respond to ATP, and whether purinergic signalling in these regions influences CO2 responsiveness in vitro and in vivo. In brain slices, cell-attached recordings of membrane potential show that CO2/H(+)-sensitive NTS neurons are activated by focal ATP application; however, purinergic P2-receptor blockade did not affect their CO2/H(+) responsiveness. CO2/H(+)-sensitive raphe neurons were unaffected by ATP or P2-receptor blockade. In vivo, ATP injection into the NTS increased cardiorespiratory activity; however, injection of a P2-receptor blocker into this region had no effect on baseline breathing or CO2/H(+) responsiveness. Injections of ATP or a P2-receptor blocker into the medullary raphe had no effect on cardiorespiratory activity or the chemoreflex. As a positive control we confirmed that ATP injection into the RTN increased breathing and blood pressure by a P2-receptor-dependent mechanism. These results suggest that purinergic signalling is a unique feature of RTN Chemoreception.
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astrocyte chemoreceptors mechanisms of h sensing by astrocytes in the retrotrapezoid nucleus and their possible contribution to respiratory drive
Experimental Physiology, 2011Co-Authors: Daniel K. Mulkey, Ian C WenkerAbstract:Central Chemoreception is the mechanism by which CO2/pH-sensitive neurons (i.e. chemoreceptors) regulate breathing, presumably in response to changes in tissue pH. A region of the brainstem called the retrotrapezoid nucleus (RTN) is thought to be an important site of Chemoreception; select neurons (i.e. chemoreceptors) in this region sense changes in CO2/H+ and send excitatory glutamatergic drive to respiratory centres to modulate the depth and frequency of breathing. Purinergic signalling may also contribute to Chemoreception; for instance, it was shown in vivo that CO2/H+ facilitates ATP release within the RTN to stimulate breathing, and recent evidence suggests that CO2/H+-sensitive RTN astrocytes are the source of this purinergic drive to breathe. In this review, we summarize evidence that RTN astrocytes sense changes in CO2/H+, identify mechanisms that are likely to confer CO2/H+ sensitivity to RTN astrocytes, including inhibition of heteromeric Kir4.1–Kir5.1 channels and activation of a depolarizing inward current generated by the sodium bicarbonate cotransporter, and discuss the extent to which astrocytes contribute to respiratory drive.
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astrocytes in the retrotrapezoid nucleus sense h by inhibition of a kir4 1 kir5 1 like current and may contribute to Chemoreception by a purinergic mechanism
Journal of Neurophysiology, 2010Co-Authors: Ian C Wenker, Orsolya Kreneisz, Akiko Nishiyama, Daniel K. MulkeyAbstract:Central Chemoreception is the mechanism by which CO2/pH sensors regulate breathing in response to tissue pH changes. There is compelling evidence that pH-sensitive neurons in the retrotrapezoid nucleus (RTN) are important chemoreceptors. Evidence also indicates that CO2/H+-evoked adenosine 5′-triphosphate (ATP) release in the RTN, from pH-sensitive astrocytes, contributes to Chemoreception. However, mechanism(s) by which RTN astrocytes sense pH is unknown and their contribution to Chemoreception remains controversial. Here, we use the brain slice preparation and a combination of patch-clamp electrophysiology and immunohistochemistry to confirm that RTN astrocytes are pH sensitive and to determine mechanisms by which they sense pH. We show that pH-sensitive RTN glia are immunoreactive for aldehyde dehydrogenase 1L1, a marker of astrocytes. In HEPES buffer the pH-sensitive current expressed by RTN astrocytes reversed near EK+ (the equilibrium potential for K+) and was inhibited by Ba2+ and desipramine (blocker of Kir4.1-containing channels), characteristics most consistent with heteromeric Kir4.1–Kir5.1 channels. In bicarbonate buffer, the sodium/bicarbonate cotransporter also contributed to the CO2/H+-sensitive current in RTN astrocytes. To test the hypothesis that RTN astrocytes contribute to Chemoreception by a purinergic mechanism, we used fluorocitrate to selectively depolarize astrocytes while measuring neuronal activity. We found that fluorocitrate increased baseline activity and pH sensitivity of RTN neurons by a P2-receptor–dependent mechanism, suggesting that astrocytes may release ATP to activate RTN chemoreceptors. We also found in bicarbonate but not HEPES buffer that P2-receptor antagonists decreased CO2 sensitivity of RTN neurons. We conclude that RTN astrocytes sense CO2/H+ in part by inhibition of a Kir4.1–Kir5.1-like current and may provide an excitatory purinergic drive to pH-sensitive neurons.
George B Richerson - One of the best experts on this subject based on the ideXlab platform.
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medullary serotonin neurons and their roles in central respiratory Chemoreception
Respiratory Physiology & Neurobiology, 2010Co-Authors: Matthew R Hodges, George B RichersonAbstract:Much progress has been made in our understanding of central Chemoreception since the seminal experiments of Fencl, Loeschcke, Mitchell and others, including identification of new brainstem regions and specific neuron types that may serve as central "sensors" of CO(2)/pH. In this review, we discuss key attributes, or minimal requirements a neuron/cell must possess to be defined as a central respiratory chemoreceptor, and summarize how well each of the various candidates fulfill these minimal criteria-especially the presence of intrinsic chemosensitivity. We then discuss some of the in vitro and in vivo evidence in support of the conclusion that medullary serotonin (5-HT) neurons are central chemoreceptors. We also provide an additional hypothesis that chemosensitive medullary 5-HT neurons are poised to integrate multiple synaptic inputs from various other sources thought to influence ventilation. Finally, we discuss open questions and future studies that may aid in continuing our advances in understanding central Chemoreception.
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5 ht neurons and central co2 Chemoreception
Handbook of Behavioral Neuroscience, 2010Co-Authors: Cardin I Dohle, George B RichersonAbstract:Abstract Many neurons within the medullary raphe project to nuclei that control respiratory motor output. Through release of serotonin (5-HT) and the colocalized neuropeptides substance P (SP) and thyrotropin-releasing hormone these neurons provide tonic drive that helps maintain ventilation. Many 5-HT neurons are closely associated with large arteries of the brainstem, where they respond to changes in arterial CO2 levels by increasing their firing rate. These properties allow them to play an important role as central respiratory chemoreceptors, causing an increase in ventilation in response to increased CO2 levels so that CO2 and pH return back to normal. Some 5-HT neurons in the midbrain play a similar role in sensing changes in blood CO2, and induce arousal when CO2 levels increase during sleep. Defects in 5-HT neurons occur in a variety of human diseases and may play a critical role in the pathophysiology of sudden infant death syndrome (SIDS), sudden unexpected death in epilepsy (SUDEP) and panic disorder, each of which may involve abnormalities of respiratory control and blood gas homeostasis.
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medullary serotonin neurons and central co2 Chemoreception
Respiratory Physiology & Neurobiology, 2009Co-Authors: Andrea E Corcoran, Matthew R Hodges, Wengang Wang, Christie J Wylie, Evan S Deneris, George B RichersonAbstract:Serotonergic (5-HT) neurons are putative central respiratory chemoreceptors, aiding in the brain's ability to detect arterial changes in PCO2 and implement appropriate ventilatory responses to maintain blood homeostasis. These neurons are in close proximity to large medullary arteries and are intrinsically chemosensitive in vitro, characteristics expected for chemoreceptors. 5-HT neurons of the medullary raphe are stimulated by hypercapnia in vivo, and their disruption results in a blunted hypercapnic ventilatory response. More recently, data collected from transgenic and knockout mice have provided further insight into the role of 5-HT in chemosensitivity. This review summarizes current evidence in support of the hypothesis that 5-HT neurons are central chemoreceptors, and addresses arguments made against this role. We also briefly explore the relationship between the medullary raphe and another chemoreceptive site, the retrotrapezoid nucleus, and discuss how they may interact during hypercapnia to produce a robust ventilatory response.
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homing in on the specific phenotype s of central respiratory chemoreceptors
Experimental Physiology, 2005Co-Authors: George B Richerson, W Wang, Matthew R Hodges, C I Dohle, Ana DiezsampedroAbstract:To some it may seem that we now know less about respiratory Chemoreception than we did 20 years ago. Back then, it was widely accepted that the central respiratory chemoreceptors (CRCs) were located exclusively on or near the surface of the ventrolateral medulla (VLMS). Now, instead, it is generally believed that there are widespread sites of Chemoreception, and there is little agreement on when and how each of these sites is involved in respiratory control. However, those in the field know that this actually is progress, primarily because we have gone from simply identifying candidate regions, to identifying specific neuronal subtypes that may be the sensors. In this invited review, we have been asked to discuss some of the current controversies in the field. First, we define the minimal requirements for a cell to be a CRC, and what assumptions can not be made without more data. Then we review the evidence that two neuronal subtypes, serotonergic neurones of the midline raphe and glutamatergic neurones of the retrotrapezoid nucleus, are chemoreceptors. There is evidence supporting a role in respiratory Chemoreception for both types of neurone, as well as the other candidates, but there is also information that is missing. Future work will need to focus on which of the candidates are indeed chemoreceptors, what percentage of the overall response each one contributes, and how this percentage varies under different conditions.
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medullary serotonergic neurones and adjacent neurones that express neurokinin 1 receptors are both involved in Chemoreception in vivo
The Journal of Physiology, 2004Co-Authors: Eugene E Nattie, George B Richerson, Douglas A LappiAbstract:Neurokinin-1 receptor (NK1R)-expressing neurones that are involved in Chemoreception at the retrotrapezoid nucleus (Nattie & Li, 2002b) are also prominent at locations that contain medullary serotonergic neurones, which are chemosensitive in vitro. In medullary regions containing both types, we evaluated their role in central Chemoreception by specific cell killing. We injected (2×100 nl) (a) substance P–saporin (SP-SAP; 1μm) to kill NK1R-expressing neurones, (b) a novel conjugate of a monoclonal antibody to the serotonin transporter (SERT) and saporin (anti-SERT-SAP; 1μm) to kill serotonergic neurones, or (c) SP-SAP and anti-SERT-SAP together to kill both types. Controls received IgG-SAP injections (1μm). There was no double-labelling of NK1R-immunoreactive (ir) and tryptophan-hydroxylase (TPOH)-ir neurones. Cell (somatic profile) counts showed that NK1R-ir neurones in the SP-SAP group were reduced by 31%; TPOH-ir neurones in the anti-SERT-SAP group by 28%; and NK1R-ir and TPOH-ir neurones, respectively, in the combined lesion group by 55% and 31% (P < 0.001; two-way ANOVA; P < 0.05, Tukey's post hoc test). The treatments had no significant effect on sleep/wake time, body temperature, or oxygen consumption but all three reduced the ventilatory response to 7% inspired CO2 in wakefulness and sleep by a similar amount. SP-SAP treatment decreased the averaged CO2 responses (3, 7 and 14 days after lesions) in wakefulness and sleep by 21% and 16%, anti-SERT-SAP decreased the responses by 15% and 18%, and the combined treatment decreased the responses by 12% and 12% (P < 0.001; two-way ANOVA; P < 0.05, Tukey's post hoc test). We conclude that separate populations of serotonergic and adjacent NK1R-expressing neurones in the medulla are both involved in central Chemoreception in vivo.
Patrice G Guyenet - One of the best experts on this subject based on the ideXlab platform.
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Chemoreception and asphyxia induced arousal
Respiratory Physiology & Neurobiology, 2013Co-Authors: Patrice G Guyenet, Stephen B G AbbottAbstract:Arousal protects against the adverse and potentially fatal effects of asphyxia during sleep. Asphyxia stimulates the carotid bodies and central chemoreceptors but the sequence of events leading to arousal is uncertain. In this review, the theoretical mechanisms leading to arousal from sleep are briefly summarized and the issue of whether central respiratory chemoreceptors (CRCs) or other types of CO2-responsive CNS neurons contribute to asphyxia-induced arousal is discussed. We focus on the role of the retrotrapezoid nucleus, the raphe and the locus coeruleus and emphasize the anatomical and neurophysiological evidence which suggests that these putative central chemoreceptors could contribute to arousal independently of their effects on breathing. Finally, we describe recent attempts to test the contribution of specific brainstem pathways to asphyxia-induced arousal using optogenetic and other tools and the possible contribution of a group of hypoxia-sensitive brainstem neurons (the C1 cells) to breathing and arousal.
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the respiratory Chemoreception conundrum light at the end of the tunnel
Brain Research, 2013Co-Authors: Patrice G Guyenet, Stephen B G Abbott, Ruth L. StornettaAbstract:Arterial PCO₂ is tightly regulated via changes in breathing. A rise in PCO₂ activates the carotid bodies and exerts additional effects on neurons located within the CNS, causing an increase in lung ventilation. Central respiratory Chemoreception refers to the component of this homeostatic reflex that is triggered by activation of receptors located within the brain (central chemoreceptors). Throughout the body, CO₂ generally operates via the proxy of pH. Since countless proteins, ion channels and neurons display some degree of pH-sensitivity, the notion that central respiratory Chemoreception could rely on a few specialized neurons seems a priori counter-intuitive. Yet, two types of neurons currently stand out as critically important for breathing regulation by CO₂: the retrotrapezoid nucleus (RTN) and the raphe. RTN neurons are glutamatergic, strongly activated by hypercapnia in vivo and by CO₂ or protons in slices. These neurons target selectively the pontomedullary regions implicated in generating the respiratory rhythm and pattern. Their response to CO₂ seems to involve both cell-autonomous and paracrine effects of CO₂, the latter presumably mediated by the surrounding glia. The specific connections that these excitatory neurons establish with the rest of the breathing network are likely to be the main explanation of their importance to respiratory Chemoreception. Serotonergic neurons have a powerful stimulatory effect on breathing, they facilitate the chemoreflexes and a subset of them likely function as CO₂ sensors. Opto- and pharmacogenetic methods have played an important role in assessing the contribution of RTN and serotonergic neurons as well as glial cells to respiration. These particular experiments are emphasized here for thematic reasons although the current perception of the importance of the RTN and serotonergic cells to respiratory Chemoreception also relies on many other types of evidence. A small portion of this evidence is presented as background. This article is part of a Special Issue entitled Optogenetics (7th BRES).
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central respiratory Chemoreception
The Journal of Comparative Neurology, 2010Co-Authors: Patrice G Guyenet, Ruth L. Stornetta, Douglas A. BaylissAbstract:By definition central respiratory chemoreceptors (CRCs) are cells that are sensitive to changes in brain PCO(2) or pH and contribute to the stimulation of breathing elicited by hypercapnia or metabolic acidosis. CO(2) most likely works by lowering pH. The pertinent proton receptors have not been identified and may be ion channels. CRCs are probably neurons but may also include acid-sensitive glia and vascular cells that communicate with neurons via paracrine mechanisms. Retrotrapezoid nucleus (RTN) neurons are the most completely characterized CRCs. Their high sensitivity to CO(2) in vivo presumably relies on their intrinsic acid sensitivity, excitatory inputs from the carotid bodies and brain regions such as raphe and hypothalamus, and facilitating influences from neighboring astrocytes. RTN neurons are necessary for the respiratory network to respond to CO(2) during the perinatal period and under anesthesia. In conscious adults, RTN neurons contribute to an unknown degree to the pH-dependent regulation of breathing rate, inspiratory, and expiratory activity. The abnormal prenatal development of RTN neurons probably contributes to the congenital central hypoventilation syndrome. Other CRCs presumably exist, but the supportive evidence is less complete. The proposed locations of these CRCs are the medullary raphe, the nucleus tractus solitarius, the ventrolateral medulla, the fastigial nucleus, and the hypothalamus. Several wake-promoting systems (serotonergic and catecholaminergic neurons, orexinergic neurons) are also putative CRCs. Their contribution to central respiratory Chemoreception may be behavior dependent or vary according to the state of vigilance.
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the retrotrapezoid nucleus and central Chemoreception
Tzu Chi Medical Journal, 2008Co-Authors: Patrice G Guyenet, Ruth L. Stornetta, Douglas A. Bayliss, Daniel K. Mulkey, Thiago S Moreira, Ana T TakakuraAbstract:Abstract The functional role of retrotrapezoid nucleus (RTN) neurons as the central chemoreceptors and the potential implications of Phox2b expressed in these neurons will be discussed. RTN resides at the ventral medullary surface. RTN lesions reduce central respiratory Chemoreception (CRC). RTN neurons are glutamatergic propriobulbar interneurons that selectively innervate the ventral respiratory column and other medullary regions essential to breathing. Their response to CO 2 is presumably intrinsic. RTN neurons uniformly express Phox2b, a transcription factor whose mutation in man causes a loss of CRC and central sleep apnea. RTN neurons are activated by stimulation of the carotid bodies, restrained by inhibitory inputs from the central respiratory pattern generator and from lung afferents and their response to CO 2 is sensitized by serotonin and by peptides released by serotonin neurons. The properties of RTN neurons are consistent with those expected from specialized central respiratory chemoreceptors. These data also suggest that respiratory reflexes operate in part by regulating the activity of central chemoreceptors. RTN neurons and the neurons that relay carotid body inputs to the respiratory centers express Phox2b. This peculiarity probably accounts for the loss of CRC associated with Phox2b mutations in man (central congenital hypoventilation syndrome).
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Retrotrapezoid nucleus and central Chemoreception
The Journal of physiology, 2008Co-Authors: Patrice G Guyenet, Ruth L. Stornetta, Douglas A. BaylissAbstract:The ‘distributed Chemoreception theory’ attributes the central chemoreflex (the stimulation of breathing by CNS acidification) to the cumulative effects of pH on multiple classes of respiratory neurons as well as on their tonic sources of drive. Opinions differ as to how many classes of pH-sensitive neurons contribute to the central chemoreflex but the number of candidates is high and growing fast. The ‘specialized chemoreceptor theory’, endorsed here, attributes the chemoreflex to a limited number of specialized neurons. These neurons (the central chemoreceptors) would drive a respiratory pattern generator that is not or minimally activated by acidification. In this review we first describe the properties of the retrotrapezoid nucleus (RTN) and argue that this nucleus may contain the most important central chemoreceptors. Next, we subject the assumptions that underlie the distributed Chemoreception theory to a critical analysis. We propose several explanations for the apparent contradiction between the two competing theories of central Chemoreception. We attribute much of the current controversy to premature extrapolations of the effects of acidification on neurons recorded in vitro (chemosensitivity) and to a semantic confusion between chemosensitivity and Chemoreception (the mechanism by which CO2 or pH activates breathing in vivo).
Ruth L. Stornetta - One of the best experts on this subject based on the ideXlab platform.
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the respiratory Chemoreception conundrum light at the end of the tunnel
Brain Research, 2013Co-Authors: Patrice G Guyenet, Stephen B G Abbott, Ruth L. StornettaAbstract:Arterial PCO₂ is tightly regulated via changes in breathing. A rise in PCO₂ activates the carotid bodies and exerts additional effects on neurons located within the CNS, causing an increase in lung ventilation. Central respiratory Chemoreception refers to the component of this homeostatic reflex that is triggered by activation of receptors located within the brain (central chemoreceptors). Throughout the body, CO₂ generally operates via the proxy of pH. Since countless proteins, ion channels and neurons display some degree of pH-sensitivity, the notion that central respiratory Chemoreception could rely on a few specialized neurons seems a priori counter-intuitive. Yet, two types of neurons currently stand out as critically important for breathing regulation by CO₂: the retrotrapezoid nucleus (RTN) and the raphe. RTN neurons are glutamatergic, strongly activated by hypercapnia in vivo and by CO₂ or protons in slices. These neurons target selectively the pontomedullary regions implicated in generating the respiratory rhythm and pattern. Their response to CO₂ seems to involve both cell-autonomous and paracrine effects of CO₂, the latter presumably mediated by the surrounding glia. The specific connections that these excitatory neurons establish with the rest of the breathing network are likely to be the main explanation of their importance to respiratory Chemoreception. Serotonergic neurons have a powerful stimulatory effect on breathing, they facilitate the chemoreflexes and a subset of them likely function as CO₂ sensors. Opto- and pharmacogenetic methods have played an important role in assessing the contribution of RTN and serotonergic neurons as well as glial cells to respiration. These particular experiments are emphasized here for thematic reasons although the current perception of the importance of the RTN and serotonergic cells to respiratory Chemoreception also relies on many other types of evidence. A small portion of this evidence is presented as background. This article is part of a Special Issue entitled Optogenetics (7th BRES).
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central respiratory Chemoreception
The Journal of Comparative Neurology, 2010Co-Authors: Patrice G Guyenet, Ruth L. Stornetta, Douglas A. BaylissAbstract:By definition central respiratory chemoreceptors (CRCs) are cells that are sensitive to changes in brain PCO(2) or pH and contribute to the stimulation of breathing elicited by hypercapnia or metabolic acidosis. CO(2) most likely works by lowering pH. The pertinent proton receptors have not been identified and may be ion channels. CRCs are probably neurons but may also include acid-sensitive glia and vascular cells that communicate with neurons via paracrine mechanisms. Retrotrapezoid nucleus (RTN) neurons are the most completely characterized CRCs. Their high sensitivity to CO(2) in vivo presumably relies on their intrinsic acid sensitivity, excitatory inputs from the carotid bodies and brain regions such as raphe and hypothalamus, and facilitating influences from neighboring astrocytes. RTN neurons are necessary for the respiratory network to respond to CO(2) during the perinatal period and under anesthesia. In conscious adults, RTN neurons contribute to an unknown degree to the pH-dependent regulation of breathing rate, inspiratory, and expiratory activity. The abnormal prenatal development of RTN neurons probably contributes to the congenital central hypoventilation syndrome. Other CRCs presumably exist, but the supportive evidence is less complete. The proposed locations of these CRCs are the medullary raphe, the nucleus tractus solitarius, the ventrolateral medulla, the fastigial nucleus, and the hypothalamus. Several wake-promoting systems (serotonergic and catecholaminergic neurons, orexinergic neurons) are also putative CRCs. Their contribution to central respiratory Chemoreception may be behavior dependent or vary according to the state of vigilance.
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the retrotrapezoid nucleus and central Chemoreception
Tzu Chi Medical Journal, 2008Co-Authors: Patrice G Guyenet, Ruth L. Stornetta, Douglas A. Bayliss, Daniel K. Mulkey, Thiago S Moreira, Ana T TakakuraAbstract:Abstract The functional role of retrotrapezoid nucleus (RTN) neurons as the central chemoreceptors and the potential implications of Phox2b expressed in these neurons will be discussed. RTN resides at the ventral medullary surface. RTN lesions reduce central respiratory Chemoreception (CRC). RTN neurons are glutamatergic propriobulbar interneurons that selectively innervate the ventral respiratory column and other medullary regions essential to breathing. Their response to CO 2 is presumably intrinsic. RTN neurons uniformly express Phox2b, a transcription factor whose mutation in man causes a loss of CRC and central sleep apnea. RTN neurons are activated by stimulation of the carotid bodies, restrained by inhibitory inputs from the central respiratory pattern generator and from lung afferents and their response to CO 2 is sensitized by serotonin and by peptides released by serotonin neurons. The properties of RTN neurons are consistent with those expected from specialized central respiratory chemoreceptors. These data also suggest that respiratory reflexes operate in part by regulating the activity of central chemoreceptors. RTN neurons and the neurons that relay carotid body inputs to the respiratory centers express Phox2b. This peculiarity probably accounts for the loss of CRC associated with Phox2b mutations in man (central congenital hypoventilation syndrome).
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Retrotrapezoid nucleus and central Chemoreception
The Journal of physiology, 2008Co-Authors: Patrice G Guyenet, Ruth L. Stornetta, Douglas A. BaylissAbstract:The ‘distributed Chemoreception theory’ attributes the central chemoreflex (the stimulation of breathing by CNS acidification) to the cumulative effects of pH on multiple classes of respiratory neurons as well as on their tonic sources of drive. Opinions differ as to how many classes of pH-sensitive neurons contribute to the central chemoreflex but the number of candidates is high and growing fast. The ‘specialized chemoreceptor theory’, endorsed here, attributes the chemoreflex to a limited number of specialized neurons. These neurons (the central chemoreceptors) would drive a respiratory pattern generator that is not or minimally activated by acidification. In this review we first describe the properties of the retrotrapezoid nucleus (RTN) and argue that this nucleus may contain the most important central chemoreceptors. Next, we subject the assumptions that underlie the distributed Chemoreception theory to a critical analysis. We propose several explanations for the apparent contradiction between the two competing theories of central Chemoreception. We attribute much of the current controversy to premature extrapolations of the effects of acidification on neurons recorded in vitro (chemosensitivity) and to a semantic confusion between chemosensitivity and Chemoreception (the mechanism by which CO2 or pH activates breathing in vivo).
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the retrotrapezoid nucleus and central Chemoreception
Advances in Experimental Medicine and Biology, 2008Co-Authors: Patrice G Guyenet, Ruth L. Stornetta, Douglas A. Bayliss, Daniel K. Mulkey, Thiago S Moreira, Ana T TakakuraAbstract:Central respiratory Chemoreception (CRC) is the mechanism by which brain pCO2 regulates breathing. The molecular and cellular basis of CRC is still poorly understood. In this review, we describe the properties of a cluster of pH-responsive neurons located in the retrotrapezoid region of the medulla oblongata and analyze whether these cells qualify as central respiratory chemoreceptors.