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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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Photostimulation of Phox2b Medullary Neurons Activates Cardiorespiratory Function in Conscious Rats
American journal of respiratory and critical care medicine, 2010Co-Authors: Roy Kanbar, Ruth L. Stornetta, Devin R. Cash, Stephen J. Lewis, Patrice G GuyenetAbstract:Rationale: Hypoventilation is typically treated with positive pressure ventilation or, in extreme cases, by phrenic nerve stimulation. This preclinical study explores whether direct stimulation of Central Chemoreceptors could be used as an alternative method to stimulate breathing. Objectives: To determine whether activation of the retrotrapezoid nucleus (RTN), which is located in the rostral ventrolateral medulla (RVLM), stimulates breathing with appropriate selectivity. Methods: A lentivirus was used to induce expression of the photoactivatable cationic channel channelrhodopsin-2 (ChR2) by RVLM Phox2b-containing neurons, a population that consists of Central Chemoreceptors (the ccRTN neurons) and blood pressure (BP)-regulating neurons (the C1 cells). The transfected neurons were activated with pulses of laser light. Respiratory effects were measured by plethysmography or diaphragmatic EMG recording and cardiovascular effects by monitoring BP, renal sympathetic nerve discharge, and the baroreflex. Measurements and Main Results: The RVLM contained 600 to 900 ChR2-transfected neurons (63% C1, 37% ccRTN). RVLM photostimulation significantly increased breathing rate (+42%), tidal volume (21%), minute volume (68%), and peak expiratory flow (48%). Photostimulation increased diaphragm EMG amplitude (19%) and frequency (21%). Photostimulation increased BP (4 mmHg) and renal sympathetic nerve discharge (43%) while decreasing heart rate (15 bpm). Conclusions: Photostimulation of ChR2-transfected RVLM Phox2b neurons produces a vigorous stimulation of breathing accompanied by a small sympathetically mediated increase in BP. These results demonstrate that breathing can be relatively selectively activated in resting unanesthetized mammals via optogenetic manipulation of RVLM neurons presumed to be Central Chemoreceptors. This methodology could perhaps be used in the future to enhance respiration in humans.
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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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Central Chemoreceptors and sympathetic vasomotor outflow
The Journal of Physiology, 2006Co-Authors: Thiago S. Moreira, Ana C. Takakura, Eduardo Colombari, Patrice G GuyenetAbstract:In the absence of input from carotid bodies and cardiopulmonary receptors hypercapnia markedly increases sympathetic nerve discharge (SND) to the heart and blood vessels (Hanna et al. 1988). The effect of CO2 is generally attributed to the following chain of events: brain extracellular fluid acidification stimulates Central ‘respiratory’ Chemoreceptors, these Chemoreceptors activate the respiratory pattern generator (CPG) and the CPG ultimately drives the sympathetic generating network by phasically exciting the sympathoexcitatory neurons of the rostral ventrolateral medulla (RVLM) (Millhorn & Eldridge, 1986; Richter & Spyer, 1990; Guyenet & Koshiya, 1992). This theory relies on the following evidence. SND activation by Central Chemoreceptors occurs in bursts that are synchronized with the Central respiratory cycle (Millhorn, 1986; Millhorn & Eldridge, 1986; Guyenet et al. 1990; Habler et al. 1994). Damage to the ventrolateral medullary surface via cooling, lesions or chemicals typically attenuates PND and the respiratory oscillations of SND in roughly proportional manner (Hanna et al. 1979; Millhorn, 1986; Millhorn & Eldridge, 1986). During Central chemoreceptor stimulation, RVLM sympathoexcitatory neurons exhibit patterns of Central respiratory-related activity that are similar to those of barosensitive sympathetic ganglionic neurons (McAllen, 1987; Haselton & Guyenet, 1989; Darnall & Guyenet, 1990; Guyenet et al. 1990; Miyawaki et al. 1995). However, a number of assumptions underlying the currently accepted view on how CO2 affects SND have not been tested. For example, the proposed circuit presumes that the sympathetic generating network does not contain pH-responsive elements. Already challenged 25 years ago (Trzebski & Kubin, 1981), this premise is even less persuasive at present given recent evidence that the pontomedullary region may contain multiple sites for respiratory chemoreception (nucleus of the solitary tract (NTS), retrotrapezoid nucleus (RTN), pre-Botzinger complex, raphe) (Nattie & Li, 1996; Feldman et al. 2003; Hodges et al. 2004; Mulkey et al. 2004; Putnam et al. 2004; Richerson et al. 2005). Noradrenergic neurons are pH-sensitive (Pineda & Aghajanian, 1997) and RVLM sympathoexcitatory neurons may also have this property given that they express high levels of TASK channels, have close relationships with capillaries and possess dendrites that reach the ventral medullary surface (Milner et al. 1987, 1989; Washburn et al. 2003). Second, the observation that RVLM vasomotor neurons are respiratory rhythmic is insufficient to conclude that these cells cause the increased SND associated with Central chemoreceptor stimulation. Only one study has examined whether the overall activity of these neurons is actually increased by Central chemoreceptor stimulation (Haselton & Guyenet, 1989) and none has examined whether their degree of activation is commensurate with the rise in sympathetic vasomotor tone. Third, the fact that SND or RVLM neurons are activated in bursts during Central chemoreceptor stimulation does not mean that such bursts are caused by respiratory rhythmic excitatory volleys to the RVLM neurons. Respiratory synchronous bursts can be sculpted by periodic inhibitory inputs from a background of tonic excitation. Many ventral respiratory group (VRG) expiratory neurons and the chemosensitive neurons of RTN derive their respiratory modulation in this fashion during Central chemoreceptor stimulation (Sun et al. 2001; Guyenet et al. 2005a). The same type of synaptic mechanism could also account for the Central respiratory modulation of RVLM neurons since their principal tonically active GABAergic input from caudal ventrolateral medulla (CVLM) neurons is strongly respiratory modulated (Schreihofer & Guyenet, 2003; Mandel & Schreihofer, 2006). The goal of the present experiments is to test several of the unproven assumptions that underlie our present understanding of how Central Chemoreceptors activate vasomotor SND. The main objectives are to test rigorously the role of RVLM neurons in this reflex, to determine whether the activation of these cells relies on glutamate-mediated excitatory inputs and to circumscribe the region of the medulla oblongata which contains the pH-sensitive elements that are primarily responsible for elevating sympathetic vasomotor tone.
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Central Chemoreceptors and sympathetic vasomotor outflow.
The Journal of physiology, 2006Co-Authors: Thiago S. Moreira, Ana C. Takakura, Eduardo Colombari, Patrice G GuyenetAbstract:The present study explores how elevations in brain P(CO(2)) increase the sympathetic nerve discharge (SND). SND, phrenic nerve discharge (PND) and putative sympathoexcitatory vasomotor neurons of the rostral ventrolateral medulla (RVLM) were recorded in anaesthetized sino-aortic denervated and vagotomized rats. Hypercapnia (end-expiratory CO(2) from 5% to 10%) increased SND (97 +/- 6%) and the activity of RVLM neurons (67 +/- 4%). Injection of kynurenic acid (Kyn, ionotropic glutamate receptor antagonist) into RVLM or the retrotrapezoid nucleus (RTN) eliminated or reduced PND, respectively, but did not change the effect of CO(2) on SND. Bilateral injection of Kyn or muscimol into the rostral ventral respiratory group (rVRG-pre-Bötzinger region, also called CVLM) eliminated PND while increasing the stimulatory effect of CO(2) on SND. Muscimol injection into commissural part of the solitary tract nucleus (commNTS) had no effect on PND or SND activation by CO(2). As expected, injection of Kyn into RVLM or muscimol into commNTS virtually blocked the effect of carotid body stimulation on SND in rats with intact carotid sinus nerves. In conclusion, CO(2) increases SND by activating RVLM sympathoexcitatory neurons. The relevant Central Chemoreceptors are probably located within or close to RVLM and not in the NTS or in the rVRG-pre-Bötzinger/CVLM region. RVLM sympathoexcitatory neurons may be intrinsically pH-sensitive and/or receive excitatory synaptic inputs from RTN Chemoreceptors. Activation of the Central respiratory network reduces the overall sympathetic response to CO(2), presumably by activating barosensitive CVLM neurons and inhibiting RTN Chemoreceptors.
Eugene E Nattie - One of the best experts on this subject based on the ideXlab platform.
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The Enhanced CO2 Chemoreflex is Associated with Increased Number of CO2-activated Orexin Neurons in the Lateral Hypothalamus in Spontaneously Hypertensive Rats (SHRs)
The FASEB Journal, 2016Co-Authors: Eugene E Nattie, Sarah H. RoyAbstract:Activation of Central Chemoreceptors by CO2 increases arterial blood pressure (ABP), sympathetic nerve activity (SNA), and breathing. Experiments using SHRs, a well-established neurogenic hypertens...
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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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Comprehensive Physiology - 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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why do we have both peripheral and Central Chemoreceptors
Journal of Applied Physiology, 2006Co-Authors: Eugene E NattieAbstract:The peripheral Chemoreceptors, the carotid (and aortic) bodies, detect arterial hypoxemia and stimulate breathing. At normal arterial Po2 (PaO2) values, they provide a tonic excitatory input to the brain stem ([6][1]), and with hypoxia they respond dramatically as PaO2 falls below 70 Torr. Thus, for
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CO2 dialysis in nucleus tractus solitarius region of rat increases ventilation in sleep and wakefulness.
Journal of applied physiology (Bethesda Md. : 1985), 2002Co-Authors: Eugene E NattieAbstract:To evaluate the function of widely distributed Central Chemoreceptors during sleep and wakefulness in the rat, we focally stimulate single chemoreceptor sites during naturally occurring sleep-wake ...
Thiago S. Moreira - One of the best experts on this subject based on the ideXlab platform.
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Raphe Pallidus is Not Important to Central Chemoreception in a Rat Model of Parkinson's Disease.
Neuroscience, 2017Co-Authors: Luiz M. Oliveira, Thiago S. Moreira, Ana C. TakakuraAbstract:Abstract Central Chemoreceptors are primarily sensitive to changes in CO2/H+, and such changes lead to intense breathing activity. Medullary raphe and retrotrapezoid nucleus (RTN) neurons are candidates for Central Chemoreceptors because they are unusually pH sensitive. The pathophysiology of Parkinson’s disease (PD) is related to the reduction of neurons in the substantia nigra pars compacta (SNpc) that express dopamine, although other neurons can also be degenerated in this pathology. In rodent models of PD, we showed an impairment of the hypercapnia ventilatory response due to a reduction in the number of RTN chemosensitive neurons. Here, we aimed to investigate if serotonine-expressing neurons in the Raphe pallidus/parapyramidal region (RPa/PPy) are also involved in the modulation of breathing during Central chemoreception activation in a PD animal model. PD was induced in male Wistar rats with bilateral injection of 6-OHDA (6-hydroxydopamine; 24 µg/µl) into the striatum, which leads to a reduction in the catecholaminergic neurons of the SNpc by 89%. In PD animals, we noticed a reduction in the number of RPa neurons that project to the RTN, without a change in the number of hypercapnia-activated (7% CO2) raphe neurons. The PD animals that received injection of the toxin saporin anti-SERT into the RPA/PPy region did not show a further reduction of respiratory frequency (fR) or ventilation (VE) at rest or during hypercapnia challenge. These experiments demonstrate that serotonergic neurons of RPa/PPy are not involved in the breathing responses induced by Central chemoreceptor activation in a PD animal model.
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Central Chemoreceptors and neural mechanisms of cardiorespiratory control
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas, 2011Co-Authors: Thiago S. Moreira, Ana C. Takakura, Rosélia S. Damasceno, Barbara Falquetto, Leonardo T. Totola, Cleyton R. Sobrinho, Danielle A. M. T. Ragioto, F.p. ZoleziAbstract:The arterial partial pressure (PCO2 ) of carbon dioxide is virtually constant because of the close match between the metabolic production of this gas and its excretion via breathing. Blood gas homeostasis does not rely solely on changes in lung ventilation, but also to a considerable extent on circulatory adjustments that regulate the transport of CO2 from its sites of production to the lungs. The neural mechanisms that coordinate circulatory and ventilatory changes to achieve blood gas homeostasis are the subject of this review. Emphasis will be placed on the control of sympathetic outflow by Central Chemoreceptors. High levels of CO2 exert an excitatory effect on sympathetic outflow that is mediated by specialized Chemoreceptors such as the neurons located in the retrotrapezoid region. In addition, high CO2 causes an aversive awareness in conscious animals, activating wakepromoting pathways such as the noradrenergic neurons. These neuronal groups, which may also be directly activated by brain acidification, have projections that contribute to the CO 2-induced rise in breathing and sympathetic outflow. However, since the level of activity of the retrotrapezoid nucleus is regulated by converging inputs from wake-promoting systems, behavior-specific inputs from higher centers and by chemical drive, the main focus of the present manuscript is to review the contribution of Central Chemoreceptors to the control of autonomic and respiratory mechanisms.
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Central Chemoreceptors and sympathetic vasomotor outflow
The Journal of Physiology, 2006Co-Authors: Thiago S. Moreira, Ana C. Takakura, Eduardo Colombari, Patrice G GuyenetAbstract:In the absence of input from carotid bodies and cardiopulmonary receptors hypercapnia markedly increases sympathetic nerve discharge (SND) to the heart and blood vessels (Hanna et al. 1988). The effect of CO2 is generally attributed to the following chain of events: brain extracellular fluid acidification stimulates Central ‘respiratory’ Chemoreceptors, these Chemoreceptors activate the respiratory pattern generator (CPG) and the CPG ultimately drives the sympathetic generating network by phasically exciting the sympathoexcitatory neurons of the rostral ventrolateral medulla (RVLM) (Millhorn & Eldridge, 1986; Richter & Spyer, 1990; Guyenet & Koshiya, 1992). This theory relies on the following evidence. SND activation by Central Chemoreceptors occurs in bursts that are synchronized with the Central respiratory cycle (Millhorn, 1986; Millhorn & Eldridge, 1986; Guyenet et al. 1990; Habler et al. 1994). Damage to the ventrolateral medullary surface via cooling, lesions or chemicals typically attenuates PND and the respiratory oscillations of SND in roughly proportional manner (Hanna et al. 1979; Millhorn, 1986; Millhorn & Eldridge, 1986). During Central chemoreceptor stimulation, RVLM sympathoexcitatory neurons exhibit patterns of Central respiratory-related activity that are similar to those of barosensitive sympathetic ganglionic neurons (McAllen, 1987; Haselton & Guyenet, 1989; Darnall & Guyenet, 1990; Guyenet et al. 1990; Miyawaki et al. 1995). However, a number of assumptions underlying the currently accepted view on how CO2 affects SND have not been tested. For example, the proposed circuit presumes that the sympathetic generating network does not contain pH-responsive elements. Already challenged 25 years ago (Trzebski & Kubin, 1981), this premise is even less persuasive at present given recent evidence that the pontomedullary region may contain multiple sites for respiratory chemoreception (nucleus of the solitary tract (NTS), retrotrapezoid nucleus (RTN), pre-Botzinger complex, raphe) (Nattie & Li, 1996; Feldman et al. 2003; Hodges et al. 2004; Mulkey et al. 2004; Putnam et al. 2004; Richerson et al. 2005). Noradrenergic neurons are pH-sensitive (Pineda & Aghajanian, 1997) and RVLM sympathoexcitatory neurons may also have this property given that they express high levels of TASK channels, have close relationships with capillaries and possess dendrites that reach the ventral medullary surface (Milner et al. 1987, 1989; Washburn et al. 2003). Second, the observation that RVLM vasomotor neurons are respiratory rhythmic is insufficient to conclude that these cells cause the increased SND associated with Central chemoreceptor stimulation. Only one study has examined whether the overall activity of these neurons is actually increased by Central chemoreceptor stimulation (Haselton & Guyenet, 1989) and none has examined whether their degree of activation is commensurate with the rise in sympathetic vasomotor tone. Third, the fact that SND or RVLM neurons are activated in bursts during Central chemoreceptor stimulation does not mean that such bursts are caused by respiratory rhythmic excitatory volleys to the RVLM neurons. Respiratory synchronous bursts can be sculpted by periodic inhibitory inputs from a background of tonic excitation. Many ventral respiratory group (VRG) expiratory neurons and the chemosensitive neurons of RTN derive their respiratory modulation in this fashion during Central chemoreceptor stimulation (Sun et al. 2001; Guyenet et al. 2005a). The same type of synaptic mechanism could also account for the Central respiratory modulation of RVLM neurons since their principal tonically active GABAergic input from caudal ventrolateral medulla (CVLM) neurons is strongly respiratory modulated (Schreihofer & Guyenet, 2003; Mandel & Schreihofer, 2006). The goal of the present experiments is to test several of the unproven assumptions that underlie our present understanding of how Central Chemoreceptors activate vasomotor SND. The main objectives are to test rigorously the role of RVLM neurons in this reflex, to determine whether the activation of these cells relies on glutamate-mediated excitatory inputs and to circumscribe the region of the medulla oblongata which contains the pH-sensitive elements that are primarily responsible for elevating sympathetic vasomotor tone.
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Central Chemoreceptors and sympathetic vasomotor outflow.
The Journal of physiology, 2006Co-Authors: Thiago S. Moreira, Ana C. Takakura, Eduardo Colombari, Patrice G GuyenetAbstract:The present study explores how elevations in brain P(CO(2)) increase the sympathetic nerve discharge (SND). SND, phrenic nerve discharge (PND) and putative sympathoexcitatory vasomotor neurons of the rostral ventrolateral medulla (RVLM) were recorded in anaesthetized sino-aortic denervated and vagotomized rats. Hypercapnia (end-expiratory CO(2) from 5% to 10%) increased SND (97 +/- 6%) and the activity of RVLM neurons (67 +/- 4%). Injection of kynurenic acid (Kyn, ionotropic glutamate receptor antagonist) into RVLM or the retrotrapezoid nucleus (RTN) eliminated or reduced PND, respectively, but did not change the effect of CO(2) on SND. Bilateral injection of Kyn or muscimol into the rostral ventral respiratory group (rVRG-pre-Bötzinger region, also called CVLM) eliminated PND while increasing the stimulatory effect of CO(2) on SND. Muscimol injection into commissural part of the solitary tract nucleus (commNTS) had no effect on PND or SND activation by CO(2). As expected, injection of Kyn into RVLM or muscimol into commNTS virtually blocked the effect of carotid body stimulation on SND in rats with intact carotid sinus nerves. In conclusion, CO(2) increases SND by activating RVLM sympathoexcitatory neurons. The relevant Central Chemoreceptors are probably located within or close to RVLM and not in the NTS or in the rVRG-pre-Bötzinger/CVLM region. RVLM sympathoexcitatory neurons may be intrinsically pH-sensitive and/or receive excitatory synaptic inputs from RTN Chemoreceptors. Activation of the Central respiratory network reduces the overall sympathetic response to CO(2), presumably by activating barosensitive CVLM neurons and inhibiting RTN Chemoreceptors.
Ana C. Takakura - One of the best experts on this subject based on the ideXlab platform.
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Raphe Pallidus is Not Important to Central Chemoreception in a Rat Model of Parkinson's Disease.
Neuroscience, 2017Co-Authors: Luiz M. Oliveira, Thiago S. Moreira, Ana C. TakakuraAbstract:Abstract Central Chemoreceptors are primarily sensitive to changes in CO2/H+, and such changes lead to intense breathing activity. Medullary raphe and retrotrapezoid nucleus (RTN) neurons are candidates for Central Chemoreceptors because they are unusually pH sensitive. The pathophysiology of Parkinson’s disease (PD) is related to the reduction of neurons in the substantia nigra pars compacta (SNpc) that express dopamine, although other neurons can also be degenerated in this pathology. In rodent models of PD, we showed an impairment of the hypercapnia ventilatory response due to a reduction in the number of RTN chemosensitive neurons. Here, we aimed to investigate if serotonine-expressing neurons in the Raphe pallidus/parapyramidal region (RPa/PPy) are also involved in the modulation of breathing during Central chemoreception activation in a PD animal model. PD was induced in male Wistar rats with bilateral injection of 6-OHDA (6-hydroxydopamine; 24 µg/µl) into the striatum, which leads to a reduction in the catecholaminergic neurons of the SNpc by 89%. In PD animals, we noticed a reduction in the number of RPa neurons that project to the RTN, without a change in the number of hypercapnia-activated (7% CO2) raphe neurons. The PD animals that received injection of the toxin saporin anti-SERT into the RPA/PPy region did not show a further reduction of respiratory frequency (fR) or ventilation (VE) at rest or during hypercapnia challenge. These experiments demonstrate that serotonergic neurons of RPa/PPy are not involved in the breathing responses induced by Central chemoreceptor activation in a PD animal model.
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Central Chemoreceptors and neural mechanisms of cardiorespiratory control
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas, 2011Co-Authors: Thiago S. Moreira, Ana C. Takakura, Rosélia S. Damasceno, Barbara Falquetto, Leonardo T. Totola, Cleyton R. Sobrinho, Danielle A. M. T. Ragioto, F.p. ZoleziAbstract:The arterial partial pressure (PCO2 ) of carbon dioxide is virtually constant because of the close match between the metabolic production of this gas and its excretion via breathing. Blood gas homeostasis does not rely solely on changes in lung ventilation, but also to a considerable extent on circulatory adjustments that regulate the transport of CO2 from its sites of production to the lungs. The neural mechanisms that coordinate circulatory and ventilatory changes to achieve blood gas homeostasis are the subject of this review. Emphasis will be placed on the control of sympathetic outflow by Central Chemoreceptors. High levels of CO2 exert an excitatory effect on sympathetic outflow that is mediated by specialized Chemoreceptors such as the neurons located in the retrotrapezoid region. In addition, high CO2 causes an aversive awareness in conscious animals, activating wakepromoting pathways such as the noradrenergic neurons. These neuronal groups, which may also be directly activated by brain acidification, have projections that contribute to the CO 2-induced rise in breathing and sympathetic outflow. However, since the level of activity of the retrotrapezoid nucleus is regulated by converging inputs from wake-promoting systems, behavior-specific inputs from higher centers and by chemical drive, the main focus of the present manuscript is to review the contribution of Central Chemoreceptors to the control of autonomic and respiratory mechanisms.
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Central Chemoreceptors and sympathetic vasomotor outflow
The Journal of Physiology, 2006Co-Authors: Thiago S. Moreira, Ana C. Takakura, Eduardo Colombari, Patrice G GuyenetAbstract:In the absence of input from carotid bodies and cardiopulmonary receptors hypercapnia markedly increases sympathetic nerve discharge (SND) to the heart and blood vessels (Hanna et al. 1988). The effect of CO2 is generally attributed to the following chain of events: brain extracellular fluid acidification stimulates Central ‘respiratory’ Chemoreceptors, these Chemoreceptors activate the respiratory pattern generator (CPG) and the CPG ultimately drives the sympathetic generating network by phasically exciting the sympathoexcitatory neurons of the rostral ventrolateral medulla (RVLM) (Millhorn & Eldridge, 1986; Richter & Spyer, 1990; Guyenet & Koshiya, 1992). This theory relies on the following evidence. SND activation by Central Chemoreceptors occurs in bursts that are synchronized with the Central respiratory cycle (Millhorn, 1986; Millhorn & Eldridge, 1986; Guyenet et al. 1990; Habler et al. 1994). Damage to the ventrolateral medullary surface via cooling, lesions or chemicals typically attenuates PND and the respiratory oscillations of SND in roughly proportional manner (Hanna et al. 1979; Millhorn, 1986; Millhorn & Eldridge, 1986). During Central chemoreceptor stimulation, RVLM sympathoexcitatory neurons exhibit patterns of Central respiratory-related activity that are similar to those of barosensitive sympathetic ganglionic neurons (McAllen, 1987; Haselton & Guyenet, 1989; Darnall & Guyenet, 1990; Guyenet et al. 1990; Miyawaki et al. 1995). However, a number of assumptions underlying the currently accepted view on how CO2 affects SND have not been tested. For example, the proposed circuit presumes that the sympathetic generating network does not contain pH-responsive elements. Already challenged 25 years ago (Trzebski & Kubin, 1981), this premise is even less persuasive at present given recent evidence that the pontomedullary region may contain multiple sites for respiratory chemoreception (nucleus of the solitary tract (NTS), retrotrapezoid nucleus (RTN), pre-Botzinger complex, raphe) (Nattie & Li, 1996; Feldman et al. 2003; Hodges et al. 2004; Mulkey et al. 2004; Putnam et al. 2004; Richerson et al. 2005). Noradrenergic neurons are pH-sensitive (Pineda & Aghajanian, 1997) and RVLM sympathoexcitatory neurons may also have this property given that they express high levels of TASK channels, have close relationships with capillaries and possess dendrites that reach the ventral medullary surface (Milner et al. 1987, 1989; Washburn et al. 2003). Second, the observation that RVLM vasomotor neurons are respiratory rhythmic is insufficient to conclude that these cells cause the increased SND associated with Central chemoreceptor stimulation. Only one study has examined whether the overall activity of these neurons is actually increased by Central chemoreceptor stimulation (Haselton & Guyenet, 1989) and none has examined whether their degree of activation is commensurate with the rise in sympathetic vasomotor tone. Third, the fact that SND or RVLM neurons are activated in bursts during Central chemoreceptor stimulation does not mean that such bursts are caused by respiratory rhythmic excitatory volleys to the RVLM neurons. Respiratory synchronous bursts can be sculpted by periodic inhibitory inputs from a background of tonic excitation. Many ventral respiratory group (VRG) expiratory neurons and the chemosensitive neurons of RTN derive their respiratory modulation in this fashion during Central chemoreceptor stimulation (Sun et al. 2001; Guyenet et al. 2005a). The same type of synaptic mechanism could also account for the Central respiratory modulation of RVLM neurons since their principal tonically active GABAergic input from caudal ventrolateral medulla (CVLM) neurons is strongly respiratory modulated (Schreihofer & Guyenet, 2003; Mandel & Schreihofer, 2006). The goal of the present experiments is to test several of the unproven assumptions that underlie our present understanding of how Central Chemoreceptors activate vasomotor SND. The main objectives are to test rigorously the role of RVLM neurons in this reflex, to determine whether the activation of these cells relies on glutamate-mediated excitatory inputs and to circumscribe the region of the medulla oblongata which contains the pH-sensitive elements that are primarily responsible for elevating sympathetic vasomotor tone.
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Central Chemoreceptors and sympathetic vasomotor outflow.
The Journal of physiology, 2006Co-Authors: Thiago S. Moreira, Ana C. Takakura, Eduardo Colombari, Patrice G GuyenetAbstract:The present study explores how elevations in brain P(CO(2)) increase the sympathetic nerve discharge (SND). SND, phrenic nerve discharge (PND) and putative sympathoexcitatory vasomotor neurons of the rostral ventrolateral medulla (RVLM) were recorded in anaesthetized sino-aortic denervated and vagotomized rats. Hypercapnia (end-expiratory CO(2) from 5% to 10%) increased SND (97 +/- 6%) and the activity of RVLM neurons (67 +/- 4%). Injection of kynurenic acid (Kyn, ionotropic glutamate receptor antagonist) into RVLM or the retrotrapezoid nucleus (RTN) eliminated or reduced PND, respectively, but did not change the effect of CO(2) on SND. Bilateral injection of Kyn or muscimol into the rostral ventral respiratory group (rVRG-pre-Bötzinger region, also called CVLM) eliminated PND while increasing the stimulatory effect of CO(2) on SND. Muscimol injection into commissural part of the solitary tract nucleus (commNTS) had no effect on PND or SND activation by CO(2). As expected, injection of Kyn into RVLM or muscimol into commNTS virtually blocked the effect of carotid body stimulation on SND in rats with intact carotid sinus nerves. In conclusion, CO(2) increases SND by activating RVLM sympathoexcitatory neurons. The relevant Central Chemoreceptors are probably located within or close to RVLM and not in the NTS or in the rVRG-pre-Bötzinger/CVLM region. RVLM sympathoexcitatory neurons may be intrinsically pH-sensitive and/or receive excitatory synaptic inputs from RTN Chemoreceptors. Activation of the Central respiratory network reduces the overall sympathetic response to CO(2), presumably by activating barosensitive CVLM neurons and inhibiting RTN Chemoreceptors.
Jerome A Dempsey - One of the best experts on this subject based on the ideXlab platform.
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peripheral Chemoreceptors determine the respiratory sensitivity of Central Chemoreceptors to co2 role of carotid body co2
The Journal of Physiology, 2015Co-Authors: Curtis A Smith, Gregory M Blain, K S Henderson, Jerome A DempseyAbstract:We asked if the type of carotid body (CB) chemoreceptor stimulus influenced the ventilatory gain of the Central Chemoreceptors to CO2. The effect of CB normoxic hypocapnia, normocapnia and hypercapnia (carotid body ≈ 22, 41 and 68 mmHg, respectively) on the ventilatory CO2 sensitivity of Central Chemoreceptors was studied in seven awake dogs with vascularly-isolated and extracorporeally-perfused CBs. Chemosensitivity with one CB was similar to that in intact dogs. In four CB-denervated dogs, absence of hyper-/hypoventilatory responses to CB perfusion with of 19–75 mmHg confirmed separation of the perfused CB circulation from the brain. The group mean Central CO2 response slopes were increased 303% for minute ventilation ()(P ≤ 0.01) and 251% for mean inspiratory flow rate (VT/TI) (P ≤ 0.05) when the CB was hypercapnic vs. hypocapnic; Central CO2 response slopes for tidal volume (VT), breathing frequency (fb) and rate of rise of the diaphragm EMG increased in 6 of 7 animals but the group mean changes did not reach statistical significance. Group mean Central CO2 response slopes were also increased 237% for (P ≤ 0.01) and 249% for VT/TI(P ≤ 0.05) when the CB was normocapnic vs. hypocapnic, but no significant differences in any of the Central ventilatory response indices were found between CB normocapnia and hypercapnia. These hyperadditive effects of CB hyper-/hypocapnia agree with previous findings using CB hyper-/hypoxia.We propose that hyperaddition is the dominant form of chemoreceptor interaction in quiet wakefulness when the chemosensory control system is intact, response gains physiological, and carotid body Chemoreceptors are driven by a wide range of O2 and/or CO2. Key points The influence of specific carotid body (CB) normoxic hypocapnia, hypercapnia and normocapnia on the ventilatory sensitivity of Central Chemoreceptors to systemic hypercapnia was assessed in seven awake dogs with extracorporeal perfusion of the vascularly isolated CB. Chemosensitivity in this preparation was similar to that in the intact animal. Separation of CB circulation from that of the brain was confirmed. When the isolated CB was hypercapnic vs. hypocapnic and when the isolated CB was normocapnic vs. hypocapnic, the group mean Central CO2 response slopes of minute ventilation () (P ≤ 0.01) and mean inspiratory flow rate (VT/TI) (P ≤ 0.05) increased significantly. Tidal volume (VT), breathing frequency (fb)and rate of rise of diaphragm EMG were increased in 6 of 7 dogs but did not achieve statistical significance. We propose that hyperaddition is the dominant form of chemoreceptor interaction under conditions of quiet wakefulness in intact animals and over a wide range of CB and . Introduction Peripheral–Central chemoreceptor interactive effects on control of breathing have been observed using animal models with isolated perfusion of the carotid body and/or Central Chemoreceptors in such varied conditions as eupnoea, apnoea, hypercapnia, and hypoxia (Day & Wilson, 2007,2009; Smith et al. 2007,2010; Blain et al. 2009,2010; Dempsey et al. 2012; Fiamma et al. 2013). However, the exact nature of these chemoreceptor interactions are controversial with studies in a wide variety of experimental preparations and theoretical models claiming additive, hyperadditive, or hypoadditive effects on the control of breathing (Duffin, 1990; Duffin & Mateika, 2013; Teppema & Smith, 2013; Wilson & Day, 2013). Based on these divergent findings some investigators (Wilson & Day, 2013; Guyenet, 2014) have suggested a ‘hybrid’ model as a basis for peripheral–Central interaction, whereby variations in both the experimental models and in the prevailing physiological conditions and/or chemoreceptor stimuli may markedly alter the nature of the chemoreceptor interactions (also see Discussion). Accordingly, in the present study we have tested the nature of the peripheral–Central interaction under novel experimental conditions consisting of hypercapnic stimulation and hypocapnic inhibition at the level of the isolated CB chemoreceptor. This represents an important advance in addressing the interaction problem for several reasons. First, comparing normoxic hypercapnia/hypocapnia to results from our prior use of hypoxia/hyperoxia at the carotid body (Blain et al. 2010) provides a test of the equivalence of the observed hyperadditive interactive effect in the presence of both major peripheral chemoreceptor stimuli, i.e. CO2 and O2. Second, perturbations in per se have widespread physiological significance in the control of breathing and breathing stability during wakefulness and sleep, which appear to depend critically upon peripheral–Central chemoreceptor interactions (Smith et al. 2007; Dempsey et al. 2012; Fiamma et al. 2013). Third, we tested these interactive effects in a unique awake canine preparation which incorporates two essential characteristics for quantifying the nature of these interactions, namely (a) that the preparation’s chemoresponsiveness is within the physiological range and close to that in the intact animal, and (b) that Central and peripheral Chemoreceptors are truly separated both anatomically and functionally. Fourth, although there is no direct evidence we are aware of that the carotid sinus nerve discharge pattern can encode information concerning the nature of the carotid body stimulus, there are some lines of evidence showing that carotid body hypercapnia might have quite different cardiorespiratory influences from carotid body hypoxaemia. For example, in the awake goat, carotid body hypoxia, even for very short periods beyond the acute phase, progressively increased the ventilatory response whereas specific carotid body hypercapnia did not (Bisgard et al. 1986). In anesthetized goats short periods of hypoxia sensitized output of the carotid body chemoreceptor (Nielsen et al. 1988), whereas hypercapnia did not (Engwall et al. 1988). In anaesthetized rats, carotid body denervation prevented the response of CO2 sensitive neurons in the retrotrapezoid nucleus to very brief exposures of reduced , but had no effect on their response to inhaled CO2(Mulkey et al. 2004). In anaesthetized rats conditioned by exposure to chronic intermittent hypoxia for 10 days, acute intermittent hypoxia elicited long-term facilitation of carotid sinus nerve output whereas acute intermittent hyperoxic hypercapnia did not (Peng et al. 2003). Further, in awake humans, acute periods of arterial isocapnic hypoxaemia or asphyxia elicited marked lingering after-effects on muscle sympathetic nerve activity once the stimulus was removed whereas similar periods of arterial normoxic hypercapnia did not (Morgan et al. 1995; Xie et al. 2000,2001). We found that, in the awake dog, specific carotid body stimulation/inhibition by means of hyper- or hypocapnia resulted in hyperadditive interaction when the Central Chemoreceptors were stimulated by means of increased . The similarity of these hyperadditive interactions to those caused primarily by means of changes in carotid body suggest that short-term changes in and at the carotid body have equivalent effects on peripheral–Central interaction for a given change in baseline ventilation.
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peripheral Chemoreceptors determine the respiratory sensitivity of Central Chemoreceptors to co2
The Journal of Physiology, 2010Co-Authors: Curtis A Smith, Gregory M Blain, K S Henderson, Jerome A DempseyAbstract:We assessed the contribution of carotid body Chemoreceptors to the ventilatory response to specific CNS hypercapnia in eight unanaesthetized, awake dogs. We denervated one carotid body (CB) and used extracorporeal blood perfusion of the reversibly isolated remaining CB to maintain normal CB blood gases (normoxic, normocapnic perfusate), to inhibit (hyperoxic, hypocapnic perfusate) or to stimulate (hypoxic, normocapnic perfusate) the CB chemoreflex, while the systemic circulation, and therefore the CNS and Central Chemoreceptors, were exposed consecutively to four progressive levels of systemic arterial hypercapnia via increased fractional inspired CO2 for 7 min at each level. Neither unilateral CB denervation nor CB perfusion, per se, affected breathing. Relative to CB control conditions (normoxic, normocapnic perfusion), we found that CB chemoreflex inhibition decreased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 19% of control values (range 0–38%; n= 6), whereas CB chemoreflex stimulation increased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 223% of control values (range 204–235%; n= 4). We conclude that the gain of the CNS CO2/H+ Chemoreceptors in dogs is critically dependent on CB afferent activity and that CNS–CB interaction results in hyperadditive ventilatory responses to Central hypercapnia.
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Peripheral Chemoreceptors determine the respiratory sensitivity of Central Chemoreceptors to CO(2).
The Journal of physiology, 2010Co-Authors: Gregory M Blain, Curtis A Smith, K S Henderson, Jerome A DempseyAbstract:We assessed the contribution of carotid body Chemoreceptors to the ventilatory response to specific CNS hypercapnia in eight unanaesthetized, awake dogs. We denervated one carotid body (CB) and used extracorporeal blood perfusion of the reversibly isolated remaining CB to maintain normal CB blood gases (normoxic, normocapnic perfusate), to inhibit (hyperoxic, hypocapnic perfusate) or to stimulate (hypoxic, normocapnic perfusate) the CB chemoreflex, while the systemic circulation, and therefore the CNS and Central Chemoreceptors, were exposed consecutively to four progressive levels of systemic arterial hypercapnia via increased fractional inspired CO(2) for 7 min at each level. Neither unilateral CB denervation nor CB perfusion, per se, affected breathing. Relative to CB control conditions (normoxic, normocapnic perfusion), we found that CB chemoreflex inhibition decreased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 19% of control values (range 0-38%; n = 6), whereas CB chemoreflex stimulation increased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 223% of control values (range 204-235%; n = 4). We conclude that the gain of the CNS CO(2)/H(+) Chemoreceptors in dogs is critically dependent on CB afferent activity and that CNS-CB interaction results in hyperadditive ventilatory responses to Central hypercapnia.
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the apneic threshold during non rem sleep in dogs sensitivity of carotid body vs Central Chemoreceptors
Journal of Applied Physiology, 2007Co-Authors: Curtis A Smith, K S Henderson, Bruno Chenuel, Jerome A DempseyAbstract:The relative importance of peripheral vs. Central Chemoreceptors in causing apnea/unstable breathing during sleep is unresolved. This has never been tested in an unanesthetized preparation with int...
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response time and sensitivity of the ventilatory response to co2 in unanesthetized intact dogs Central vs peripheral Chemoreceptors
Journal of Applied Physiology, 2006Co-Authors: Curtis A Smith, K S Henderson, Bruno Chenuel, J R Rodman, Jerome A DempseyAbstract:We assessed the speed of the ventilatory response to square-wave changes in alveolar Pco2 and the relative gains of the steady-state ventilatory response to CO2 of the Central Chemoreceptors vs. th...