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Regulation of Breathing and Autonomic Outflows by Chemoreceptors

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Abstract

Lung ventilation fluctuates widely with behavior but arterial PCO2 remains stable. Under normal conditions, the chemoreflexes contribute to PaCO2 stability by producing small corrective cardiorespiratory adjustments mediated by lower brainstem circuits. Carotid body (CB) information reaches the respiratory pattern generator (RPG) via nucleus solitarius (NTS) glutamatergic neurons which also target rostral ventrolateral medulla (RVLM) presympathetic neurons thereby raising sympathetic nerve activity (SNA). Chemoreceptors also regulate presympathetic neurons and cardiovagal preganglionic neurons indirectly via inputs from the RPG. Secondary effects of chemoreceptors on the autonomic outflows result from changes in lung stretch afferent and baroreceptor activity. Central respiratory chemosensitivity is caused by direct effects of acid on neurons and indirect effects of CO2 via astrocytes. Central respiratory chemoreceptors are not definitively identified but the retrotrapezoid nucleus (RTN) is a particularly strong candidate. The absence of RTN likely causes severe central apneas in congenital central hypoventilation syndrome. Like other stressors, intense chemosensory stimuli produce arousal and activate circuits that are wake‐ or attention‐promoting. Such pathways (e.g., locus coeruleus, raphe, and orexin system) modulate the chemoreflexes in a state‐dependent manner and their activation by strong chemosensory stimuli intensifies these reflexes. In essential hypertension, obstructive sleep apnea and congestive heart failure, chronically elevated CB afferent activity contributes to raising SNA but breathing is unchanged or becomes periodic (severe CHF). Extreme CNS hypoxia produces a stereotyped cardiorespiratory response (gasping, increased SNA). The effects of these various pathologies on brainstem cardiorespiratory networks are discussed, special consideration being given to the interactions between central and peripheral chemoreflexes. © 2014 American Physiological Society. Compr Physiol 4:1511‐1562, 2014.

Figure 1. Figure 1. Organigram of the chemoreflexes. Cascade of cardiorespiratory responses elicited in anesthetized mammals by hypoxic stimulation of the carotid bodies or by hypercapnia. These cardiorespiratory responses are elaborated primarily within spinal and pontomedullary circuits. The same circuits are also presumably recruited by small perturbations of the blood gases in the conscious state to stabilize PCO2. Large acute perturbations of blood gases produce arousal, aversive sensations and stress, responses that involve numerous other brain regions and processes. The direct effects of hypoxia on the CNS are not considered here. Green arrows denote cell activation (e.g., carotid bodies by hypoxia) or a globally excitatory connection (e.g., effect of the carotid bodies, CBs, on the RPG), or an increase in a dependent variable [e.g., effect of CO2 on cerebral blood flow (CBF) resulting in a “washout” of brain CO2]. Red arrows have the opposite meaning. The baroreflex (BaroR) potentiates or attenuates the chemoreflexes depending on the direction of the change in arterial pressure (AP). Slowly adapting lung stretch receptors (SARs) exert a feedback regulation on the RPG and on central chemoreceptors (CCRs) and inhibit the cardiovagal outflow (CVPSN, cardiovagal parasympathetic nerve activity). The chemoreceptors, both central and peripheral, activate the sympathetic nervous system (SNS) both via the RPG and independently of it.
Figure 2. Figure 2. Pontomedullary regions responsible for eupneic breathing and for generating the autonomic outflows to the cardiovascular system: anatomy and simplified circuitry. (A1) Parasagittal section through the pons and medulla oblongata of a rodent. The regions colored in magenta contain the principal building blocks of the respiratory pattern generator. The ventral respiratory column (VRC) contains four functional compartments aligned in rostrocaudal order (Bötzinger Complex (BötC), pre‐BötC, rostral ventral respiratory group (rVRG) and caudal VRG (cVRG)). The retrotrapezoid nucleus (RTN) resides at the rostral end of the VRC under the facial motor nucleus. In this article, the term RTN refers specifically to a cluster of about 2000 CO2‐activated Phox2b‐ir glutamatergic neurons (in rats, 800 in mice). (A2) Minimal circuitry responsible for the generation of eupneic breathing [adapted, with permission, from Lindsey, Ryback & Smith (247)]. The drawing depicts some of the neuronal interconnections within and between the four compartments of the ventral respiratory column and a few of the connections of RTN neurons (for details see text). The parafacial respiratory group (pfRG) is a physiologically defined entity now believed to be specifically involved in the generation of active expiration (331). Its constituent neurons and their location are not yet defined. Bötzinger augmenting expiratory neurons have been included by some authors in the pfRG (328). Inhibitory (GABAergic or glycinergic) neurons are represented in red, glutamatergic neurons in green, motoneurons in blue, connections with both excitatory and inhibitory components in magenta (e.g., neurons transmitting information from arterial baroreceptors, pulmonary stretch afferents, the carotid bodies etc.). (B1) The regions colored in magenta are thought to contain the main components of the network that generates the autonomic outflows to the cardiovascular system. From an autonomic regulation standpoint, the ventrolateral medulla can be subdivided into three regions whose anatomical relationship with the respiratory compartments can be appreciated by comparing panels A1 and B1. (B2) Schematic of cardiovagal parasympathetic neurons, RVLM presympathetic neurons and connections responsible for their regulation by arterial baroreceptors. Abbreviations: aug‐E, augmenting expiratory neurons; aug‐I, augmenting inspiratory neurons (a.k.a. inspiratory premotor neurons); CVLM, caudal VLM; DRG, dorsal respiratory group (caudolateral portion of the NTS); early‐I, early‐inspiratory neurons, early‐I(1) and early‐I(2) are postulated to have distinct input‐output functions; IVLM, intermediate VLM; Itr, intertrigeminal region; KF, Kölliker‐Fuse nucleus; LPBN, lateral parabrachial nuclei; LRt, lateral reticular nucleus; Mo5, trigeminal motor nucleus; NTS, nucleus of the solitary tract; pfRG, parafacial respiratory group; Pn, pontine nuclei; post‐I, postinspiratory; preI/I, preinspiratory/inspiratory (putative rhythmogenic neurons); scp, superior cerebellar peduncle; SO, superior olive; SPGN, sympathetic preganglionic neurons; SPN sympathetic (post)ganglionic neuron; VRC, ventral respiratory column.
Figure 3. Figure 3. Regulation of the sympathetic vasomotor outflow by the respiratory pattern generator. (A) Plausible circuitry responsible for coupling respiration with the sympathetic nerve activity to the cardiovascular system. Sympathetic ganglionic neurons (SPNs) display stereotyped patterns of respiratory modulation in deafferented preparations (vagotomized, barodenervated). Two of the most commonly found patterns in rats (early‐I and post‐I) are depicted in D [top traces, average integrated phrenic nerve discharge, iPND; lower trace iPND‐triggered rate histogram depicting the probability of firing of a single SPN during the central respiratory cycle; redrawn, with permission, after (72)]. These SPN patterns are virtually identical to those of single RVLM presympathetic neurons [shown in B; redrawn, with permission, from (168)]. The IVLM contains GABAergic neurons that are activated by arterial baroreceptor stimulation and inhibit RVLM presympathetic neurons (panel A). The respiratory modulation of these IVLM GABAergic neurons is approximately the mirror image of that of the RVLM presympathetic neurons [C; reprinted from Mandel and Schreihofer (266) with permission from Wiley & Sons] hence the hypothesis that IVLM neurons with early‐inspiratory discharge produce post‐I modulation in RVLM presympathetic neurons and vice versa (red arrows in C). The depicted inputs from the RPG to IVLM neurons are plausible but speculative. (E) Intracellular recordings of RVLM presympathetic neurons in an arterially perfused midcollicular transected rat preparation [from Moraes et al. (294) with permission]. The early‐I (left trace) and the post‐I patterns (middle trace) are instantly recognizable. The right panel shows a presympathetic RVLM neuron that exhibits an extra peak of activity during late expiration. The latter recording was made in a rat subjected to chronic intermittent hypoxia which caused late‐expiratory activity in an abdominal nerve at rest (not shown) and an additional late‐E peak of activity in the thoracic chain (red arrow pointing down and to the right above the thoracic chain SNA trace, tSNA). An excitatory input from pfRG has been tentatively proposed as the source of this late‐expiratory activation (illustrated in A).
Figure 4. Figure 4. Gain and loss of function of RTN Phox2b neurons in conscious rodents: effect on breathing and the hypercapnic ventilatory reflex (HCVR). (A) Steady‐state ventilatory response of a conscious rat exposed to graded levels of hypercapnia. Breathing was measured by whole body plethysmography [reprinted from (236) with permission from Elsevier]. Note that, at 8% FiCO2, fR (respiratory rate) doubles and VE triples. (B) Unilateral acidification of the RTN with a dialysis probe containing a fluid equilibrated with 25% CO2 produces a small (24% average) increase in VE [adapted from Li et al. J. Appl. Physiol. (240) with permission]. (C) Unilateral optogenetic activation (20Hz) of around 35% of RTN Phox2b neurons triples VE in a conscious rat [adapted, with permission, from (4)]. (C1) Typical example (plethysmography); (C2‐C4) average responses (from top to bottom: frequency, tidal volume and minute volume) to unilateral optogenetic stimulation of RTN neurons. (C5) Selective expression of ChR2‐mCherry fusion protein by RTN (i.e., Phox2b+) neurons in one such animal (Phox2b in green; mCherry in red). (D1) Attenuation of the hypercapnic ventilatory reflex by i.c.v. allatostatin administration to a conscious rat in which an unknown fraction of RTN neurons were transduced with the allatostatin receptor. (D2) Average results from five rats [(from Marina et al. (270) with permission]. (E1) Absence of HCVR in neonatal (day 9) transgenic mice in which a mutated form of transcription factor Phox2b (Phox2b‐27ala) is expressed selectively by cells of rhombomere 3 and 5 lineage (Phox2b27Alacki; Egr2cre/0) preventing or aborting RTN neuron development. (E2) Group data. (E3) Partial recovery (one third) of the HCVR in adult Phox2b27Alacki; Egr2cre/0 mice. (E4) Absence of Phox2b‐ir neurons in the RTN of a Phox2b27Alacki; Egr2cre/0 mouse (embryonic day 14; RTN identified by white oval, Phox2b in red) [E1‐E4 reprinted from Ramanantsoa et al. (347) with permission].
Figure 5. Figure 5. Gain and loss of function of RTN Phox2b neurons in conscious rodents: effect on breathing and the hypercapnic ventilatory reflex (HCVR). (A) Steady‐state ventilatory response of a conscious rat exposed to graded levels of hypercapnia. Breathing was measured by whole body plethysmography [reprinted from (236) with permission from Elsevier]. Note that, at 8% FiCO2, fR (respiratory rate) doubles and VE triples. (B) Unilateral acidification of the RTN with a dialysis probe containing a fluid equilibrated with 25% CO2 produces a small (24% average) increase in VE [adapted from Li et al. J. Appl. Physiol. (240) with permission]. (C) Unilateral optogenetic activation (20Hz) of around 35% of RTN Phox2b neurons triples VE in a conscious rat [adapted, with permission, from (4)]. (C1) Typical example (plethysmography); (C2‐C4) average responses (from top to bottom: frequency, tidal volume and minute volume) to unilateral optogenetic stimulation of RTN neurons. (C5) Selective expression of ChR2‐mCherry fusion protein by RTN (i.e., Phox2b+) neurons in one such animal (Phox2b in green; mCherry in red). (D1) Attenuation of the hypercapnic ventilatory reflex by i.c.v. allatostatin administration to a conscious rat in which an unknown fraction of RTN neurons were transduced with the allatostatin receptor. (D2) Average results from five rats [(from Marina et al. (270) with permission]. (E1) Absence of HCVR in neonatal (day 9) transgenic mice in which a mutated form of transcription factor Phox2b (Phox2b‐27ala) is expressed selectively by cells of rhombomere 3 and 5 lineage (Phox2b27Alacki; Egr2cre/0) preventing or aborting RTN neuron development. (E2) Group data. (E3) Partial recovery (one third) of the HCVR in adult Phox2b27Alacki; Egr2cre/0 mice. (E4) Absence of Phox2b‐ir neurons in the RTN of a Phox2b27Alacki; Egr2cre/0 mouse (embryonic day 14; RTN identified by white oval, Phox2b in red) [E1‐E4 reprinted from Ramanantsoa et al. (347) with permission].
Figure 6. Figure 6. Activation of RTN neurons by CO2. (A) Location and anatomical projections of RTN neurons (definition of RTN in Fig. 2 legend; abbreviations as in Fig. 2). (B) Transverse section through the lower right quadrant of the rat medulla oblongata at the level of the dotted line in A. The facial motor nucleus is in blue (choline acetyl‐transferase immunoreactivity), the C1 presympathetic neurons are in red (tyrosine hydroxylase) and phox2b immunoreactivity (green, nuclear localization) identifies RTN neurons [adapted, with permission, from (402)]. (C) Response of an RTN neuron to graded hypercapnia in an anesthetized rat (end‐expiratory CO2 shown in top trace) [adapted, with permission, from (402)]. (D) Example of one RTN neuron excited by brief hypoxia (carotid body stimulation, bottom trace) and by hypercapnia (end‐expiratory CO2 in green). After i.c.v. administration of the broad spectrum glutamatergic blocker kynurenic acid, the cell no longer responds to hypoxia but its response to hypercapnia is unaffected [adapted, with permission, from (301)]. (E) RTN CO2‐activated neuron labeled juxtacellularly with biotinamide in vivo (green fluorescence) has a Phox2b‐ir nucleus [adapted, with permission, from (402)]. (F) Structure of an RTN neuron whose cell body was located at the ventral surface of the medulla oblongata (in vivo recording, juxtacellular labeling with biotinamide, and transverse plane projection). Note the extensive dendrites on the ventral surface [adapted, with permission, from (301)]. (G1) Two intracellularly labeled RTN neurons recorded in a Phox2b‐eGFP transgenic mouse coronal slice (green eGFP, red biotinamide). (G2) Representative acid sensitivity of one such neuron recorded at room temperature (cell attached recording, integrated rate histogram, 10 s bin) [adapted, with permission, from (231)]. (H1) RTN Phox2b+ neuron acutely isolated from a Phox2b‐eGFP mouse. (H2) Acid sensitivity of such an acutely isolated RTN neuron. [adapted, with permission, from (447)]. Note that the cell responds to a change in pH, not to CO2 per se. I1, selective expression of TASK‐2 potassium channels by Phox2b+ RTN neurons in mice [adapted from Gestreau et al. (137) with permission]. Left panel shows TASK‐2 expression monitored with LacZ reaction product. Middle panel shows that TASK‐2 expressing neurons are eliminated in a mouse line in which RTN neurons express the 27‐ala Phox2b mutation and fail to develop (Task2+/−; Phox2b27Ala/+). Right panel: Task‐2 expressing neurons from a Task2+/‐ mouse (ventral surface view) showing the superficial location in perfect register with the RTN. I2, reduced acid sensitivity of RTN neurons in Task‐2 knock‐out mice compared to Task‐2 +/− control mice [adapted, with permission, from (446)].
Figure 7. Figure 7. Serotonergic neurons and breathing. (A) Selective expression of ChR2‐mCherry fusion protein by raphe obscurus serotonergic neurons in an e‐PET Cre mouse [adapted, with permission, after (86)]. (B) Photostimulation of ChR2‐expressing raphe obscurus serotonergic neurons in such a mouse (ketamine/dexmedetomidine initial anesthesia with 0.3% to 0.6% isoflurane supplementation) increases diaphragm EMG amplitude (top trace) and respiratory rate (fR, second from top). Bottom traces shows a single raphe serotonergic unit being photoactivated every time the laser light was pulsed [adapted, with permission, after (86)]. (C) Selective optogenetic photostimulation of ChR2‐expressing raphe obscurus serotonergic neurons in a conscious mouse (whole body plethysmography). The response has the same slow ON‐slow OFF kinetics as in the anesthetized mouse [adapted, with permission, after (155)]. (D) Robust acid sensitivity of a serotonergic neuron in culture [reprinted from Richerson (354)] adapted with permission from Macmillan Publishers Ltd., Nature Neuroscience (5), 2004). (E1) In an arterially perfused rat preparation, serotonergic neurons are either modestly inhibited or modestly excited by CO2. (E2) In this preparation, hypercapnia had no effect on the mean activity of the serotonergic population at large (all 5‐HT) [from Iceman et al. (188) with permission]. (F) Putative serotonergic neuron recorded in conscious cats showing a modest but dose‐dependent increase in discharge rate (2.7 to 3.9 Hz; +44% at 6% FiCO2). The effect of CO2 essentially disappeared during non‐REM sleep [reproduced from Veasey et al. (441) with permission]. (G) Serotonin2A receptor antagonism dramatically slows the pre‐Bötzinger complex rhythm in a slice (top traces, mass activity of pre‐Bötzinger complex neurons, bottom traces whole cell recording of a presumed rhythmogenic neuron) [reproduced from Peña and Ramirez (338) with permission]. (H1‐2) Iontophoretic application of serotonin activates RTN neurons by a constant amount regardless of the level of end‐expiratory CO2 [H1, representative example, H2 average results; adapted, with permission, from (300)]. (I) Selective global inhibition of CNS serotonergic neurons (DREADD methodology) attenuates the hypercapnic ventilatory reflex of a conscious mouse [after Ray et al. (350) reprinted with permission from AAAS]. (J) Interpretations: serotonergic neurons activate breathing via innumerable mechanisms (e.g., direct projection to RTN, the RPG, dorsolateral pons, motoneurons, and indirect effects via changes in vigilance). The integrity of serotonergic neurons is required for full expression of the hypercapnic ventilatory reflex, possibly because a fraction of serotonergic neuron is directly responsive to acidification in vivo.
Figure 8. Figure 8. Serotonergic neurons and breathing. (A) Selective expression of ChR2‐mCherry fusion protein by raphe obscurus serotonergic neurons in an e‐PET Cre mouse [adapted, with permission, after (86)]. (B) Photostimulation of ChR2‐expressing raphe obscurus serotonergic neurons in such a mouse (ketamine/dexmedetomidine initial anesthesia with 0.3% to 0.6% isoflurane supplementation) increases diaphragm EMG amplitude (top trace) and respiratory rate (fR, second from top). Bottom traces shows a single raphe serotonergic unit being photoactivated every time the laser light was pulsed [adapted, with permission, after (86)]. (C) Selective optogenetic photostimulation of ChR2‐expressing raphe obscurus serotonergic neurons in a conscious mouse (whole body plethysmography). The response has the same slow ON‐slow OFF kinetics as in the anesthetized mouse [adapted, with permission, after (155)]. (D) Robust acid sensitivity of a serotonergic neuron in culture [reprinted from Richerson (354)] adapted with permission from Macmillan Publishers Ltd., Nature Neuroscience (5), 2004). (E1) In an arterially perfused rat preparation, serotonergic neurons are either modestly inhibited or modestly excited by CO2. (E2) In this preparation, hypercapnia had no effect on the mean activity of the serotonergic population at large (all 5‐HT) [from Iceman et al. (188) with permission]. (F) Putative serotonergic neuron recorded in conscious cats showing a modest but dose‐dependent increase in discharge rate (2.7 to 3.9 Hz; +44% at 6% FiCO2). The effect of CO2 essentially disappeared during non‐REM sleep [reproduced from Veasey et al. (441) with permission]. (G) Serotonin2A receptor antagonism dramatically slows the pre‐Bötzinger complex rhythm in a slice (top traces, mass activity of pre‐Bötzinger complex neurons, bottom traces whole cell recording of a presumed rhythmogenic neuron) [reproduced from Peña and Ramirez (338) with permission]. (H1‐2) Iontophoretic application of serotonin activates RTN neurons by a constant amount regardless of the level of end‐expiratory CO2 [H1, representative example, H2 average results; adapted, with permission, from (300)]. (I) Selective global inhibition of CNS serotonergic neurons (DREADD methodology) attenuates the hypercapnic ventilatory reflex of a conscious mouse [after Ray et al. (350) reprinted with permission from AAAS]. (J) Interpretations: serotonergic neurons activate breathing via innumerable mechanisms (e.g., direct projection to RTN, the RPG, dorsolateral pons, motoneurons, and indirect effects via changes in vigilance). The integrity of serotonergic neurons is required for full expression of the hypercapnic ventilatory reflex, possibly because a fraction of serotonergic neuron is directly responsive to acidification in vivo.
Figure 9. Figure 9. Glial cells and central respiratory chemosensitivity. (A) Acidification increases intracellular calcium fluorescence in medullary astrocytes [from Gourine et al. (146) reprinted with permission from AAAS]. (B) Optogenetic depolarization of ChR2‐expressing ventrolateral medullary astrocytes activates the phrenic outflow in an anesthetized rat. Note the very slow onset of the response to light and its persistence [adapted, with permission, from (146) reprinted with permission from AAAS]. (C) Activation of RTN neurons by CO2 in a slice of neonate rat brain is attenuated by application of the P2 receptor antagonists PPADS or suramin. Summary data (right panels): about a quarter of the overall response of RTN neurons to 15% CO2 could be mediated by ATP release in this preparation [reproduced from Wenker et al. (454) with permission]. (D) Schema of the contribution of ventral medullary surface (VMS) astrocytes to central respiratory chemosensitivity according to (145) [after Gourine and Kasparov, Exp. Phsiol. (96), 2011 reprinted with permission from John Wiley & Sons]. VMS astrocytes are thought to mediate the hypercapnic ventilatory reflex by simultaneously activating RTN neurons and undefined components of the central pattern generating (CPG). ATP release by astrocytes may be a calcium‐dependent exocytotic process triggered by intracellular acidification and/or a leak through connexin channels (Cx26 primarily) opened by molecular CO2 via carbamylation.
Figure 10. Figure 10. Sympathetic nerve activation by carotid body stimulation: lower brainstem pathways. The four experiments depicted around the interpretative schematic (A‐D, clockwise from top right) suggest that, in anesthetized rodents, carotid body stimulation increases sympathetic vasomotor tone via two pathways that converge on RVLM presympathetic neurons, only one of which depends on the respiratory pattern generator. (A) Microinjection of the GABA mimetic agonist muscimol into the commissural portion of the NTS abolishes the response to cyanide [adapted, with permission, from (295)]. (B) Injection of muscimol into the rVRG eliminates the phrenic nerve discharge but does not change the sympathetic response to carotid body activation (N2, 10 s nitrogen inhalation) [adapted, with permission, from (217)]. (C) Injection of muscimol into the pre‐Bötzinger complex, eliminates the phrenic nerve discharge and eliminates the respiratory oscillations of the sympathetic nerve discharge elicited by carotid body stimulation. However, the sympathoexcitation produced by carotid body stimulation persists. The response of a simultaneously recorded single RVLM presympathetic neuron is also shown. Note that muscimol produces the same effect on the neuron as on SNA, that is, muscimol changes the response from respiratory synchronous oscillations to a tonic activation [adapted, with permission, from (216)]. (D) Administration of kynurenic acid into the RVLM dramatically reduces SNA activation caused by carotid body stimulation [after (295) reprinted with permission from the Society for Neuroscience]. The respiratory dependent pathway of the chemoreflex is considered in greater detail in Fig. 3).
Figure 11. Figure 11. Regulation of the cardiovagal parasympathetic outflow by the respiratory pattern generator. (A1‐3) [Reproduced from McAllen et al. (278), reprinted with permission.] Intracellular recordings of cardiovagal ganglionic neurons from an arterially perfused rat preparation in which the lungs are not inflated therefore reflexes from lung stretch receptors are absent (A1). The firing properties of cardiovagal preganglionic neurons (CVPGN) were inferred from the discharge pattern of the ganglionic neurons (A2) or the EPSPs recorded from these neurons (A3). Activation of the carotid bodies with cyanide or of arterial baroreceptors by raising perfusion pressure produced the expected robust excitation of cardiovagal neurons, and so did the activation of the diving reflex (A2). A3, PND‐triggered histograms of EPSPs recorded in cardiovagal ganglionic neurons (CVGNs) indicate that, in this preparation, CVPGNs discharge preferentially during the postinspiratory phase. (B) Schematic interpretation based on A2‐3 and C. Rat cardiovagal preganglionic neurons could be receiving inhibitory inputs from early‐I and Aug‐E neurons. The existence of inhibitory input during inspiration has been documented in slices as shown in C. Pulmonary stretch receptors (inactive in an arterially perfused preparation) inhibit cardiovagal preganglionic neurons, possibly via a direct input from GABAergic “pump cells” located within the NTS. Carotid body stimulation produces opposite effects on CVPGN activity depending on the intensity of the stimulus. Mild stimulation inhibits these neurons via the RPG, presumably via inhibitory inputs from early‐I and post‐I neurons as shown in B. Acute and intense stimulation of the carotid bodies (e.g., with cyanide) activates cardiovagal preganglionic neurons as shown in A2. This effect may be mediated by polymodal NTS neurons that also respond to noxious stimulation of the airways (pathway not represented). Post‐I glutamatergic neurons are an alternative plausible source of excitation of cardiovagal preganglionic neurons and other vagal efferents with a post‐I discharge pattern but the existence of such neurons has yet to be demonstrated. (Panel C was originally published in (153), and has been reproduced by permission of Oxford University Press [http://www.oxfordscholarship.com/view/10.1093/acprof:oso/9780195306637.001.0001/acprof‐9780195306637]).
Figure 12. Figure 12. Feedback regulation of RTN neurons and interaction between central and peripheral respiratory chemoreflexes. (A1‐4) Four examples of RTN neurons showing different types of respiratory modulation which can be interpreted as post‐I and E‐aug inhibition in cell 1, early‐I and post‐I inhibition in cell 2, early‐I only in cell 3, and early‐I, post‐I and E‐AUG in cell 4 [adapted, with permission, from (158)]. (B) Typical RTN neuron devoid of respiratory modulation at low end‐expiratory CO2. This cell exhibits the early‐I/post‐I pattern when FiCO2 is increased (unpublished example from P. Guyenet). C, single RTN neuron inhibited by lung‐inflation [Tp, tracheal pressure, iPND integrated rectified phrenic nerve discharge; adapted, with permission, from (296)]. (D1) Single RTN neuron recorded in a vagally intact anesthetized rat showing the complex respiratory modulation of the cell (integrated rate histogram and rectified PND triggered on expiratory CO2 shown as bottom trace). (D2) Average steady‐state response of RTN neurons to end‐expiratory CO2 in the same preparation as D1 [D1‐D2 adapted, with permission, from (158)]. (E1 and E2) Similar recordings after i.c.v. administration of the glutamatergic antagonist kynurenic acid. (E1) PND and the respiratory modulation of the RTN neuron was abolished by kynurenic acid. (E2) The relationship between the discharge rate of RTN neurons and end‐expiratory CO2 became linear after kynurenic acid administration [adapted, with permission, from (158)]. (F) Interpretation of the results shown in A‐E: the response of RTN neurons to CO2 is saturable because of the existence of inhibitory feedback from lung stretch receptors and from the RPG. G, schematic wiring diagram based on A‐E. (H) Hypothetical scenario in which the RPG is unusually active or excitable (left). In such a case, respiratory feedback to the RTN would minimize the contribution of this nucleus to ventilation causing hypoadditivity between the peripheral and central chemoreflexes. On the other hand, additivity would result from a situation in which the RPG is moderately excitable (right panel). (I) Possible hyperadditivity scenario. RTN hyperpolarization at rest (right panel) could result in hyperadditivity between the central and peripheral chemoreflexes. In this configuration, moderate hypercapnia alone would produce a minimal stimulation of breathing because RTN depolarization would be largely subthreshold. Carotid body stimulation would depolarize RTN neurons above their discharge threshold causing them to respond vigorously to the previously ineffective hypercapnic stimulus, hence the apparent hyperadditivity of the reflexes.
Figure 13. Figure 13. Feedback regulation of RTN neurons and interaction between central and peripheral respiratory chemoreflexes. (A1‐4) Four examples of RTN neurons showing different types of respiratory modulation which can be interpreted as post‐I and E‐aug inhibition in cell 1, early‐I and post‐I inhibition in cell 2, early‐I only in cell 3, and early‐I, post‐I and E‐AUG in cell 4 [adapted, with permission, from (158)]. (B) Typical RTN neuron devoid of respiratory modulation at low end‐expiratory CO2. This cell exhibits the early‐I/post‐I pattern when FiCO2 is increased (unpublished example from P. Guyenet). C, single RTN neuron inhibited by lung‐inflation [Tp, tracheal pressure, iPND integrated rectified phrenic nerve discharge; adapted, with permission, from (296)]. (D1) Single RTN neuron recorded in a vagally intact anesthetized rat showing the complex respiratory modulation of the cell (integrated rate histogram and rectified PND triggered on expiratory CO2 shown as bottom trace). (D2) Average steady‐state response of RTN neurons to end‐expiratory CO2 in the same preparation as D1 [D1‐D2 adapted, with permission, from (158)]. (E1 and E2) Similar recordings after i.c.v. administration of the glutamatergic antagonist kynurenic acid. (E1) PND and the respiratory modulation of the RTN neuron was abolished by kynurenic acid. (E2) The relationship between the discharge rate of RTN neurons and end‐expiratory CO2 became linear after kynurenic acid administration [adapted, with permission, from (158)]. (F) Interpretation of the results shown in A‐E: the response of RTN neurons to CO2 is saturable because of the existence of inhibitory feedback from lung stretch receptors and from the RPG. G, schematic wiring diagram based on A‐E. (H) Hypothetical scenario in which the RPG is unusually active or excitable (left). In such a case, respiratory feedback to the RTN would minimize the contribution of this nucleus to ventilation causing hypoadditivity between the peripheral and central chemoreflexes. On the other hand, additivity would result from a situation in which the RPG is moderately excitable (right panel). (I) Possible hyperadditivity scenario. RTN hyperpolarization at rest (right panel) could result in hyperadditivity between the central and peripheral chemoreflexes. In this configuration, moderate hypercapnia alone would produce a minimal stimulation of breathing because RTN depolarization would be largely subthreshold. Carotid body stimulation would depolarize RTN neurons above their discharge threshold causing them to respond vigorously to the previously ineffective hypercapnic stimulus, hence the apparent hyperadditivity of the reflexes.


Figure 1. Organigram of the chemoreflexes. Cascade of cardiorespiratory responses elicited in anesthetized mammals by hypoxic stimulation of the carotid bodies or by hypercapnia. These cardiorespiratory responses are elaborated primarily within spinal and pontomedullary circuits. The same circuits are also presumably recruited by small perturbations of the blood gases in the conscious state to stabilize PCO2. Large acute perturbations of blood gases produce arousal, aversive sensations and stress, responses that involve numerous other brain regions and processes. The direct effects of hypoxia on the CNS are not considered here. Green arrows denote cell activation (e.g., carotid bodies by hypoxia) or a globally excitatory connection (e.g., effect of the carotid bodies, CBs, on the RPG), or an increase in a dependent variable [e.g., effect of CO2 on cerebral blood flow (CBF) resulting in a “washout” of brain CO2]. Red arrows have the opposite meaning. The baroreflex (BaroR) potentiates or attenuates the chemoreflexes depending on the direction of the change in arterial pressure (AP). Slowly adapting lung stretch receptors (SARs) exert a feedback regulation on the RPG and on central chemoreceptors (CCRs) and inhibit the cardiovagal outflow (CVPSN, cardiovagal parasympathetic nerve activity). The chemoreceptors, both central and peripheral, activate the sympathetic nervous system (SNS) both via the RPG and independently of it.


Figure 2. Pontomedullary regions responsible for eupneic breathing and for generating the autonomic outflows to the cardiovascular system: anatomy and simplified circuitry. (A1) Parasagittal section through the pons and medulla oblongata of a rodent. The regions colored in magenta contain the principal building blocks of the respiratory pattern generator. The ventral respiratory column (VRC) contains four functional compartments aligned in rostrocaudal order (Bötzinger Complex (BötC), pre‐BötC, rostral ventral respiratory group (rVRG) and caudal VRG (cVRG)). The retrotrapezoid nucleus (RTN) resides at the rostral end of the VRC under the facial motor nucleus. In this article, the term RTN refers specifically to a cluster of about 2000 CO2‐activated Phox2b‐ir glutamatergic neurons (in rats, 800 in mice). (A2) Minimal circuitry responsible for the generation of eupneic breathing [adapted, with permission, from Lindsey, Ryback & Smith (247)]. The drawing depicts some of the neuronal interconnections within and between the four compartments of the ventral respiratory column and a few of the connections of RTN neurons (for details see text). The parafacial respiratory group (pfRG) is a physiologically defined entity now believed to be specifically involved in the generation of active expiration (331). Its constituent neurons and their location are not yet defined. Bötzinger augmenting expiratory neurons have been included by some authors in the pfRG (328). Inhibitory (GABAergic or glycinergic) neurons are represented in red, glutamatergic neurons in green, motoneurons in blue, connections with both excitatory and inhibitory components in magenta (e.g., neurons transmitting information from arterial baroreceptors, pulmonary stretch afferents, the carotid bodies etc.). (B1) The regions colored in magenta are thought to contain the main components of the network that generates the autonomic outflows to the cardiovascular system. From an autonomic regulation standpoint, the ventrolateral medulla can be subdivided into three regions whose anatomical relationship with the respiratory compartments can be appreciated by comparing panels A1 and B1. (B2) Schematic of cardiovagal parasympathetic neurons, RVLM presympathetic neurons and connections responsible for their regulation by arterial baroreceptors. Abbreviations: aug‐E, augmenting expiratory neurons; aug‐I, augmenting inspiratory neurons (a.k.a. inspiratory premotor neurons); CVLM, caudal VLM; DRG, dorsal respiratory group (caudolateral portion of the NTS); early‐I, early‐inspiratory neurons, early‐I(1) and early‐I(2) are postulated to have distinct input‐output functions; IVLM, intermediate VLM; Itr, intertrigeminal region; KF, Kölliker‐Fuse nucleus; LPBN, lateral parabrachial nuclei; LRt, lateral reticular nucleus; Mo5, trigeminal motor nucleus; NTS, nucleus of the solitary tract; pfRG, parafacial respiratory group; Pn, pontine nuclei; post‐I, postinspiratory; preI/I, preinspiratory/inspiratory (putative rhythmogenic neurons); scp, superior cerebellar peduncle; SO, superior olive; SPGN, sympathetic preganglionic neurons; SPN sympathetic (post)ganglionic neuron; VRC, ventral respiratory column.


Figure 3. Regulation of the sympathetic vasomotor outflow by the respiratory pattern generator. (A) Plausible circuitry responsible for coupling respiration with the sympathetic nerve activity to the cardiovascular system. Sympathetic ganglionic neurons (SPNs) display stereotyped patterns of respiratory modulation in deafferented preparations (vagotomized, barodenervated). Two of the most commonly found patterns in rats (early‐I and post‐I) are depicted in D [top traces, average integrated phrenic nerve discharge, iPND; lower trace iPND‐triggered rate histogram depicting the probability of firing of a single SPN during the central respiratory cycle; redrawn, with permission, after (72)]. These SPN patterns are virtually identical to those of single RVLM presympathetic neurons [shown in B; redrawn, with permission, from (168)]. The IVLM contains GABAergic neurons that are activated by arterial baroreceptor stimulation and inhibit RVLM presympathetic neurons (panel A). The respiratory modulation of these IVLM GABAergic neurons is approximately the mirror image of that of the RVLM presympathetic neurons [C; reprinted from Mandel and Schreihofer (266) with permission from Wiley & Sons] hence the hypothesis that IVLM neurons with early‐inspiratory discharge produce post‐I modulation in RVLM presympathetic neurons and vice versa (red arrows in C). The depicted inputs from the RPG to IVLM neurons are plausible but speculative. (E) Intracellular recordings of RVLM presympathetic neurons in an arterially perfused midcollicular transected rat preparation [from Moraes et al. (294) with permission]. The early‐I (left trace) and the post‐I patterns (middle trace) are instantly recognizable. The right panel shows a presympathetic RVLM neuron that exhibits an extra peak of activity during late expiration. The latter recording was made in a rat subjected to chronic intermittent hypoxia which caused late‐expiratory activity in an abdominal nerve at rest (not shown) and an additional late‐E peak of activity in the thoracic chain (red arrow pointing down and to the right above the thoracic chain SNA trace, tSNA). An excitatory input from pfRG has been tentatively proposed as the source of this late‐expiratory activation (illustrated in A).


Figure 4. Gain and loss of function of RTN Phox2b neurons in conscious rodents: effect on breathing and the hypercapnic ventilatory reflex (HCVR). (A) Steady‐state ventilatory response of a conscious rat exposed to graded levels of hypercapnia. Breathing was measured by whole body plethysmography [reprinted from (236) with permission from Elsevier]. Note that, at 8% FiCO2, fR (respiratory rate) doubles and VE triples. (B) Unilateral acidification of the RTN with a dialysis probe containing a fluid equilibrated with 25% CO2 produces a small (24% average) increase in VE [adapted from Li et al. J. Appl. Physiol. (240) with permission]. (C) Unilateral optogenetic activation (20Hz) of around 35% of RTN Phox2b neurons triples VE in a conscious rat [adapted, with permission, from (4)]. (C1) Typical example (plethysmography); (C2‐C4) average responses (from top to bottom: frequency, tidal volume and minute volume) to unilateral optogenetic stimulation of RTN neurons. (C5) Selective expression of ChR2‐mCherry fusion protein by RTN (i.e., Phox2b+) neurons in one such animal (Phox2b in green; mCherry in red). (D1) Attenuation of the hypercapnic ventilatory reflex by i.c.v. allatostatin administration to a conscious rat in which an unknown fraction of RTN neurons were transduced with the allatostatin receptor. (D2) Average results from five rats [(from Marina et al. (270) with permission]. (E1) Absence of HCVR in neonatal (day 9) transgenic mice in which a mutated form of transcription factor Phox2b (Phox2b‐27ala) is expressed selectively by cells of rhombomere 3 and 5 lineage (Phox2b27Alacki; Egr2cre/0) preventing or aborting RTN neuron development. (E2) Group data. (E3) Partial recovery (one third) of the HCVR in adult Phox2b27Alacki; Egr2cre/0 mice. (E4) Absence of Phox2b‐ir neurons in the RTN of a Phox2b27Alacki; Egr2cre/0 mouse (embryonic day 14; RTN identified by white oval, Phox2b in red) [E1‐E4 reprinted from Ramanantsoa et al. (347) with permission].


Figure 5. Gain and loss of function of RTN Phox2b neurons in conscious rodents: effect on breathing and the hypercapnic ventilatory reflex (HCVR). (A) Steady‐state ventilatory response of a conscious rat exposed to graded levels of hypercapnia. Breathing was measured by whole body plethysmography [reprinted from (236) with permission from Elsevier]. Note that, at 8% FiCO2, fR (respiratory rate) doubles and VE triples. (B) Unilateral acidification of the RTN with a dialysis probe containing a fluid equilibrated with 25% CO2 produces a small (24% average) increase in VE [adapted from Li et al. J. Appl. Physiol. (240) with permission]. (C) Unilateral optogenetic activation (20Hz) of around 35% of RTN Phox2b neurons triples VE in a conscious rat [adapted, with permission, from (4)]. (C1) Typical example (plethysmography); (C2‐C4) average responses (from top to bottom: frequency, tidal volume and minute volume) to unilateral optogenetic stimulation of RTN neurons. (C5) Selective expression of ChR2‐mCherry fusion protein by RTN (i.e., Phox2b+) neurons in one such animal (Phox2b in green; mCherry in red). (D1) Attenuation of the hypercapnic ventilatory reflex by i.c.v. allatostatin administration to a conscious rat in which an unknown fraction of RTN neurons were transduced with the allatostatin receptor. (D2) Average results from five rats [(from Marina et al. (270) with permission]. (E1) Absence of HCVR in neonatal (day 9) transgenic mice in which a mutated form of transcription factor Phox2b (Phox2b‐27ala) is expressed selectively by cells of rhombomere 3 and 5 lineage (Phox2b27Alacki; Egr2cre/0) preventing or aborting RTN neuron development. (E2) Group data. (E3) Partial recovery (one third) of the HCVR in adult Phox2b27Alacki; Egr2cre/0 mice. (E4) Absence of Phox2b‐ir neurons in the RTN of a Phox2b27Alacki; Egr2cre/0 mouse (embryonic day 14; RTN identified by white oval, Phox2b in red) [E1‐E4 reprinted from Ramanantsoa et al. (347) with permission].


Figure 6. Activation of RTN neurons by CO2. (A) Location and anatomical projections of RTN neurons (definition of RTN in Fig. 2 legend; abbreviations as in Fig. 2). (B) Transverse section through the lower right quadrant of the rat medulla oblongata at the level of the dotted line in A. The facial motor nucleus is in blue (choline acetyl‐transferase immunoreactivity), the C1 presympathetic neurons are in red (tyrosine hydroxylase) and phox2b immunoreactivity (green, nuclear localization) identifies RTN neurons [adapted, with permission, from (402)]. (C) Response of an RTN neuron to graded hypercapnia in an anesthetized rat (end‐expiratory CO2 shown in top trace) [adapted, with permission, from (402)]. (D) Example of one RTN neuron excited by brief hypoxia (carotid body stimulation, bottom trace) and by hypercapnia (end‐expiratory CO2 in green). After i.c.v. administration of the broad spectrum glutamatergic blocker kynurenic acid, the cell no longer responds to hypoxia but its response to hypercapnia is unaffected [adapted, with permission, from (301)]. (E) RTN CO2‐activated neuron labeled juxtacellularly with biotinamide in vivo (green fluorescence) has a Phox2b‐ir nucleus [adapted, with permission, from (402)]. (F) Structure of an RTN neuron whose cell body was located at the ventral surface of the medulla oblongata (in vivo recording, juxtacellular labeling with biotinamide, and transverse plane projection). Note the extensive dendrites on the ventral surface [adapted, with permission, from (301)]. (G1) Two intracellularly labeled RTN neurons recorded in a Phox2b‐eGFP transgenic mouse coronal slice (green eGFP, red biotinamide). (G2) Representative acid sensitivity of one such neuron recorded at room temperature (cell attached recording, integrated rate histogram, 10 s bin) [adapted, with permission, from (231)]. (H1) RTN Phox2b+ neuron acutely isolated from a Phox2b‐eGFP mouse. (H2) Acid sensitivity of such an acutely isolated RTN neuron. [adapted, with permission, from (447)]. Note that the cell responds to a change in pH, not to CO2 per se. I1, selective expression of TASK‐2 potassium channels by Phox2b+ RTN neurons in mice [adapted from Gestreau et al. (137) with permission]. Left panel shows TASK‐2 expression monitored with LacZ reaction product. Middle panel shows that TASK‐2 expressing neurons are eliminated in a mouse line in which RTN neurons express the 27‐ala Phox2b mutation and fail to develop (Task2+/−; Phox2b27Ala/+). Right panel: Task‐2 expressing neurons from a Task2+/‐ mouse (ventral surface view) showing the superficial location in perfect register with the RTN. I2, reduced acid sensitivity of RTN neurons in Task‐2 knock‐out mice compared to Task‐2 +/− control mice [adapted, with permission, from (446)].


Figure 7. Serotonergic neurons and breathing. (A) Selective expression of ChR2‐mCherry fusion protein by raphe obscurus serotonergic neurons in an e‐PET Cre mouse [adapted, with permission, after (86)]. (B) Photostimulation of ChR2‐expressing raphe obscurus serotonergic neurons in such a mouse (ketamine/dexmedetomidine initial anesthesia with 0.3% to 0.6% isoflurane supplementation) increases diaphragm EMG amplitude (top trace) and respiratory rate (fR, second from top). Bottom traces shows a single raphe serotonergic unit being photoactivated every time the laser light was pulsed [adapted, with permission, after (86)]. (C) Selective optogenetic photostimulation of ChR2‐expressing raphe obscurus serotonergic neurons in a conscious mouse (whole body plethysmography). The response has the same slow ON‐slow OFF kinetics as in the anesthetized mouse [adapted, with permission, after (155)]. (D) Robust acid sensitivity of a serotonergic neuron in culture [reprinted from Richerson (354)] adapted with permission from Macmillan Publishers Ltd., Nature Neuroscience (5), 2004). (E1) In an arterially perfused rat preparation, serotonergic neurons are either modestly inhibited or modestly excited by CO2. (E2) In this preparation, hypercapnia had no effect on the mean activity of the serotonergic population at large (all 5‐HT) [from Iceman et al. (188) with permission]. (F) Putative serotonergic neuron recorded in conscious cats showing a modest but dose‐dependent increase in discharge rate (2.7 to 3.9 Hz; +44% at 6% FiCO2). The effect of CO2 essentially disappeared during non‐REM sleep [reproduced from Veasey et al. (441) with permission]. (G) Serotonin2A receptor antagonism dramatically slows the pre‐Bötzinger complex rhythm in a slice (top traces, mass activity of pre‐Bötzinger complex neurons, bottom traces whole cell recording of a presumed rhythmogenic neuron) [reproduced from Peña and Ramirez (338) with permission]. (H1‐2) Iontophoretic application of serotonin activates RTN neurons by a constant amount regardless of the level of end‐expiratory CO2 [H1, representative example, H2 average results; adapted, with permission, from (300)]. (I) Selective global inhibition of CNS serotonergic neurons (DREADD methodology) attenuates the hypercapnic ventilatory reflex of a conscious mouse [after Ray et al. (350) reprinted with permission from AAAS]. (J) Interpretations: serotonergic neurons activate breathing via innumerable mechanisms (e.g., direct projection to RTN, the RPG, dorsolateral pons, motoneurons, and indirect effects via changes in vigilance). The integrity of serotonergic neurons is required for full expression of the hypercapnic ventilatory reflex, possibly because a fraction of serotonergic neuron is directly responsive to acidification in vivo.


Figure 8. Serotonergic neurons and breathing. (A) Selective expression of ChR2‐mCherry fusion protein by raphe obscurus serotonergic neurons in an e‐PET Cre mouse [adapted, with permission, after (86)]. (B) Photostimulation of ChR2‐expressing raphe obscurus serotonergic neurons in such a mouse (ketamine/dexmedetomidine initial anesthesia with 0.3% to 0.6% isoflurane supplementation) increases diaphragm EMG amplitude (top trace) and respiratory rate (fR, second from top). Bottom traces shows a single raphe serotonergic unit being photoactivated every time the laser light was pulsed [adapted, with permission, after (86)]. (C) Selective optogenetic photostimulation of ChR2‐expressing raphe obscurus serotonergic neurons in a conscious mouse (whole body plethysmography). The response has the same slow ON‐slow OFF kinetics as in the anesthetized mouse [adapted, with permission, after (155)]. (D) Robust acid sensitivity of a serotonergic neuron in culture [reprinted from Richerson (354)] adapted with permission from Macmillan Publishers Ltd., Nature Neuroscience (5), 2004). (E1) In an arterially perfused rat preparation, serotonergic neurons are either modestly inhibited or modestly excited by CO2. (E2) In this preparation, hypercapnia had no effect on the mean activity of the serotonergic population at large (all 5‐HT) [from Iceman et al. (188) with permission]. (F) Putative serotonergic neuron recorded in conscious cats showing a modest but dose‐dependent increase in discharge rate (2.7 to 3.9 Hz; +44% at 6% FiCO2). The effect of CO2 essentially disappeared during non‐REM sleep [reproduced from Veasey et al. (441) with permission]. (G) Serotonin2A receptor antagonism dramatically slows the pre‐Bötzinger complex rhythm in a slice (top traces, mass activity of pre‐Bötzinger complex neurons, bottom traces whole cell recording of a presumed rhythmogenic neuron) [reproduced from Peña and Ramirez (338) with permission]. (H1‐2) Iontophoretic application of serotonin activates RTN neurons by a constant amount regardless of the level of end‐expiratory CO2 [H1, representative example, H2 average results; adapted, with permission, from (300)]. (I) Selective global inhibition of CNS serotonergic neurons (DREADD methodology) attenuates the hypercapnic ventilatory reflex of a conscious mouse [after Ray et al. (350) reprinted with permission from AAAS]. (J) Interpretations: serotonergic neurons activate breathing via innumerable mechanisms (e.g., direct projection to RTN, the RPG, dorsolateral pons, motoneurons, and indirect effects via changes in vigilance). The integrity of serotonergic neurons is required for full expression of the hypercapnic ventilatory reflex, possibly because a fraction of serotonergic neuron is directly responsive to acidification in vivo.


Figure 9. Glial cells and central respiratory chemosensitivity. (A) Acidification increases intracellular calcium fluorescence in medullary astrocytes [from Gourine et al. (146) reprinted with permission from AAAS]. (B) Optogenetic depolarization of ChR2‐expressing ventrolateral medullary astrocytes activates the phrenic outflow in an anesthetized rat. Note the very slow onset of the response to light and its persistence [adapted, with permission, from (146) reprinted with permission from AAAS]. (C) Activation of RTN neurons by CO2 in a slice of neonate rat brain is attenuated by application of the P2 receptor antagonists PPADS or suramin. Summary data (right panels): about a quarter of the overall response of RTN neurons to 15% CO2 could be mediated by ATP release in this preparation [reproduced from Wenker et al. (454) with permission]. (D) Schema of the contribution of ventral medullary surface (VMS) astrocytes to central respiratory chemosensitivity according to (145) [after Gourine and Kasparov, Exp. Phsiol. (96), 2011 reprinted with permission from John Wiley & Sons]. VMS astrocytes are thought to mediate the hypercapnic ventilatory reflex by simultaneously activating RTN neurons and undefined components of the central pattern generating (CPG). ATP release by astrocytes may be a calcium‐dependent exocytotic process triggered by intracellular acidification and/or a leak through connexin channels (Cx26 primarily) opened by molecular CO2 via carbamylation.


Figure 10. Sympathetic nerve activation by carotid body stimulation: lower brainstem pathways. The four experiments depicted around the interpretative schematic (A‐D, clockwise from top right) suggest that, in anesthetized rodents, carotid body stimulation increases sympathetic vasomotor tone via two pathways that converge on RVLM presympathetic neurons, only one of which depends on the respiratory pattern generator. (A) Microinjection of the GABA mimetic agonist muscimol into the commissural portion of the NTS abolishes the response to cyanide [adapted, with permission, from (295)]. (B) Injection of muscimol into the rVRG eliminates the phrenic nerve discharge but does not change the sympathetic response to carotid body activation (N2, 10 s nitrogen inhalation) [adapted, with permission, from (217)]. (C) Injection of muscimol into the pre‐Bötzinger complex, eliminates the phrenic nerve discharge and eliminates the respiratory oscillations of the sympathetic nerve discharge elicited by carotid body stimulation. However, the sympathoexcitation produced by carotid body stimulation persists. The response of a simultaneously recorded single RVLM presympathetic neuron is also shown. Note that muscimol produces the same effect on the neuron as on SNA, that is, muscimol changes the response from respiratory synchronous oscillations to a tonic activation [adapted, with permission, from (216)]. (D) Administration of kynurenic acid into the RVLM dramatically reduces SNA activation caused by carotid body stimulation [after (295) reprinted with permission from the Society for Neuroscience]. The respiratory dependent pathway of the chemoreflex is considered in greater detail in Fig. 3).


Figure 11. Regulation of the cardiovagal parasympathetic outflow by the respiratory pattern generator. (A1‐3) [Reproduced from McAllen et al. (278), reprinted with permission.] Intracellular recordings of cardiovagal ganglionic neurons from an arterially perfused rat preparation in which the lungs are not inflated therefore reflexes from lung stretch receptors are absent (A1). The firing properties of cardiovagal preganglionic neurons (CVPGN) were inferred from the discharge pattern of the ganglionic neurons (A2) or the EPSPs recorded from these neurons (A3). Activation of the carotid bodies with cyanide or of arterial baroreceptors by raising perfusion pressure produced the expected robust excitation of cardiovagal neurons, and so did the activation of the diving reflex (A2). A3, PND‐triggered histograms of EPSPs recorded in cardiovagal ganglionic neurons (CVGNs) indicate that, in this preparation, CVPGNs discharge preferentially during the postinspiratory phase. (B) Schematic interpretation based on A2‐3 and C. Rat cardiovagal preganglionic neurons could be receiving inhibitory inputs from early‐I and Aug‐E neurons. The existence of inhibitory input during inspiration has been documented in slices as shown in C. Pulmonary stretch receptors (inactive in an arterially perfused preparation) inhibit cardiovagal preganglionic neurons, possibly via a direct input from GABAergic “pump cells” located within the NTS. Carotid body stimulation produces opposite effects on CVPGN activity depending on the intensity of the stimulus. Mild stimulation inhibits these neurons via the RPG, presumably via inhibitory inputs from early‐I and post‐I neurons as shown in B. Acute and intense stimulation of the carotid bodies (e.g., with cyanide) activates cardiovagal preganglionic neurons as shown in A2. This effect may be mediated by polymodal NTS neurons that also respond to noxious stimulation of the airways (pathway not represented). Post‐I glutamatergic neurons are an alternative plausible source of excitation of cardiovagal preganglionic neurons and other vagal efferents with a post‐I discharge pattern but the existence of such neurons has yet to be demonstrated. (Panel C was originally published in (153), and has been reproduced by permission of Oxford University Press [http://www.oxfordscholarship.com/view/10.1093/acprof:oso/9780195306637.001.0001/acprof‐9780195306637]).


Figure 12. Feedback regulation of RTN neurons and interaction between central and peripheral respiratory chemoreflexes. (A1‐4) Four examples of RTN neurons showing different types of respiratory modulation which can be interpreted as post‐I and E‐aug inhibition in cell 1, early‐I and post‐I inhibition in cell 2, early‐I only in cell 3, and early‐I, post‐I and E‐AUG in cell 4 [adapted, with permission, from (158)]. (B) Typical RTN neuron devoid of respiratory modulation at low end‐expiratory CO2. This cell exhibits the early‐I/post‐I pattern when FiCO2 is increased (unpublished example from P. Guyenet). C, single RTN neuron inhibited by lung‐inflation [Tp, tracheal pressure, iPND integrated rectified phrenic nerve discharge; adapted, with permission, from (296)]. (D1) Single RTN neuron recorded in a vagally intact anesthetized rat showing the complex respiratory modulation of the cell (integrated rate histogram and rectified PND triggered on expiratory CO2 shown as bottom trace). (D2) Average steady‐state response of RTN neurons to end‐expiratory CO2 in the same preparation as D1 [D1‐D2 adapted, with permission, from (158)]. (E1 and E2) Similar recordings after i.c.v. administration of the glutamatergic antagonist kynurenic acid. (E1) PND and the respiratory modulation of the RTN neuron was abolished by kynurenic acid. (E2) The relationship between the discharge rate of RTN neurons and end‐expiratory CO2 became linear after kynurenic acid administration [adapted, with permission, from (158)]. (F) Interpretation of the results shown in A‐E: the response of RTN neurons to CO2 is saturable because of the existence of inhibitory feedback from lung stretch receptors and from the RPG. G, schematic wiring diagram based on A‐E. (H) Hypothetical scenario in which the RPG is unusually active or excitable (left). In such a case, respiratory feedback to the RTN would minimize the contribution of this nucleus to ventilation causing hypoadditivity between the peripheral and central chemoreflexes. On the other hand, additivity would result from a situation in which the RPG is moderately excitable (right panel). (I) Possible hyperadditivity scenario. RTN hyperpolarization at rest (right panel) could result in hyperadditivity between the central and peripheral chemoreflexes. In this configuration, moderate hypercapnia alone would produce a minimal stimulation of breathing because RTN depolarization would be largely subthreshold. Carotid body stimulation would depolarize RTN neurons above their discharge threshold causing them to respond vigorously to the previously ineffective hypercapnic stimulus, hence the apparent hyperadditivity of the reflexes.


Figure 13. Feedback regulation of RTN neurons and interaction between central and peripheral respiratory chemoreflexes. (A1‐4) Four examples of RTN neurons showing different types of respiratory modulation which can be interpreted as post‐I and E‐aug inhibition in cell 1, early‐I and post‐I inhibition in cell 2, early‐I only in cell 3, and early‐I, post‐I and E‐AUG in cell 4 [adapted, with permission, from (158)]. (B) Typical RTN neuron devoid of respiratory modulation at low end‐expiratory CO2. This cell exhibits the early‐I/post‐I pattern when FiCO2 is increased (unpublished example from P. Guyenet). C, single RTN neuron inhibited by lung‐inflation [Tp, tracheal pressure, iPND integrated rectified phrenic nerve discharge; adapted, with permission, from (296)]. (D1) Single RTN neuron recorded in a vagally intact anesthetized rat showing the complex respiratory modulation of the cell (integrated rate histogram and rectified PND triggered on expiratory CO2 shown as bottom trace). (D2) Average steady‐state response of RTN neurons to end‐expiratory CO2 in the same preparation as D1 [D1‐D2 adapted, with permission, from (158)]. (E1 and E2) Similar recordings after i.c.v. administration of the glutamatergic antagonist kynurenic acid. (E1) PND and the respiratory modulation of the RTN neuron was abolished by kynurenic acid. (E2) The relationship between the discharge rate of RTN neurons and end‐expiratory CO2 became linear after kynurenic acid administration [adapted, with permission, from (158)]. (F) Interpretation of the results shown in A‐E: the response of RTN neurons to CO2 is saturable because of the existence of inhibitory feedback from lung stretch receptors and from the RPG. G, schematic wiring diagram based on A‐E. (H) Hypothetical scenario in which the RPG is unusually active or excitable (left). In such a case, respiratory feedback to the RTN would minimize the contribution of this nucleus to ventilation causing hypoadditivity between the peripheral and central chemoreflexes. On the other hand, additivity would result from a situation in which the RPG is moderately excitable (right panel). (I) Possible hyperadditivity scenario. RTN hyperpolarization at rest (right panel) could result in hyperadditivity between the central and peripheral chemoreflexes. In this configuration, moderate hypercapnia alone would produce a minimal stimulation of breathing because RTN depolarization would be largely subthreshold. Carotid body stimulation would depolarize RTN neurons above their discharge threshold causing them to respond vigorously to the previously ineffective hypercapnic stimulus, hence the apparent hyperadditivity of the reflexes.
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Further Reading

Dutschmann M, Dick TE. Pontine mechanisms of respiratory control. Compr Physiol 2:2443-2469,2012

Forster HV, Haouzi P, Dempsey JA. Control of breathing during exercise. Compr Physiol 2:743-777,2012

Funk GD. Neuromodulation: purinergic signaling in respiratory control. Compr Physiol 3:331-363,2013

Gallego J. Genetic diseases: congenital central hypoventilation, Rett, and Prader-Willi syndromes. Compr Physiol 2:2255-2279,2012

Horner RL. Neural control of the upper airway: integrative physiological mechanisms and relevance for sleep disordered breathing. Compr Physiol 2:479-535,2012

Javaheri S, Dempsey JA. Central sleep apnea. Compr Physiol 3:141-163,2013

White DP, Younes MK. Obstructive sleep apnea. Compr Physiol 2:2541-2594,2012

Zhang SX, Wang Y, Gozal D. Pathological consequences of intermittent hypoxia in the central nervous system. Compr Physiol 2:1767-1777,2012


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Patrice G. Guyenet. Regulation of Breathing and Autonomic Outflows by Chemoreceptors. Compr Physiol 2014, 4: 1511-1562. doi: 10.1002/cphy.c140004