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Physiological Reviews, Vol. 79, No. 2, April 1999, pp. 325-360
Copyright ©1999 by the American Physiological Society
Unité Propre de Recherche, Centre National de la Recherche Scientifique 9011, Biologie des Rythmes et du Développement, Marseille; and Laboratoire de Neurophysiologie Clinique et Expérimentale, Amiens, France
I. INTRODUCTION
II. IN VIVO NEONATAL VENTILATORY PATTERN
A. Main Characteristics of the In Vivo Neonatal Respiratory Pattern
B. Afferent Regulation of Neonatal Respiratory Activity
III. MATURATIONAL CHANGES IN RESPIRATORY RHYTHMOGENESIS
A. Newborn Respiratory Rhythm Generator
B. Fetal Respiratory Rhythm Generator
C. Adult Medullary Respiratory Network
IV. MATURATION OF THE RESPIRATORY MOTONEURONS
A. Upper Airway Motoneurons
B. Phrenic Motoneurons
V. MATURATIONAL CHANGES IN RESPIRATORY MODULATION
A. Chemosensitivity
B. Serotonergic Modulation
C. Catecholaminergic Modulation
D. Neuropeptides
VI. IN VITRO APPROACHES AND RESULTS
A. Hypoxia and the In Vitro Central Respiratory Network
B. Respiratory Network and the Respiratory Circuits
VII. SUMMARY
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ABSTRACT |
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Hilaire, Gérard and
Bernard Duron.
Maturation of the Mammalian Respiratory System. Physiol. Rev. 79: 325-360, 1999.
In this review, the maturational changes occurring in
the mammalian respiratory network from fetal to adult ages are
analyzed. Most of the data presented were obtained on rodents using in
vitro approaches. In gestational day 18 (E18) fetuses, this
network functions but is not yet able to sustain a stable respiratory activity, and most of the neonatal modulatory processes are not yet
efficient. Respiratory motoneurons undergo relatively little cell
death, and even if not yet fully mature at E18, they are capable of
firing sustained bursts of potentials. Endogenous serotonin exerts a
potent facilitation on the network and appears to be necessary for the
respiratory rhythm to be expressed. In E20 fetuses and neonates, the
respiratory activity has become quite stable. Inhibitory processes are
not yet necessary for respiratory rhythmogenesis, and the rostral
ventrolateral medulla (RVLM) contains inspiratory bursting pacemaker
neurons that seem to constitute the kernel of the network. The activity
of the network depends on CO2 and pH levels, via
cholinergic relays, as well as being modulated at both the RVLM and
motoneuronal levels by endogenous serotonin, substance P, and
catecholamine mechanisms. In adults, the inhibitory processes become
more important, but the RVLM is still a crucial area. The neonatal
modulatory processes are likely to continue during adulthood, but they
are difficult to investigate in vivo. In conclusion, 1)
serotonin, which greatly facilitates the activity of the respiratory
network at all developmental ages, may at least partly define its
maturation; 2) the RVLM bursting pacemaker neurons may be
the kernel of the network from E20 to adulthood, but their existence
and their role in vivo need to be further confirmed in both neonatal
and adult mammals.
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I. INTRODUCTION |
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In this review, we describe the maturational changes occurring from the fetal stage to adulthood in the structural, functional, and regulatory processes at work in the central respiratory network. This network can be defined as a set of neurons located in the medulla and the cervical spinal cord that exhibit rhythmic electrical activity in phase with respiration. Some of these neurons are respiratory motoneurons (Mns), and special attention is paid in this review to those controlling the upper airways (especially the hypoglossal Mns, or XII-Mns, innervating the tongue) and the diaphragm (the phrenic Mns, or Phr-Mns). The other components include medullary and spinal interneurons. In this review, we focus in particular on those located in the medulla, which form the so-called respiratory centers, i.e., the part of the network that produces the rhythmic central drive received by the respiratory Mns.
In vivo studies on neonatal ventilatory activity are first reviewed. Obvious developmental changes have been described at the overall level which are likely to originate, at least partly, from central maturation, but almost no information is available so far about the changes occurring at the level of the respiratory medullary neurons. The maturation of the mechanisms underlying respiratory rhythmogenesis is then documented based on in vitro experiments performed on neonatal rodents (for review, see Ref. 350), whereas studies on the adult central respiratory network have been carried out for a long time on cats (for review, see Ref. 35). Problems arise here due to the interspecies and age-related differences (these are thoroughly discussed in sect. III). Because rat and cat adult respiratory networks may be different, there is little point in attempting to make deductions about maturational changes on the basis of comparisons between data on neonatal rats and adult cats. Fortunately, the discrepancies between the data on adult cats and neonatal rats have led to increasing attention being paid to the adult rodent respiratory network. We therefore first present the in vitro results obtained on newborn rodents (and even fetuses) and then those obtained on more mature animals, with special reference to rodents. Several experimental data support the idea that a special set of neurons in the rostral ventrolateral medulla (RVLM) may be respiratory bursting pacemaker neurons acting as primary respiratory neurons in neonates as well as in adults.
Ventilatory movements, which have been previously reviewed (190, 291), are complex motor acts that involve several types of muscles. To be efficient, the contractions of these muscles must be perfectly coordinated, and this is achieved at the level of the medulla as well as at that of the Mns that integrate central and peripheral inputs. We therefore report here on the morphological and electrophysiological maturation of the respiratory Mns.
Some of the mechanisms whereby respiratory activity is adapted to the physiological conditions are then analyzed at the levels of both the medullary respiratory centers and the respiratory Mns. Among the numerous modulatory substances involved, some of those that have been particularly well documented (serotonin, catecholamines, neuropeptides) have been described in greater detail. It has emerged that serotonin (5-HT) may play a crucial role; this is one of the first neuromediators to be expressed during ontogeny (43, 257, 265, 382), it is involved in nervous maturational processes (482), and it modulates the activity of the central network by acting at various levels (89, 181, 283, 293, 301, 302, 320), even at the fetal stage (86).
Most of the latest results have been obtained under in vitro conditions, and their physiological validity still remains to be confirmed. If the in vitro data turn out to be as reliable as they seem to be at present, we will be able to state with certainty that the respiratory bursting pacemaker neurons of the RVLM constitute the kernel of both the neonatal and adult respiratory networks. Meanwhile, however, we can work on the thought-provoking hypothesis that thanks to the plasticity of the respiratory network, several mechanisms may possibly be responsible for respiratory rhythmicity, depending on the state of the network.
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II. IN VIVO NEONATAL VENTILATORY PATTERN |
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The in vivo data reported below illustrate some of the main developmental changes occurring in the ventilatory pattern from birth to adulthood. These data provide an overall picture of the changes in respiratory movements, in terms of their frequency, the characteristics of the respiratory cycle, and those of the electromyogram (EMG) discharge pattern, for example, and little information is available so far on the unitary activity of neonatal respiratory medullary neurons and Mns in vivo.
A. Main Characteristics of the In Vivo Neonatal Respiratory
Pattern
1. Paradoxical neonatal respiratory movements
One of the first points worth mentioning is the immaturity of the
rib cage effectors. In infants, a paradoxical inward movement of the
rib cage has been commonly observed during inspiration (74, 229, 312). The muscular
effort necessary for a normal tidal volume during these paradoxical
movements is four times greater than during normal respiratory
movements (152). The paradoxical inward deflection of the
rib cage may be due to the combined effects of the highly compliant rib
cage and the small intercostal muscle tone versus the development of
the maximal diaphragmatic force. The low rigidity of the rib cage may
be due to relatively immature segmental reflex loops and spindle
afferents (424). The maturation of the proprioceptive
reflex loops has been mainly studied in lumbosacral Mns
(140, 141). There exist
intercostal-diaphragmatic reflexes in adult cats (77,
392, 426), young kittens (456), and newborn infants (230), but abolishing proprioceptive
afferents does not affect the intercostal muscle activity until
postnatal day 14 (P14) (104, 424).
Given the abundance of the spindle afferents within the various rib
cage muscles, the inward respiratory movements observed may be due to a
deficient proprioceptive regulation of the lateral intercostal muscles
(98, 99, 217, 246,
267), but this does not rule out the possibility that the
immaturity of the central command may be also involved. Decerebration
of kittens induced a flexor activity in all the thoracic muscles (435, 480), instead of the classical extensor
rigidity observed in adult cats that results from a 2. Variability of the neonatal respiratory activity
One of the other main characteristics of the neonatal
respiratory activity is its irregularity. Unpredictable spontaneous changes in respiration occur frequently in newborn animals and infants
(see Fig. 1A), consisting of a
mixture of episodes such as apnea, bradypnea, eupnea, and tachypnea.
These episodes have been reported to occur in unanesthetized neonates
of various species ranging in size from mice to infants
(72, 124, 160,
312). Respiratory frequency at birth, often inversely
correlated with the body weight, is slow in preterm infants that
present an exacerbated respiratory variability. These infants breathe
periodically or show prolonged apneas lasting for more than 20 s
(398) along with bradycardia, which is rarely observed in
full-term infants (208). The central apneas are often
preceded by a sigh or accompanied by body movements (481)
and are more frequent during active sleep and in the awake state, while
quiet sleep is associated with more regular respiration
(74, 361). The variability of the neonatal central rhythm may originate from 1) the intrinsic
properties of the respiratory rhythm generator and/or 2)
peripheral and central afferents acting on the rhythm generator. The
frequency of occurrence of central apneas decreases with age, and in
full-term babies, they tend to be replaced by obstructive apneas
similar to those observed in adults (105). Central apneas
have been reported to occur in unanesthetized decerebrate kittens
(266) and in anesthetized kittens and rabbit pups
(266, 460). Anesthesia stabilizes the respiratory activity and decreases the occurrence of central apneas. This improvement under anesthesia may be due to a depression of the
afferent messages impinging on the respiratory rhythm generator.
-loop central
control (103). The flexor rigidity induced by
decerebration persists until P40 and suggests an abnormal central
control on Mn activity.

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Fig. 1.
Some developmental characteristics of neonatal respiration. In
A, variability of preterm infant respiration. Top
and bottom traces, raw and integrated diaphragmatic
electromyogram (EMG) discharges, respectively. Note spontaneous
transitions from eupnea to tachypnea (A1) and bradypnea
(A2). In B, discharge pattern of adult cat
phrenic nerve (B1) and diaphragmatic EMG of preterm infant
(B2) and newborn rat (B3; 2 successive
inspirations). In neonates, inspiratory bursts are abrupt, are of short
duration, and show low-frequency oscillation within discharge.
The particular respiratory response of neonates to hypoxia should be mentioned here, although it will be dealt with in greater detail in sections VA2 and VIA. In adults, hypoxia induces sustained hyperventilation, whereas this facilitatory response is very weak, and transient in neonates, and is followed by a marked respiratory depression (42, 208, 404). The initial facilitatory response disappears completely in cold environments (58).
3. Respiratory cycle characteristics
The respiratory cycle differs between adults and neonates, since the inspiratory time (TI) is shorter and the expiratory time (TE) is longer in neonates than in adults. In decerebrate cats (266), for example, the adult TI and TE are ~1.30 and 1.45 s, respectively, with a TI/TE of 0.90, whereas the neonatal TI and TE are ~0.76 and 2.18 s, respectively, with a TI/TE of 0.35 on P7. The TI/TE increases with age, reaching 0.41 on P14, 0.74 on P21, and an almost adult value (0.88) at 5 wk of age. Similar low ratios have been reported in the case of unanesthetized neonatal mice and rabbits (312) and human infants (173). The lengthening of TI with age is one of the most conspicuous developmental changes; it has been observed even in the opossum, where TI at birth is ~100 ms, whereas the adult values are four to eight times longer (119). In neonates, most of the ventilatory adaptations involve TE changes, whereas TI remains quite constant. The decrease in respiratory frequency induced by either hypoxia or the deepening of anesthesia results from an increase in TE, whereas TI remains unchanged (401, 460).
Diaphragmatic and phrenic (Phr) nerve recordings have shown the existence of developmental changes (268, 448). In the adult cat, the amplitude of the Phr discharge increases slowly during inspiration (Fig. 1B1), due to the increasing discharge frequency of the individual Phr-Mns and the delayed recruitment of Mns throughout the inspiratory phase (191). In the kitten, this increasing pattern of discharge is no longer observed; the onset and offset of the discharge are abrupt, and the Phr discharge recorded at low speed resembles a gasp (268). In the preterm infant and the decerebrate newborn rat, a similar pattern was observed (Fig. 1, B2 and B3). The central mechanisms governing the recruitment of individual Phr-Mns during inspiration seem to differ between the newborn and the adult cat (182, 191, 268).
In the adult cat, high-frequency oscillations have been observed within the Phr burst, as well as within the recurrent, hypoglossal, and medullary respiratory neuron discharges (65, 68, 281). These oscillations occur at a frequency of ~60 Hz in the adult and are present within the neonatal Phr discharge, but their frequency is lower, i.e., ~20 Hz in kittens (268), newborn rats (Fig. 1B3), newborn dogs (448), and even in preterm human infants (Ref. 100 and Fig. 1B2). Because the Phr oscillations are thought to reflect medullary synaptic processes, the neonatal low-frequency oscillations suggest the existence of differences between neonate and adult medullary respiratory networks.
B. Afferent Regulation of Neonatal Respiratory Activity
1. Pulmonary afferent regulation
Among the respiratory afferent systems, the most thoroughly
studied so far is the vagal pulmonary afferent system, since
Hering-Breuer's demonstration in 1868 (178) that lung
inflation and deflation inhibits and facilitates inspiration,
respectively. Activating the vagal pulmonary stretch receptors by
applying lung inflation inhibits the central inspiratory command
(3, 358, 483, 484), while bivagotomy slows down the respiratory frequency, mainly via a
TI increase, and increases the amplitude of the inspiratory discharge in all adult mammals but humans, where this regulation does
not seem to occur (398, 401). In adult cats,
the vagal pulmonary afferents play an even more crucial role after
pneumotaxic center lesion (66, 67), since
after bivagotomy, the normal breathing pattern is replaced by an
apneustic breathing pattern characterized by very long inspirations
(inspiratory cramps with TI >5 s) interrupted by very
short expirations. At birth, vagal respiratory regulation exists since respiratory rhythm
is depressed by vagotomy in kittens (101,
102) and newborn rats (320,
439), but it differs from the adult pattern. Vagotomy
performed on decerebrate kittens slows down the respiratory rate,
lengthens TI, and reinforces the inspiratory activity, as in adults, but these inspiratory changes are quite moderate
(102). The decrease in respiratory frequency is mainly due
to lengthening of TE and is associated with a distinct
enhancement of expiratory muscle activity (Fig.
2A). Vagotomy in kittens
increases TE and TI 10- and 4-fold,
respectively, compared with 1.2- and 2-fold, respectively, in adult
cats. This paradoxical expiratory facilitation gradually disappears
with age, and the adult pattern of response to bivagotomy is reached by
about P21 (102, 460). In decerebrate kittens
with pneumotaxic center lesion, bivagotomy does not result in the adult
apneustic breathing pattern (102, 460) but in
very long "active expiratory apneas" (>1 min) interrupted by short inspirations (102). The adult apneustic pattern is not
observed until P21. The predominance of expiratory activity in neonates can be said to be part of the general motor behavior, which is mainly
characterized by the activation of the flexor muscle group to which the
expiratory muscles belong. This is suggested by the predominance of
TE versus TI during eupnea, by the flexor
activity of expiratory muscles observed during decerebration rigidity, and by the expiratory cramps elicited after vagal and pontine afferent
eliminations. Thus removing the upper central structures and vagal
afferents makes the expression of the neonatal flexor (expiratory)
activity possible.

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Fig. 2.
Respiratory vagal regulation in neonates. In A, effect of
vagotomy in decerebrate postnatal day 1 (P1) kitten.
Top and bottom traces, integrated and raw EMG
discharges, respectively, of third inspiratory interchondral muscle
before (A1) and after bivagotomy (A2). Bivagotomy
decreases respiratory rate, mainly by increasing expiratory duration,
and induces recruitment of previously silent expiratory triangularis
sternum muscle of third intercostal space. In B,
Hering-Breuer deflation reflex (between arrows) in P2 (B1)
and P21 (B2) decerebrate kittens. Top and
bottom traces, diaphragmatic EMG discharge and tracheal
pressure changes, respectively. Pulmonary deflation activates
inspiratory discharges of P2 and P21 neonates, but inspiratory
activation is weak on P2.
Overinflating the lungs of neonatal cats and rabbits elicits an inspiratory inhibition (75, 101, 102, 460), and vagal inspiratory inhibition is also observed in vitro in newborn rats (193, 319). In decerebrate kittens, tracheal occlusion performed at the very end of inspiration to maintain the lungs in the inflated status lengthens TE and delays the occurrence of the next inspiration. Conversely, tracheal occlusion at the very end of expiration reinforces the next inspiratory discharge in decerebrate kittens (102) and newborn rabbits (75). These pulmonary responses are stronger in neonates than in adults, since the adult lungs have to be overinflated or overdeflated to elicit any clear-cut respiratory changes. In human infants, the pulmonary vagal regulation of respiration is weak or absent, depending on age. The inflating reflex is weak at 32 wk of postconceptional age; it peaks at 38 wk and declines thereafter (38). It may be absent in full-term babies during the first few days of life (73). Airway occlusion at the end of expiration may strengthen the next inspiration in preterm and term infants (343), but this was not the case in full-term infants during quiet sleep (450). At birth, infants behave no differently from adult humans, in whom the inflating reflex is not present (398).
Although lung deflation induces inspiratory activation, the sustained reinforcement of inspiratory activity observed in adult cats is not present in kittens (Ref. 101 and Fig. 2B1). The adult response appears around P21 (Fig. 2B2). The pulmonary stretch receptor discharges seem to be similar in neonatal and adult cats (424, 269), although few low-threshold receptors are found on P3 (424), but receptors of both types are present on P7 (269). In neonates, the receptors are mainly located in the intrathoracic trachea, and their maximum firing rate is slightly lower than in adults (269). Despite their late myelinization in the vagus nerve (267) and their low sensitivity, the neonatal pulmonary stretch receptors are functional at birth. Therefore, the existence of vagal inspiratory inhibition observed in vivo in neonatal cats, rabbits, and rats (75, 101, 102, 460) compared with the lack of sustained inspiratory reinforcement observed during deflation at birth suggests a functional immaturity of the vagal system of regulation, which may be due to both the neonatal rib cage compliance and an immature central network.
2. Trigeminal afferent regulation
The sneeze reflex is one of the main reflexes triggered by nasal mucosa stimulation. In adult cats, it is characterized by a preparatory inspiratory phase (long and intense inspiratory activity), followed by a brief expiratory burst with a rapid onset (233, 474, 476). In kittens, mechanical stimulation applied to the nasal mucosa elicits markedly different sneeze responses depending on age. At birth, the response consists almost entirely of expiratory efforts, which are longer, occur after longer delays than in adults, and are not preceded by any inspiratory preparation (232, 476). In addition, the aspiration reflex cannot be elicited in newborn kittens, whereas in adult cats, it can be evoked by stimulating the inferior nasal meatus and consists of a sudden increase in inspiratory activity that is not followed by an expiratory effort (473). Both sneeze and aspiration reflexes show the adult pattern by P21. Although the nasal afferents might not be completely mature at birth, their immaturity alone does not explain their ability to activate expiration and their inability to activate inspiration during trigeminal reflexes. Moreover, a study on c-fos expression during the sneeze reflex has provided evidence that the maturation of sneezing depends on the development of the central relays necessary for peripheral inputs to be integrated by the neurons involved in respiratory control (270). Therefore, a lack of central connectivity associated with the immaturity of the central pattern generator seems to be a plausible explanation (475).
Respiratory changes induced by activating buccal trigeminal afferents have been tested in the kitten (473, 224). In anesthetized and decerebrate kittens from P0 to P3-5, applying tiny amounts of water to the mouths induces long apneas (>60 s) and only rarely swallowings. Swallowing coexists with long apneas up to P15 but, on P21, the adult pattern appears, in which swallowing disturbs only one to two respiratory movements. Both electrical stimulation applied to the central end of the lingual nerve and mechanical oral stimulation lead to a strong reinforcement of XII-Mn and expiratory muscle activities during apnea. Serotonin is likely to be involved in the oral trigeminal-induced apnea, since its application to the fourth ventricle in decerebrate kittens induced similar apneas (223, 224), whereas intraperitoneal application of 5-HT antagonist suppressed the oral trigeminal-induced apneas (Duron, unpublished results).
3. Cutaneous afferent regulation
It has been known for a long time that friction applied to infants at birth activates inspiration, and activating cutaneous afferents in newborn kittens greatly facilitates respiration. Nonnociceptive cutaneous stimulation applied to the neck and back reinforces the frequency and amplitude of respiratory movements in decerebrate kittens (266) and preterm infants (100). The fact that the activation of nonnociceptive cutaneous afferents efficiently stimulates inspiration even under anesthesia indicates that a highly potent reflex is involved. After P14, this response becomes very difficult to trigger under anesthesia, but it persists in decerebrate kittens until becoming inconsistent, as in adult cats (266). More intense cutaneous stimulation, consisting for example of pinching the ventral face of the neck, thorax, and abdomen, inhibits inspiration, elicits apnea and bradypnea, and concomitantly activates the XII-Mns and the expiratory muscles (224). This might possibly correlate with asymmetrical effects of the dorsal and ventral cutaneous afferents. Finally, activating cutaneous afferents by applying electrical stimulation to the saphenous nerve of kittens increases the respiratory frequency, and this effect persists for a long time after the end of the stimulation (459). The long-lasting nature of this effect shows the importance of nonspecific systems in the maintenance of neonatal breathing.
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III. MATURATIONAL CHANGES IN RESPIRATORY RHYTHMOGENESIS |
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In this section, we focus on the mechanisms through which the respiratory network generates a rhythmic command at different ages. We first report in vitro experiments performed on the neonatal rodent respiratory centers, and then those performed on fetuses using similar in vitro approaches, before reviewing the data available on adult mammals, with a special emphasis on rodents. In the adult cat brain stem, three main groups of respiratory neurons have been identified (for review, see Ref. 35), namely, two medullary groups, the ventral and dorsal respiratory groups (VRG and DRG, respectively), and a third pontine group, forming the pneumotaxic center. The DRG and the pneumotaxic center seem likely to play an important role in respiratory rhythmogenesis in the adult cat (35, 66, 67), but whether they are of any functional importance is questionable in the adult rat (149, 193, 284, 496).
A. Newborn Respiratory Rhythm Generator
1. In vitro neonatal rodent brain stem-spinal cord
preparations
In 1984, Suzue (449) reported that it was possible to
record rhythmic bursts in the cervical roots giving rise to Phr nerve, as well as in the XII roots, after isolating the medulla and the cervical spinal cord of neonatal rats in vitro (Fig.
3). These bursts recur in vitro for
several hours, but their low frequency (5-10/min), the low
TI/TE, and the unusual decreasing pattern of Phr bursts are not in agreement with what was generally recognized at that time as constituting respiratory activity in the adult anesthetized cat (35, 191). In addition,
after elimination of pontine and vagal afferents, the neonatal in vitro
respiratory network does not produce the apneustic pattern observed in
adult cats after bivagotomy and elimination of the pons
(35, 66, 67). Despite Suzue's
arguments (449) supporting the idea that these in vitro
Phr bursts are of respiratory origin, few scientists were convinced at
that time that these preparations were actually suitable for
respiratory network studies. It has been demonstrated by now, however,
that the in vitro Phr bursts 1) originate from the medulla,
since they were abolished after upper cervical transection but persist
after elimination of the pons (192, 449);
2) induce rhythmic inflation movements of the chest that are
accompanied by synchronous diaphragmatic and thoracic EMG discharges
(192, 449); 3) occur concomitantly
with the firing of neurons located in the VRG area (87, 155, 345-356,
and see Fig. 3A); and 4) are sensitive to pH,
CO2 levels (294), and vagal afferent
activation (277, 319).

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Fig. 3.
Rostral ventrolateral medulla (RVLM), a crucial area for in vitro
neonatal respiratory rhythm. Top left, schematic arrangement
showing in vitro brain stem-cervical cord preparation of neonatal
rat (ventral surface upward) and in vitro phrenic bursts. Black dot
indicates location of RVLM area where inspiratory neurons can be
recorded (A, from top to bottom,
intracellular activity of a RVLM inspiratory neuron, integrated and raw
phrenic discharges). In RVLM, electrical stimulation and drug
applications (performed at arrow in B
D via a
multi-barreled micropipette) affect occurrence of integrated
phrenic bursts. A single shock applied in RVLM on-switches
immediately a premature phrenic burst (B) while
norepinephrine (C) and serotonin (D) applications
in RVLM decrease and increase respiratory frequency, respectively.
Numerous scientists are therefore now using Suzue's model or similar models. Three different approaches using different experimental materials can be distinguished: 1) Suzue's isolated in vitro brain stem-spinal cord preparation from neonatal rats (192-194, 283, 285, 293-295, 345-356), mice (180, 181), and even opossums (117, 326, 500); 2) in vitro brain stem slices in which only the most indispensable part of the network is preserved (366-369, 383-385, 436-439); and 3) in vitro-like perfused brain stem of maturing mice and guinea pigs (306-310, 363-365). With all these in vitro approaches, there are several unique advantages, such as the possibility of changing the extracellular medium, directly stimulating, destroying, or recording from different regions, performing patch-clamp recordings under the most favorable conditions, and even using optical imaging procedures (355).
2. RVLM and respiratory rhythmogenesis
A restricted area of the RVLM was quickly found to be crucial for respiratory rhythmogenesis in vitro (16, 17, 87, 114-116, 345-356, 436-439). This finding was first suggested by electrical stimulation (see Fig. 3B) and lesion experiments. A single electrical shock delivered to the RVLM during mid-expiration can almost induce a similar Phr burst to that which would normally have occurred 2-3 s later. Electrolytic lesions performed in the same area abolished the respiratory rhythmicity, while local drug applications (5-HT, substance P, catecholamine, and high-K+ medium) almost immediately induced respiratory frequency changes (89, 115, 116, 437; see Fig. 3, C and D). In the histological checks performed to locate the efficient sites, no well-defined nucleus was observed but a diffuse region extending from the caudal end of the facial nucleus to the rostral end of the nucleus ambiguus. This area is referred to as the RVLM, although other names have been proposed, such as the pre-Bötzinger complex (PBC) (437). Upon applying the neonatal rat in vitro approach to the neonatal mouse, the neonatal mouse respiratory network was found to also remain functional in vitro and electrical stimulation and lesion of the RVLM induced and abolished inspiration, respectively (180).
3. Respiratory neurons of the RVLM
The patterns of distribution and the activity of the medullary neurons firing in phase with the Phr bursts have been studied in these neonatal preparations. Various research groups have classified the medullary neurons as belonging to several types on the basis of their discharge patterns (16, 17, 345-356, 363-369, 391, 436-439). No consensus has yet been reached as to how many types of respiratory neurons actually exist, but we describe here one of the most thorough attempts to answer this question (345-356).
Neurons that are depolarized and fire several hundreds of milliseconds before the Phr bursts have been called preinspiratory neurons (Pre-I). Some Pre-I neurons fire throughout inspiration (20%), but most of them are silenced for 200-400 ms during the Phr bursts and then fire again for a while at the beginning of expiration. Their silence during inspiration has been attributed to an active inhibition, but releasing the inhibition does not affect their ability to fire rhythmic bursts of spikes (see Fig. 8 of Ref. 350). The firing of Pre-I neurons has been studied under normal artificial cerebrospinal fluid (aCSF) and under modified aCSF containing low Ca2+ and high Mg2+ (87, 214, 345-348). The modified aCSF was found to be an efficient means of abolishing synaptic transmission based on the suppression of the Phr bursts observed and the silencing or the low tonic frequency of most of the recorded neurons (87, 348). However, one-half of the Pre-I neurons still showed some bursting firing ability under low-Ca2+ high-Mg2+ aCSF. These neurons, which continue to rhythmically deliver bursts of spikes when the synaptic connections have been blocked, may be inspiratory bursting pacemaker neurons (Fig. 4). When two simultaneously recorded Pre-I are subjected to low-Ca2+ high-Mg2+ aCSF, they both continue to produce bursting firing, but the bursts of spikes become desynchronized; they are resynchronized when normal aCSF is restored. The Pre-I neurons are preferentially located in the RVLM, where they extend rostrocaudally from the caudal end of the facial nucleus to the rostral end of the nucleus ambiguus. Therefore, the induction of inspiration by RVLM stimulation may result from the massive synchronous activation of the Pre-I bursting pacemaker cells. Among the neurons exhibiting a "classical" inspiratory discharge (non-Pre-I), some have also been classified in the respiratory bursting pacemaker group because they continue to fire in bursts under low-Ca2+ high-Mg2+ aCSF (87, 214). Intracellular recordings have confirmed that some inspiratory neurons respond to intracellularly injected depolarizing current by increasing the frequency of their bursts of spikes (437). Here again, these neurons are likely to be inspiratory bursting pacemaker neurons playing a major role in respiratory rhythmogenesis within the central respiratory network. The Pre-I pattern of discharge therefore does not seem to be a reliable criterion for determining pacemaker properties, since cells other than Pre-I can also be respiratory pacemaker cells.
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In addition to these Pre-I neurons, three other subtypes of inspiratory neurons have been distinguished on the basis of the synaptic events occurring during expiration, but "there were intermediate subtypes" (350). The type I neurons receive numerous excitatory postsynaptic potentials before and also after the Phr burst, when the Pre-I cells are firing, and therefore type I neurons might be driven by the Pre-I cells. Some type I neurons start firing well before the Phr bursts, as Pre-I neurons do, but do not stop during inspiration. Type II neurons fire during the Phr burst, and no discernible synaptic events occur just before or after the Phr bursts. The type III neurons also fire during the Phr bursts, but hyperpolarizing events occur just before and after the Phr bursts. Most of the inspiratory neuron types have a decreasing discharge frequency, and their distribution overlaps that of the Pre-I neurons, although they extend more caudally within the VRG. Finally, expiratory neurons have been encountered in the VRG (436, 439) and subdivided in two further groups, which either fire tonically throughout expiration or are activated only late in expiration. These neurons are actively inhibited during Phr bursts, possibly by Pre-I neurons and inspiratory neurons (17, 436, 439).
As mentioned in section III, the cat dorsal medulla contains densely packed inspiratory neurons constituting the DRG (35). Surprisingly, inspiratory neurons have never been said to be encountered so far in the dorsal medulla in any of these in vitro studies, and lesions of the rodent neonatal dorsal medulla do not affect the respiratory rhythmogenesis (193, 366, 367).
The details of the discharge pattern of the respiratory bursting pacemaker neurons (Pre-I type or not) are a relatively subsidiary issue. First, Onimaru et al. (350) recognized that "there were intermediate subtypes" (350). Second, the criteria used for neuronal classification have not been clearly defined (350). The distinction between some type I neurons, which start to fire well before the Phr bursts, and the Pre-I neurons, which also start very early and do not stop firing during inspiration (20% of the Pre-I pool), is not very clear. Finally, the neuronal pattern of discharge is too dependent on the experimental conditions (ionic aCSF composition, the catecholaminergic and serotonergic nuclei preserved at dissection). The inspiratory pause displayed by 80% of the Pre-I neurons results from an active inhibition exerted by caudal medulla that is released when the caudal medulla is lesioned and cooled (349, 350). The Pre-I pattern therefore is unlikely to occur in rhythmic slice preparations including only part of the caudal medulla. Although worthy attempts have been made by several teams to classify the respiratory neurons, we are not convinced that the discrepancies between the results should be emphasized, since they may simply reflect differences between the experimental conditions used.
The interconnections between the various groups of neonatal respiratory neurons have been analyzed by performing cross-correlation analysis. The existence of mono- or paucisynaptic excitatory connections and shared inputs has been suggested by cross-correlograms between pairs of inspiratory neurons (219, 356). With the use of the spike-triggered averaging methods (219, 354, 356), it has been established that Pre-I neurons excite inspiratory neurons and that Pre-I, type I, and type II inspiratory neurons project to the spinal cord, whereas the type III inspiratory neurons may be propriobulbar interneurons (see Ref. 35). When the excitatory amino acids mediating these interactions accumulate as the result of blocked reuptake processes, the respiratory frequency increases via the activation of non-N-methyl-D-aspartate (NMDA) receptors (154).
Some other noteworthy findings in addition to those showing the
possible existence of respiratory bursting pacemaker cells within the
medullary respiratory network are those demonstrating that
Cl
-mediated inhibition is not essential to neonatal
respiratory rhythm generation (123, 349,
367-369, 384, 427). All these
results obtained on in vitro neonatal rodent preparations but also
those obtained in rhythmic slices from rather mature mice are
consistent with the idea that respiratory rhythmogenesis does not
depend on Cl
-mediated inhibition within the central
respiratory network (386, 388) and that the
RVLM respiratory bursting pacemaker neurons may constitute a
trigger-clock imposing its rhythm on the rest of the network.
However, the functional relevance of inhibition might be more important
in vivo than in vitro (388).
B. Fetal Respiratory Rhythm Generator
From 1970 to 1990, fetal breathing movements were studied in the pregnant ovine. The occurrence of these movements was first suggested by the abdominal movements observed in human and were subsequently confirmed by direct intrauterine observations of the fetus and EMG recordings. Because this question has already been extensively reviewed (165-167, 208, 209, 227, 228, 398-404), only a few in utero studies are mentioned in section IIIB1.
1. In utero respiratory activity
Ovine fetal breathing movements are produced by rhythmic and coordinated contractions of the various respiratory muscles that trigger both intrathoracic pressure changes and amniotic liquid movements within the trachea. The diaphragm contractions are mainly responsible for these pressure changes, which are almost completely abolished after Phr nerve transection. The laryngeal dilator muscles are also rhythmically active during fetal breathing movements, since the glottis has to open for the respiratory tracheal pressure changes to occur. The genioglossal tongue muscle is normally silent but can be recruited during inspiration by artificially increasing CO2 supply or by applying cold cutaneous stimulation to the fetus. The inspiratory thoracic muscles are rhythmically activated during fetal breathing movements in the earliest fetal stages but are silent during late gestation. Their silencing, the low compliance of the chest wall, and the immature proprioceptive regulation of intercostal tone all presumably account for the paradoxical inward movements of the rib cage occurring during the late gestational period.
During early gestation, both human and ovine fetuses first produce nonrespiratory movements involving a tonic activation of the thoracic muscles and the diaphragm (208, 209, 403). Fetal breathing movements become frequent but episodic at around one-third of gestation, although fetal breathing movements can be triggered in response to cutaneous stimulation as early as 40 days of gestation in exteriorized sheep fetus. With increasing age, the tonic activity-to-fetal breathing movement time ratio decreases, but the fetal breathing movements are still episodic. On the basis of the use of a window technique (399, 403), it has been observed that fetal breathing movements, general movements, and swallowing activities occur during rapid eye movement (REM) sleep and, conversely, that they are absent during quiet sleep, except for the generalized tonic discharge occurring from time to time; the question as to whether fetal breathing movements occur in states other than REM sleep has been settled with the statement that "wakefulness is not part of fetal life" (400). Fetal breathing movements may be modulated by several endogenous substances as, for example, prostaglandin E2 (471, 327) and 5-HT (125).
Although fetal respiratory movements were known to occur in utero, little is known about the central command governing these movements, despite some noteworthy efforts in this direction (51, 205). This topic is difficult to investigate because of the inaccessibility of the fetus in utero and its great sensitivity to surgical trauma and anesthesia. In one of the latest reviews published on this subject (209), the authors concluded that "much descriptive work ... has been published, but there is a dearth of information regarding the central respiratory rhythmogenesis in the fetus." Furthermore, it was suggested that "in the future, more direct recording will be required to advance our knowledge significantly" because the few studies published on the respiratory centers have been mainly descriptive and not very informative, even allowing for the fact that they were particularly difficult to perform (51, 205).
2. In vitro fetal rat respiratory activity
Two different groups have simultaneously adapted the in vitro newborn rat brain stem-spinal cord preparation to the fetal rat and have published very similar results (85, 155).
In the fetal rat, brain stem-spinal cord preparations show two different patterns of easily distinguishable rhythmic activity. The first one takes the form of a long-lasting burst of spikes (several seconds) occurring from time to time in all the spinal roots, including the Phr ones. This activity might correspond to the tonic activity previously reported in the fetal lamb. The second type of activity consists of rhythmic bursts of spikes occurring in both the Phr and XII roots with a short duration (<1 s) and a recurrent frequency of 5-10/min. The rhythmic Phr bursts are likely to be respiratory in nature, since they occur concomitantly with respiratory chest movements when the rib cage is kept attached to the spinal cord, and they originate from the medulla since they are abolished by upper cervical transection (85). They are never observed in fetal rat preparations on gestational day 15 (E15), are occasionally seen on E16 (82), and are present in almost all preparations at older ages. In young fetuses, the inspiratory bursts often have weak amplitudes and short durations. Their amplitude and duration increase with age, and by E20, they resemble the neonatal pattern.
In comparison with the in vitro rhythmic activity recorded in newborn rat preparations, the fetal rat respiratory activity is more variable (Fig. 5A). It consists of intermingled short and long cycles including bursts of variable amplitude, although the mean respiratory frequency is in the neonatal range (85, 87, 90). The variability decreases with age from E16 to E20-21, when it almost reaches the stability of the newborn. To estimate the variability, a coefficient of variation has been defined as the SD-to-mean ratio of the cycle duration (or amplitude) measured during 60 successive respiratory cycles. The coefficient of variability ranges between 0.1 and 0.2 in neonatal rats, but it is more than twice as high in E18 fetuses, whereas intermediate values are reached by E20. The fetal rat preparation has been adapted recently to the fetal mouse, and similar results have been obtained, which confirm the stabilization of the fetal respiratory output observed with age (Hilaire, unpublished data). The inability of the isolated central rhythm generator to build up a stable motor command may be viewed as a sign of immaturity, and the stabilization with age of the motor output as a sign of maturation (57, 85, 87, 90).
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3. RVLM and fetal rat respiratory activity
In E20 fetal rat preparations, as in newborn preparations, single electrical shock stimulation applied to the RVLM results almost immediately in an unexpected Phr burst with a similar shape and amplitude to that which would normally have occurred later. This response has never been observed in E18 fetuses, however, where RVLM stimulation either has no effect or elicits a diffuse facilitation when large stimulating currents are applied (87). Electrolytic lesions performed in the RVLM abolishes respiratory rhythmogenesis in E20-21 and newborn preparations but has no effect in young E18 fetuses. Upon exploring the RVLM area with extracellular electrodes, respiratory neurons were observed at all developmental ages. When a low-Ca2+ high-Mg2+ aCSF was used to block the synaptic connections within the preparation, the rhythmic Phr bursts disappeared, and most of the RVLM respiratory neurons lost their bursting behavior. In fetal E20 preparations displaying a fairly stable rhythm, ~10% of the RVLM neurons retained a rhythmic bursting activity under low-Ca2+ high-Mg2+ aCSF (Fig. 6C). These neurons may be respiratory bursting pacemakers, likely those mentioned above in newborn rats. Surprisingly, none of these neurons has been encountered at E18, when the rhythm is unstable. It has therefore been postulated that the variable respiratory rhythm present in the young fetus may reflect an immature network, whereas in late fetal and newborn preparations, the pacemaker properties observed in some RVLM respiratory neurons may be at least partly responsible for the stable activity of the network (85, 87, 90). The variable E18 fetal rhythm may either result from the wiring properties of the medullary network or be imposed by some other neuronal networks, such as that described in the chick embryo (61, 127, 128).
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C. Adult Medullary Respiratory Network
For a long time, what was known about the adult medullary respiratory centers was based on data obtained in the cat, and only recently, data have been published on the adult rodent respiratory network. The numerous studies performed during the last few decades on the adult cat medullary network have been reviewed recently (35). Tremendous efforts have been made to locate and classify the respiratory neurons. The DRG, which is located in the dorsal part of the brain stem, contains mainly inspiratory neurons projecting toward the spinal cord, where they excite the Phr-Mns (for reviews, see Refs. 190, 291). The VRG, which is located in the vicinity of the nucleus ambiguus, is a more heterogeneous structure containing both inspiratory and expiratory cells, which have been identified as cranial Mns, bulbospinal neurons, and central interneurons. Several models have been proposed to explain the respiratory rhythmogenesis, and all are based entirely on the excitatory and the inhibitory connections within the network. The authors of one of the latest reviews on the subject (35) concluded that "brain stem respiratory activity results from the sequential activation of at least six neuronal populations, leading to two fast phase-switching transitions and three relatively long respiratory phases. Each process is conditioned by the previous one and initiates the next." The possible role of the RVLM in respiratory rhythmogenesis is described in a subchapter entitled "Other structures," beginning by "Medullary structures other than the DRG and VRG have been proposed as playing a role in the generation and control of breathing." By now, a consensus has almost been reached as to the crucial role played by the RVLM (30, 96, 122, 143, 354, 394, 396, 410-412).
1. Adult rat medullary network
The first reports on the adult rat respiratory network suggested that the medullary respiratory neurons might be located in the VRG and DRG groups (202, 413). The existence of the DRG has been questioned, however (118, 344, 491), and the results of both in vitro neonatal brain stem preparations and in vivo adult experiments have shown that it may not in fact exist in the rat (193). Intracellular soundings performed in the dorsomedial medulla show the existence of respiratory activity originating from axons but not somas (496, 497). Although respiratory activities have again been reported in the rat dorsal medulla (76, 457), the existence of the DRG in rats seems unlikely, and, if a rat DRG exists, it will certainly be of less functional significance than in the cat (457). In the mouse, the existence of a DRG seems also unlikely, at least in vitro, since ablation of the dorsal part of the medulla had no effect on respiratory activity. The data on newborn and adult rodents obtained in vivo and in vitro are therefore consistent with the idea that the DRG contributes little if at all to respiratory rhythmogenesis in these mammals.
Within the VRG, all the neuronal types previously encountered in the case of the cat were found to be present in the rat, namely, cranial Mns, respiratory bulbospinal neurons, and central interneurons (107-111, 496-498). Here again, several attempts have been made to classify these neurons in terms of the location of their soma, their pattern of discharge, and their axonal projection. The axons of the inspiratory bulbospinal neurons project to either the ipsilateral side (22/28), the contralateral side (16/28), or both (10/15; Ref. 456). Studies using cross-correlation techniques have confirmed that a substantial bilateral excitation is exerted on the Phr-Mns (95) by VRG bulbospinal neurons and have suggested that the drive to the intercostal Mns may be relayed by interneurons (455, 456). Anatomic results have been published that are in complete agreement with these electrophysiological findings. Injecting different tracers into both left and right Phr nuclei leads to the double labeling of a substantial number of bulbospinal neurons in the rostral part of the nucleus ambiguus, but only a few in the dorsal part of the medulla, while single-labeled neurons are distributed throughout the rostrocaudal extent of the medulla (376). The bulbospinal neurons are located more ventrolaterally than the laryngeal Mns in the rostral part of the nucleus ambiguus, and they are located around the laryngeal Mns at the more caudal level of the nucleus (377, 378). Propriobulbar, bulbospinal, and vagopharyngeal neurons are unevenly distributed along the rostrocaudal axis of the VRG (333, 334). The brain stem afferent connections to VRG neurons and the possible interconnections within the respiratory centers have been also studied using neuroanatomic approaches (297, 332). Pontine efferent projections from the VRG reached the perifacial areas, the parabrachial and Kolliker-Fuse nuclei, as well as the catecholaminergic A5 area (146).
2. RVLM area and adult rodent respiratory activity
The question now arises whether the RVLM plays the same crucial role in adult rodent respiratory rhythmogenesis. In an in vitro-like perfused mouse brain stem preparation (363-365), the activity of respiratory neurons displaying the Pre-I type firing was recorded in the RVLM. These neurons started to fire before the beginning of inspiration, continued to fire bursts of spikes when the synaptic connections had been blocked, and fired rhythmically when all the other respiratory neurons had been silenced (central apnea induced by stimulating C vagal fibers). The firing behavior of Pre-I neurons was assessed after switching to low-Ca2+ high-Mg2+ perfusate to block the synaptic transmission. In the absence of all synaptic transmission, seven of eight Pre-I neurons continued to discharge rhythmically and four of eight still presented a bursting activity 25 min after the synaptic blockade. Unfortunately, the single Pre-I bursting discharge shown during synaptic blockade (Fig. 9 from Ref. 365) was not very convincing, since the Pre-I pattern of discharge that recurred under synaptic blockade is very different from the control pattern (burst duration 5-10 s during synaptic blockade versus <1 s during control conditions). It may therefore be safer to wait for further confirmation of the existence of respiratory bursting pacemaker neurons in adult mice rather than making any hasty conclusions on this point. Nevertheless, these data suggest that respiratory bursting pacemaker neurons may exist in the mature mouse, although this does not rule out the possibility that other circuitries and mechanisms may be involved in the adult respiratory rhythmogenesis.
On the one hand, it has been reported that strychnine does not block
the respiratory rhythm in neonatal mice until P15, but amino acid
inhibition becomes essential later however (175,
366-369). On the other hand, data obtained on brain stem
transverse slices from P0 to P22 mice (383-385) have shown
that inhibitory synaptic events are not essential to respiratory
rhythmogenesis at birth. Their functional relevance increases with age,
but they never become essential to respiratory rhythmogenesis. Blocking
glycine receptors by strychnine did not stop rhythmicity but increased the burst frequency at all ages. Strychnine applied at concentrations between 1 and 50 µM did not abolish the respiratory rhythm in either
neonatal and adult mice, although the expiratory neuronal activity was
profoundly disturbed in adult slices. Although the inspiratory neuronal
pattern of firing remained phasic, the "expiratory neurones became
almost tonic, suggesting that these neurones are not essential for
generating rhythmic inspiratory activity" (384). The
discrepancies existing between the two rodent approaches concerning the
role of inhibitory synaptic events in respiratory rhythmogenesis may be
due to either technical differences (tilted versus transverse slices)
or the actual developmental age.
-Aminobutyric acid innervation in
the rat nucleus ambiguus increases from the fetal to the early postnatal age and then decreases (134, 135,
488). In humans, a similar pattern of development has been
observed in the cerebrospinal fluid GABA levels, which are correlated
with the conceptual age but not with the birth age (148).
The role of inhibitory mechanisms in adult respiratory rhythmogenesis
is still an open question, but these mechanisms do participate in
shaping the respiratory neuron discharge pattern (421).
The authors of in vivo studies have reported that inspiration lengthens with age, whereas the duration of the in vitro inspiratory bursts has been said to remain constant or to increase from birth to P15 (366-369, 383-385). In vivo, the inspiratory duration may be affected by inputs from both the lungs and the pneumotaxic center (66, 67). Upon suppressing both inputs in anesthetized cats, the eupneic pattern is replaced by an apneustic pattern characterized by very long inspirations interrupted by short expirations. The cat pontine mechanisms involve NMDA receptors, since an apneustic pattern is induced by the NMDA channel blocker MK-801 (131, 423) and a high density of NMDA binding sites is reported in the pneumotaxic center (415). In the anesthetized, vagotomized adult rat, the existence of apneustic breathing has been questioned, since, on the one hand, MK-801 lengthens inspiration and only occasionally induces short periods of apneusis (285), but on the other hand, local application of MK-801 to the pons induces apneusis (142). MK-801-induced apneustic breathing has been reported to occur in vagotomized Sprague-Dawley rats but not in Wistar rats (70). There seem to exist both interspecies differences and a problem as to how apneusis should be defined: inspirations are characteristically long (~5 s) during apneusis in cats (132) and guinea pigs (56) but are rather short during the so-called apneustic periods in rats and mice (~1.9, 0.5, 1.5, and 1.6 s in Swiss mice, BALB/c mice, Wistar rats, and Sprague-Dawley rats, respectively, from Table 1 of Ref. 56). In addition, apneusis can occur under anesthesia, but during wakefulness, an eupneic pattern is maintained (56), and apneusis can be elicited in the adult guinea pig under in vivo but not in vitro conditions (306). It is worth noting that the possibility of evoking apneustic breathing in kittens may be questioned (460, 102, 423). In neonatal and fetal rodents, the possibility that pontine NMDA receptors may be involved in the offset of inspiratory seems unlikely, since 1) the in vitro medullary network generates a respiratory rhythm in the absence of pulmonary and pontine afferents, 2) applying MK-801 to neonatal rat brain stem and medullary slices does not induce apneusis (145, 154), and 3) transgenic mice lacking functional NMDA receptors show a respiratory activity in vitro (121, 144). The NMDA receptors may therefore contribute to the inspiratory offset under some circumstances (anesthetized and vagotomized adults) but are unlikely to be a crucial factor from this point of view.
3. RVLM area and adult cat respiratory activity
Many in vivo results obtained on the adult cat and published in the past can now be viewed as suggesting the possible involvement of the RVLM in adult cat respiratory rhythmicity. The first transection experiments on adult cats showed that eliminating the rostral medulla abolishes rhythmic respiratory movements (478, 258). In the 1970s, respiratory changes induced at the ventral surface of the rostral medulla were taken to originate only from the chemoceptive areas (256, 282, 420). At the beginning of the 1980s, unilateral transections or reversible procaine blocks in the vicinity of the facial nuclei (the rostral limit of the RVLM) were found to alter the respiratory rhythm (157, 158). Unilateral cooling of the RVLM to 20°C completely abolished inspiratory rhythmicity, which gave rise to the idea of calling the ventral medullary area extending from the caudal part of the facial nucleus to the rostral end of the nucleus ambiguus the "apnea region" (45).
More recently, the cat RVLM was found to contain respiratory neurons that can be activated from both the DRG and VRG; this finding suggests that "RVLM neurons are component of medullary loops operating in the control of breathing" (40). In this area, pharmacological and electrical stimulation both induce respiratory changes (41). The patterns of respiratory neuronal activity have been examined in a circumscribed area of the cat RVLM, defined as the PBC and located caudal to the retrofacial nucleus and rostral to the lateral reticular nucleus (69, 422). This area appears to be a specialized subregion of the adult cat VRG corresponding to the neonatal rat RVLM. It has been proposed that the PBC remains essential to rhythm generation throughout postnatal development, since blocking the synaptic transmission in the PBC of adult cats induced central apnea (387, 396). In the adult cat, recordings from the activity of inspiratory neurons located in the PBC which displayed a Pre-I pattern of discharge showed that these neurons project to the contralateral VRG and are involved in vestibular and superior laryngeal nerve reflexes as well as in swallowing and vomiting (499). Inhibitory mechanisms play an important role in respiratory rhythmicity in the adult cat (421) and bicuculline and strychnine applied within the PBC drastically affected rhythmic Phr activity (373). These data again argue in favor of the PBC being a crucial region for respiratory rhythm generation, but also indicate that inhibitory mechanisms play an important, if not essential, role in respiratory rhythmogenesis in the adult cat in vivo.
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IV. MATURATION OF THE RESPIRATORY MOTONEURONS |
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The fact that fetal respiratory movements occur early in prenatal life means that the respiratory Mns show a rhythmic activity long before birth. On the one hand, this early sustained activity may affect their development. On the other hand, they are bound to encounter the same maturational problems as other Mns, namely, cell migration, cell death, as well as morphological and electrophysiological maturation. Mouse XII-, vagal- and Phr-Mns differ in their homeodomain protein expression, and their fate is partly defined by the Pax6 homeobox gene that is expressed by undifferentiated cells in the ventral region of the neural tube (113).
A. Upper Airway Motoneurons
The tongue contains intrinsic and extrinsic muscles that serve complex motor functions such as chewing, suckling, swallowing, coughing, vomiting, vocalizing, and breathing. The intrinsic muscles, which are devoid of bony attachments, constitute the body of the tongue. The extrinsic muscles, which are attached to bones, act as either tongue protruders (genioglossus) or retractors (hyoglossus and styloglossus). The Mns innervating tongue muscles are located in the dorsal part of the brain stem, within the XII nucleus along with genioglossal Mns located in the XII ventral subnucleus and hyoglossal and styloglossal Mns located in the dorsal subnucleus. Transynaptic tracing studies on adult rats have shown that the protrudor and retractor Mns do not have the same central drivers but share a common drive from the raphe nuclei (92).
Aside from the tongue, the remaining muscles in the upper respiratory tracts (larynx, pharynx oral and nasal cavities) are innervated by Mns located in the nucleus ambiguus. A bilateral location of the laryngeal Mns was first suggested (255, 362), but this has not been confirmed. Contrary to what occurs in the cat and the rabbit, the rat Mns innervating the cricothyroid and the posterior cricoarytenoid muscles are not arranged in distinct subgroups (377), but the Mns innervating the oropharyngeal muscles have a viscerotopic pattern of organization (334).
1. Morphological maturation
The complete pattern of adult rat XII nucleus organization is present quite early in development, by P2 (440). Most of the XII-Mns are generated largely at E10-11 (11, 12) and are present in a well-defined nucleus by E15. Mutation in Pax6 homeobox gene profoundly perturbs XII-Mn maturation and results in an apparent transformation of XII-Mns into vagal Mns (113). Cell death, which is a widespread developmental phenomenon (177, 204, 339), occurs prenatally in the case of XII-Mns, with a loss of 35% of the Mns between E16 and E19 and no significant decrease in the Mn number subsequently, which remains around 3,300 at P1 (135). Studies on the postnatal development of XII-Mns have shown that they undergo considerable changes in the dendritic organization but that the somata seem to remain quite unaffected (33, 328-331, 336, 463, 464). At birth, the dendritic tree is well extended, and its branching complexity decreases (loss of terminal branches) concomitantly with the lengthening of the remaining branches observed during the two first postnatal weeks, but the overall area of the XII-Mns (soma and dendritic trees) does not change. New dendritic branches then regenerate during the third week, while the diameter of all the existing branches increases, so that the dendritic area increases twofold.
The development of the nucleus ambiguus Mns has also been studied in the fetal rat (12, 134). By E14, a peak has been observed in the neuroblast number. They are densely clustered in the dorsal brain stem, and the ventrolateral brain stem shows no apparent nucleus ambiguus. The cells then migrate out of the proliferative zone into discrete, less dense neuronal centers, and an ill-defined compact division of the nucleus ambiguus can be seen by E15. By E17, the nucleus ambiguus is fully formed and contains around 2,700 Mns. Their number decreases significantly by E19 and E20 (2,000 and 1,600, respectively) up to P1 (~1,300), when the adult mean number is reached (1,400).
Cell death therefore occurs in the respiratory cranial Mns only during prenatal life, with no further postnatal loss in tongue, larynx, and pharynx Mns. The fate of the facial Mns is different. Their number decreases drastically from 5,000 at E15 to 3,000 at P1 and continues to decline to 2,000 after birth until P10 (19). Cell death occurs at a higher rate (~70%) and continues longer (up to P10) among the facial Mns than among the XII and nucleus ambiguus Mns. As far as the spinal Mns are concerned, conflicting results have been published, and cell death is said either to occur only at the early fetal ages or to continue during the first postnatal week (245, 337, 357, 406).
2. Maturation of the electrophysiological properties
During the first two weeks of life, the electrophysiological properties of XII-Mns undergo considerable changes: the input membrane resistance and membrane time constant decrease by ~50%, whereas the rheobase current increases by 100% (328-330, 335, 464). Although it might be expected that the electrophysiological changes originate from developmental morphological changes, it has been reported that the total surface area of XII-Mns does not increase significantly during this period (328) and that no strong correlation exists between membrane resistance and total surface area (331). It has therefore been hypothesized that the electrophysiological changes may reflect synaptic input changes (330, 335).
Anatomic and electrotonic couplings between XII-Mns exist before P10 and seem to subsequently disappear after (273). Because electrotonic coupling may contribute to the synchronization between Mns, the loss of coupling beyond P18 may at least partly explain why the XII burst shape changes from a decreasing one at birth to a bell-shaped one in older mice (384). Several currents, such as current and hyperpolarizing-activated inward current (Ih), Ca2+ have been studied in neonatal XII-Mns (360, 461-463). The Ih found in neonatal XII-Mns, based on the occurrence of a depolarizing sag during the injection of hyperpolarizing current, seems to be three times smaller in neonatal than in the adult XII-Mns, and this may contribute to the XII pattern of discharge.
3. Maturation of the pattern of discharge
In isolated in vitro perinatal brain stem-spinal cord
preparations and neonatal brain stem slices, XII-Mns are
rhythmically depolarized and fire during inspiration. In vitro, as in
vivo, the XII inspiratory bursts occur before the Phr bursts
(304), and the in vitro XII burst shape often decreases
during inspiration, like that of the in vivo cat (428). In
mouse transverse medulla slices, also rhythmic respiratory discharges
continued in XII-Mns and medullary neurons (383-385).
During the first 3 wk of life, the cycle length and the XII burst
duration do not change significantly, but the XII burst shape changes
from a decreasing one (P1
P9) to a bell-shaped one (P10
P22).
Furthermore, the strength of the coupling between XII and medullary
cell bursts decreases from younger mice (P0
P4: ratio 1/1) to older
mice (P5
P18; ratio 1/3-4). In perfused guinea pig brain stems
(307, 310), the above results reported on
mice were not confirmed; the XII burst shape could be either
decreasing, increasing, or bell shaped, and it was not specified
whether uncoupling between XII and medullary respiratory cells
occurred. This was never observed in neonatal rat preparations.
Glutamate excitatory effects are mediated via two broad classes of
ionotrophic receptors, NMDA (slow kinetics, highly permeable to
Ca2+) and non-NMDA (fast kinetics, weakly permeable to
Ca2+) receptors, and these two types of receptors are
colocalized at the same synaptic locations on the XII-Mn membranes,
but some sites contain only NMDA receptors (338).
Non-NMDA receptors mediate the transmission of the respiratory
drive to XII-Mns (145). Several data suggest that XII
and Phr-Mns are not driven by the same medullary respiratory
neurons (298, 304, 428). The XII
central drive may originate from respiratory pre-Mns located in the
reticular formation lateral to the XII nucleus (91,
92), where electrical stimulation elicits
short-latency glutamatergic excitatory postsynaptic potentials in
XII-Mns, the amplitude of which may be modulated by adenosine and
5-HT (29, 433, 434). However, no
respiratory active neurons have yet been detected in this area. In the
neonatal rat and the adult cat, the inspiratory XII-Mns are silent
during expiration, and their repolarization is a passive process,
involving no inhibitory effects during expiration (486).
-Aminobutyric acid, a key inhibitory neurotransmitter in the central
nervous system, operates via two classes of receptors,
GABAA and GABAB. In the E16 fetal rat, a very
small number of GABA-positive fibers is present into both the XII
nucleus and nucleus ambiguus. By E20, a dramatic increase in GABAergic
innervation occurs (134, 135). At birth,
GABAA receptors are present in most brain areas, especially
in brain stem regions that rely more on GABAA receptors in
early postnatal life than at more mature stages; their density increases from birth to P5, peaks at P10, and then decreases
(488). In infants, the GABA levels in the cerebrospinal
fluid show a comparable pattern during development (148).
In the adult rat, the lack of effect of the GABAB
antagonist on XII-Mn activity suggests that no permanent
GABAB inhibition is exerted directly on XII-Mns,
although the receptor is present (342).
B. Phrenic Motoneurons
The diaphragm is the main inspiratory muscle, and the maturational changes in its structural and functional organization have been studied in cats (429-431), rats (262), and baboons (272, 274). The premature and full-term baboon diaphragm contains a larger number of highly oxidative fibers, whereas the adult diaphragm is composed of a mixture of oxidative (type I) and glycolytic (type IIB) fibers (274). The neonatal diaphragm contracts and relaxes more slowly, develops less force, and is more resistant to fatigue than in adults (274).
1. Morphological maturation
In the fetal rat, the diaphragm is fully innervated by E18, and at
birth, ~80% of the Phr axons are already myelinated
(267). Phrenic motoneurons are generated in the
ventricular zone by E11-12, while the cervical roots leading to the
Phr nerve start to be formed (12). A leading group of
"pioneering" Phr axons migrates, reaching the diaphragm by E13. The
diaphragm and the growing Phr nerve descend together toward the
thoracic level by E14, and intramuscular branching commences clearly
correlated with myotube formation, which indicates the existence of
intimate regulatory signaling mechanisms between the developing muscle
and nerve (9, 10). A Pax6 homeobox
gene mutation induces a 45% decrease in the total number of Mns at
C3-C4 cervical segments by E12 which
encompasses the Phr-Mns and those in the median column
(113). The morphological changes undergone by Phr-Mns
with development have been studied by performing retrograde labeling
with carbocyanine dye, DiI, from E13
E14 to birth (10).
The Phr-Mns migrate in groups of intimately associated somata from
the ventricular zone to the ventromedial part of
C3-C6 by E14, until forming tightly aligned columns by E18. The dendritic trees extend dorsolaterally and ventromedially to the white matter and floor plate, and the somata are
in very close apposition, suggesting the possible existence of gap
junctions. Dendritic fasciculation and retraction occur concomitantly
with the development of dendritic rostrocaudal extensions by E19,
leading to a pattern of dendritic tree organization that is similar to
that observed at birth (251). The Phr-Mn diameters reach ~8 µm by E14 and gradually increase to 13-14 µm by E18 and 15-16 µm by E21, which is the postnatal P2 value. The density of the
Mns is greater at E14
E15 than at older ages, and the naturally occurring cell death is estimated to result in an ~50% decrease in
the number of Phr-Mns (168). At birth (Fig.
7), the Phr-Mns somata have 60% of
their adult volume and appear to be much more highly developed than the
nonrespiratory cervical Mns (408, 409). In
the adult rat, the Phr-Mns constitute a narrow column extending within the medial part of the cervical ventral horn from C3
to C5 (235). The adult somata are oval or
round in shape, medium sized, and tightly clustered. Synaptic buttons
are generally located on somata and dendrites. Some synaptic buttons on
axon hillocks suggest presynaptic inhibition (150).
Neuroanatomic data argue in favor of monosynaptic connections between
VRG respiratory neurons and Phr-Mns (107-110).
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2. Maturation of electrophysiological properties
The maturation of electrical properties of rat Phr-Mn
membranes has been studied from E18 to P0
P3 using identical
experimental conditions and electrode types (90).
Significant age-related changes occur, along with a decrease in the
membrane resistance and spike duration, whereas the resting potential
and rheobase current increase. These changes are completely in
agreement with the increase in soma diameter observed during gestation
(10). The mean firing threshold does not change from E18
to P0
P3, and all the Mns are able to fire a sustained burst of spikes
when they are depolarized by a 1-s pulse (Fig. 7D). Even on
E18, a stable response is consistently elicited in response to a given depolarizing pulse. These results suggest that the variability of the
fetal Phr bursts does not result from the immaturity of the membrane properties.
Like the XII-Mns, the neonatal rat and mouse Phr-Mns present an Ih current (Fig. 7E). In addition, depolarizing sag and Ih current have been observed in some fetal Phr-Mns as early as E18 and in all the neurons tested on E21 (G. Hilaire, G. E. Di Pasquale, and F. Tell, unpublished data). In Phr-Mns, the Ih current therefore starts to mature well before birth, and it may facilitate the Phr-Mn firing during delivery and at birth. The persistence of electronic coupling between neonatal Phr-Mns cannot be ruled out, but its rate of occurrence seems to be low in comparison with that of the lumbosacral Mns (77% between P0 and P3; Ref. 477). After birth, the Phr-Mn resting potential and antidromic spike amplitude show no further changes, but the axonal conduction velocity and rheobase continue to increase, whereas membrane input resistance and duration of action potential decrease (52, 53). The increase observed in the axonal conduction velocity may reflect the postnatal myelinization of some phrenic axons (267).
In addition to the Phr-Mns, interneurons have been encountered that either fire tonically or display a respiratory rhythm, since they are depolarized and fire either during inspiration or expiration. These interneurons have very different membrane properties from those of Phr-Mns at all developmental ages (namely, less polarized membrane potentials, larger membrane resistance, and lower firing threshold). It is worth noting that on E18, numerous interneurons are neither able to generate overshooting action potentials nor able to fire a sustained burst of spike when depolarized by a 1-s pulse, whereas by E21, they all fire a sustained burst of overshooting action potentials. The respiratory cervical interneurons therefore seem to mature later than the Phr-Mns. If this late maturation also occurred in the medullary respiratory interneurons constituting the respiratory centers, it would explain the unstable respiratory frequency generated at E18.
The cervical respiratory interneurons are unlikely to belong to the group of spinal interneurons undergoing postnatal cell death (247) or to be interneurons transiently excited by respiratory axons in search of targets, since cervical respiratory interneurons exist in adult animals (15, 90, 183, 184, 252, 253). In adult rats, some of the inspiratory bulbospinal neurons of the VRG (12%) may excite these interneurons, possibly monosynaptically, and these in turn may monosynaptically excite the Phr-Mns (13% of the tested interneurons). However, none of them excites the intercostal Mns (455, 456). In the cat, there is no evidence that the C5 inspiratory interneurons, despite their inspiratory modulation, convey the central respiratory drive to Phr-Mns (97). In addition, some of the adult respiratory interneurons recorded from turned out to be Renshaw cells (183, 184). Although we have looked for respiratory Renshaw-like cells in neonates, no electrophysiological evidence has yet been obtained, suggesting they are functional at this age.
3. Maturation of the pattern of discharge
The in vivo adult Phr burst has a characteristic increasing shape, especially in the deeply anesthetized cat (see Fig. 1), due to both increasing firing frequency of individual Phr-Mns and gradual recruitment during inspiration of previously silent Phr-Mns (191). The in vitro neonatal Phr burst shows a decreasing shape, however. Intracellular recordings have shown that this decreasing shape reflects the central excitatory command received by the Mns, with the maximum depolarization observed at the very beginning of inspiration (Fig. 7B). This may be partly due to the abolition of vagal afferents that may shape the inspiratory pattern (102, 120, 261, 319, 439) and to hypoxia, which may transform the Phr pattern from increasing to decreasing in perfused adult mouse brain stem preparations (363), as well as to the number of Phr-Mns recruited late during inspiration (444). The in vivo phrenic nerve discharge also has an abrupt onset in the normoxic decerebrate kitten and newborn rat (268). It is worth noting that in vivo, most of the Phr-Mns are active during normal inspiration in the kitten (only 6% of the Phr-Mns are silent), whereas almost one-half of the Phr-Mns are quiescent in adult cats (53). This means that in adults, a marked increase in the number of active diaphragmatic fibers may be obtained when necessary by recruiting previously silent Phr-Mns, whereas it is practically impossible for neonates to increase their diaphragmatic efforts. This can have drastic consequences in the case of obstructive apnea, for example.
In vitro, the fetal brain stem-spinal cord preparation generates a rhythmic Phr activity that is most variable in amplitude at E18 but stabilizes on E20. The E18 variability may reflect either the inability of the immature Phr-Mns to respond to the central command or the inability of the central network to build up a stable central drive. As reported above, although they are still immature at E18, the Phr-Mns are already able to produce stable bursts of spikes in response to depolarizing pulses. Recordings of the activity of VRG respiratory neurons in fetal and newborn preparations have shown that numerous neurons are incapable of producing stable rhythmic respiratory bursts of spikes during inspiration at E18. In young fetuses, some VRG inspiratory neurons may not fire during one Phr burst, or they may in contrast fire a burst of spikes without any concomitant Phr discharge (Fig. 6, A and B). However, from E20 onward, most of the VRG neurons fire regularly every cycle. The instability of the Phr burst amplitude at E18 is therefore likely to be due to the immaturity of the medullary network, which is not yet able to generate a stable motor command.
In experiments in which excitatory amino acid receptor antagonists, agonists, and reuptake blockers were applied to the neonatal rat cervical spinal cord, Phr-Mns were found to possess both NMDA and non-NMDA receptors, but only non-NMDA receptors are likely to be responsible for transmitting the central command to Phr-Mns (254, 275). In the adult rat, the transmission of the central drive to the Phr-Mns is also mediated by excitatory amino acids, since 1) >80% of the rat bulbospinal neurons projecting to the Phr nucleus are glutamate immunoreactive (414) and 2) NMDA and non-NMDA receptor antagonists depress the transmission of the central command to Phr-Mns in the rabbit (39).
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V. MATURATIONAL CHANGES IN RESPIRATORY MODULATION |
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The respiratory movements must be able to adjust to all the physiological situations encountered during normal life, and these adjustments depend on changes both in the central command to the Mns and in the Mn responsiveness. Among the numerous substances that may modulate the activity of the central respiratory network, it is proposed to first review chemosensitivity to O2, CO2, and pH before dealing with some selected neuromodulators such as 5-HT, catecholamines, and neuropeptides (Fig. 8).
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A. Chemosensitivity
1. Respiratory responses to CO2 and pH changes
It has been known for a long time that CO2 and pH
modulate respiration in both adult and neonate mammals, and this
modulation also occurs in the in vitro neonatal brain stem-spinal
cord preparation. Under control conditions, aCSF applied to the
preparation was gassed with 5% CO2-95% O2,
leading to a pH around 7.3. Upon eliminating the CO2
stimulus by replacing normal aCSF by aCSF gassed with pure
O2, the pH changed to ~7.8, and the respiratory motor
output is depressed in the neonatal rat (294) and opossum
(117). Applying aCSF bubbled with 8% CO2-92%
O2 increased the respiratory frequency and induced a rapid
response in almost all the VRG neurons tested (222). Most
of the inspiratory neurons depolarized while the expiratory ones
hyperpolarized. Because this response persisted under tetrodotoxin,
some medullary respiratory neurons might be intrinsically
chemosensitive (222). The interstitial CO2 and pH values in the VRG of isolated neonatal rat brain stem were found to
be ~80 mmHg and 6.9, respectively, and small variations in the
extracellular H+ were found to affect the respiratory
frequency (466). In utero, fetal breathing depends on the CO2 arterial
levels (208, 209). Upon administration of
CO2 with the use of a maternal rebreathing technique, fetal
breathing was never induced during quiet sleep, but increased when
present during REM sleep (402). This response is probably
mediated by central chemoreceptors (195). In vitro
experiments on fetal rats have shown that central chemosensitivity is
functional before birth in E20 fetuses (85). Withdrawal of the CO2 and/or pH stimuli drastically decreased the
respiratory frequency in E20 fetuses, even more strongly than in
newborn rats, since respiratory arrests occurred in the fetuses. In
younger fetuses (E17 In adult animals, various chemosensitive areas have been mapped on the
ventral surface of the medulla (35, 419). In
both adult and neonatal anesthetized goats, cooling the ventrolateral surface of the medulla results in reversible apnea, but these effects
are much slighter in the awake state (126). The proximity of the RVLM and the existence of intrinsically chemosensitive medullary
respiratory neurons (222) raise the question, however, as
to the actual location of the chemoceptors; chemosensitive areas may be
located on the ventral surface as well as deeper within the brain stem
(308, 309, 322,
323). In addition, changes in respiratory frequency and pH
in the VRG area occur simultaneously in the neonatal rat brain stem
preparation, again suggesting that some VRG respiratory cells might be
chemosensitive (466). Central chemoception is likely to involve cholinergic mechanisms
(47-50, 139). In adult animals, the
activation of muscarinic receptors at the ventral medullary surface
stimulates ventilation (81, 82,
324), and the potentiation of endogenous acetylcholine facilitates respiration in the awake state (129). In
neonatal rat (294) and opossum in vitro preparations
(117), chemosensitive respiratory changes also involve a
cholinergic relay and are affected by atropine or physostigmine added
to aCSF (294). The existence of a permanent modulation of
the brain stem respiratory output by endogenous acetylcholine, via
muscarinic receptors, has been finally demonstrated (49,
50, 294). 2. Respiratory responses to hypoxia
Hypoxia, which may be detected by peripheral and central
receptors, results in respiratory changes. In carotid
body-denervated patients, the hypoxic response might be absent
(200) and the existence of central receptors for hypoxia
in humans is discussed (405). A number of ion channels,
including the Na+ and K+ channels, are
responsive to O2 deprivation (for review, see Ref. 164),
and hypoxia directly excites vasomotor pacemaker neurons, for example,
even in the presence of TTX (446). The carotid body glomus
cells are the primary sensors for arterial O2 partial
pressure and detect the peripheral hypoxia. They enhance their afferent signals to the respiratory center, which consequently adapts the ventilatory processes to the O2 changes. Simulating a
"physiological denervation of the peripheral chemoreceptors" by
ventilating preterm infants with 100% O2 induces apnea
(13). Oxygen chemoception involves the hypoxic inhibition
of K+ channels, glomus cell depolarization activating
voltage-gated Ca2+ channels, Ca2+ influx,
and hence the secretion of various neurotransmitters, especially
dopamine. In the newborn rat, the pattern of postnatal development of
the carotid bodies shows a considerable increase in O2
sensitivity from the fetal to adult states (106). In
response to hypoxia, the carotid body firing, the Ca2+
entry, and the amount of catecholamine released, all increased with age
in newborn rats and rabbits (22, 93,
179, 203, 370). Whole cell
patch-clamp recordings suggested that Ca2+-sensitive
K+ channels may play an important role in the postnatal
maturation of hypoxic chemoception (94) and that the
activity of these channels is conspicuously enhanced between P4 and P10
(174). In both young and adult mammals, hypoxia induces a biphasic respiratory
response consisting of an initial increase in the frequency and
amplitude of the Phr bursts, followed by a respiratory depression (for
review, see Ref. 395). The initial increase is very discrete and poorly
sustained in newborn infants and animals where hypoxia mainly induces a
significant depression in ventilation (42,
208, 209, 402, 404)
and metabolic changes (313, 314, 133). In fetuses, whose living conditions are already
hypoxic, so that they constitute a kind of "Everest in utero"
(167), acute hypoxia reduces the incidence of fetal
breathing movements, as well as that of all other motor activities,
without any initial increase in respiration (470), whereas
hyperoxemia leads to fetal arousal and continuous breathing, which
suggests that high O2 levels are required to maintain
continuous breathing in the fetus (20, 21). The pattern of development of the hypoxia-induced respiratory
activation, which is absent in fetuses and weak in neonates, parallels
the pattern of carotid body maturation. However, the hypoxia-induced respiratory activation may also originate
centrally, since it has been described in adult and neonate
deafferented in vitro preparations. In perfused adult rat brain stem
preparations, hypoxia elicited by either perfusing hypoxic solution or
stopping the brain stem perfusion resulted in a rapid and reversible
arrest of the XII rhythmic bursts, but the apnea was preceded by an
initial increase in the XII burst frequency in ~20% of the
experiments (296). At the beginning of apnea, a tonic
discharge occurs in the XII nerve, in agreement with the depolarizing
effect of anoxia on the adult XII-Mns (159, 210, 356a). In perfused
maturing mouse brain stem preparations (364) and in
transverse rhythmic slices from mice older than P7 (385),
hypoxia first increased the burst frequency and thereafter reduced the
central respiratory activity, until it ceased completely. Inspiratory
neurons of the PBC are initially depolarized by hypoxia and
subsequently hyperpolarized, whereas expiratory neurons are only
hyperpolarized (380). The effects of hypoxia are age
related, since in younger neonatal mice (P0 B. Serotonergic Modulation
Serotonergic cells are aggregated in various raphe nuclei and send
projections to the whole central nervous system. They release 5-HT, one
of the first neuromediators to be expressed during ontogeny, which acts
via numerous types of receptors on multiple targets (371).
Serotonin is involved in different functions (465), and 5-HT-containing terminals have been detected in respiratory areas of
both the reticular formation (257, 390) and
the Phr nucleus (199). With the use of fetal and neonatal
rodent in vitro brain stem preparations, 5-HT has been found to exert
multiple effects on respiration, since it acts directly on both the
respiratory rhythm generator and the respiratory Mns. 1. 5-HT and central respiratory rhythm
At the medullary level, 5-HT exerts an excitatory modulation on
the activity of the neonatal rat and mouse respiratory rhythm generator, possibly via 5-HT1A receptors located within the
RVLM area (89, 181, 293,
301, 302, 319). The 5-HT
facilitatory effect was established by applying exogenous 5-HT and
related agents as well as by modifying the endogenous 5-HT levels. It has also been studied on mouse medullary slices by bath application of
exogenous 5-HT, by local application of 5-HT within the RVLM, and by
stimulation of the raphe nuclei (14). In the E18 fetal rat, the 5-HT1A excitatory modulation is so potent that
5-HT has been said to be a necessary factor for the expression of
respiratory rhythmicity; very weak concentrations of 5-HT markedly
increase the respiratory frequency, and applying a specific
5-HT1A receptor antagonist to block the facilitatory
effects of endogenous 5-HT elicits respiratory arrests. The strength of
the 5-HT facilitatory modulation decreases with age, and by E20 The question still remains as to whether 5-HT modulates the adult
respiratory rhythm. The authors of in vivo studies have frequently
reported the occurrence of respiratory changes in response to the
application of 5-HT agents (197, 198,
238, 239, 280), but these
studies have often yielded conflicting results, depending on the
species studied and the routes of administration used. For example,
5-HT can induce hyperventilation in cats and dogs (36),
can increase respiratory frequency in rabbits (271), and
can induce apnea in rats (259, 494). Cat
respiration was either depressed (intravenous route) or activated
(intracerebroventricular route) upon administering the 5-HT precursor
5-HTP (18, 279). In kittens and cats,
applying 5-HT to the floor of the fourth ventricle decreased and
increased the respiratory frequency, respectively (223,
407), whereas raphe lesions depressed the respiratory frequency (393). These discrepancies between the observed
effects of 5-HT are certainly due to the multiple peripheral and
central sites of action of 5-HT and the existence of numerous types of 5-HT receptors. Serotonin facilitates firing of DRG respiratory neurons
(207, 389, 425), which carry
5-HT immunoreactive buttons (468), and modulates VRG
respiratory cell firing (240-244). Among the various 5-HT
receptor subtypes, the effects of at least 5-HT1A and
5-HT2 receptors have been investigated; 5-HT1A
receptor antagonist treatment blocked the respiratory changes induced
by nucleus raphe obscurus stimulation, and 5-HT2 receptor
agonist depolarized most of the expiratory and postinspiratory neurons.
Activating 5-HT1A receptors converted an apneustic
breathing into nearly normal pattern of breathing (243)
and led to a prompt and effective remission in the case of a child
suffering from apneustic breathing (485). Activation of
5-HT1A receptors inhibits cat respiratory neurons via a G
protein-mediated downregulation of protein kinase A, while
activation of 5-HT2 receptors excites neurons via a protein kinase C (397). 2. 5-HT and Phr-Mns
A large network of 5-HT fibers innervates the spinal cord early in
development (43, 265, 382), and
in addition to the medullary effects of 5-HT, in vitro experiments on
neonatal rats and mice also show that 5-HT has spinal effects. First,
5-HT added to the aCSF applied to the cervical spinal cord facilitates
neonatal Phr-Mn discharge and induces a tonic firing, even in
fetuses (86). This effect is exerted by 5-HT2A
receptors that are likely to be located on the Phr membranes, since it
persists under TTX (250, 303,
304). In the adult cat, Phr-Mns receive 5-HT
innervation (199, 374) and are sensitive to
5-HT (238, 239). A second effect of 5-HT has
been recently demonstrated; activating cervical 5-HT1B
receptors was found to depress the transmission of the central
respiratory drive to the Phr-Mns (84,
250). These receptors are presumably located at the
presynaptic level, at the endings of the inspiratory axons arising from
the medullary respiratory centers, and projecting to the Phr-Mns.
These dual and opposite effects of 5-HT exerted on the same pool of Mns
illustrate one way possible to reconfigure a central network. Via
postsynaptic 5-HT2 receptors, 5-HT activates Phr-Mns,
whereas, via presynaptic 5-HT1B receptors, it gates the
transmission of the central drive to Phr-Mns to facilitate their
recruitment in nonrespiratory behavior (such as vomiting, coughing,
and/or defecation; see Refs. 190, 291). The existence of
5-HT1B modulation has not been checked yet in the fetus,
but, in the adult, it may partly explain the discrepancies existing
between the results published so far on 5-HT, since the response of the
Phr-Mns depends on the difference between the pre- and postsynaptic effects. 3. 5-HT and XII-Mns
The XII inspiratory discharge may be affected by several
substances such as alcohol (88) and 5-HT. The effects of
5-HT were first investigated in neonatal rat preparations by applying
electrical stimulation to the raphe and by bath-applying 5-HT to
the whole preparation; both of these treatments specifically depressed
the XII inspiratory output (304, 298-300).
Applying 5-HT to the XII nucleus, adding several 5-HT agents to the
aCSF, and activating 5-HT biosynthesis all yielded data suggesting that
the depression of the XII inspiratory bursts involved activation of
5-HT2 receptors located presynaptically on the terminal
endings of the XII inspiratory drivers (283,
302-304). In addition to these depressive effects, however, a weak facilitatory effect of 5-HT has also been observed. The
depressive effects of 5-HT on the XII inspiratory discharge were at
first challenged by authors of several reports on medullary slices who
observed only facilitatory effects via postsynaptic 5-HT1A
and 5-HT2 receptors (14, 27,
28, 31, 32, 453). Serotonin was subsequently found to presynaptically inhibit the transmission of glutamatergic excitatory inputs to XII-Mns
(433, 434). Because glutamate mediates the
transmission of the central respiratory drive to XII-Mns, this
finding confirms that 5-HT does in fact depress the XII inspiratory
discharge. The presynaptic modulation exerted by 5-HT is thought to
involve either 5-HT1B receptors (434) or
5-HT2 receptors (283, 293), both
of which exist within the rat XII nucleus (341). Even
5-HT1A receptors are present in this nucleus; their density
is high in the newborn (P0 Data obtained in one in vivo study argue in favor of the existence of a
5-HT inhibitory modulation of the XII inspiratory activity; in
spontaneously breathing anesthetized neonatal rats, activating the 5-HT
biosynthesis pathways by L-tryptophan load depressed the
inspiratory activity of the tongue and induced drastic obstructive
apneas (194). Because obstructive apneas were not obtained
in all the litters studied and because no such depressive effects of
5-HT have been observed in young P15 rats (194) or in
fetuses (86), it seems likely that this effect of 5-HT may be restricted to a narrow critical developmental period just after birth. The tongue inspiratory discharge is known to be depressed during
obstructive apnea (234, 416), but no such
effect of 5-HT has ever been previously reported, and this finding
therefore still requires confirmation. Contrasting results have been
published on adult and neonatal cats (223,
407). The involvement of 5-HT in obstructive apnea is in
agreement, however, with the occurrence of 1) high
5-hydroxyindolacetic acid (5-HIAA) levels during obstructive sleep apnea (71), 2) a dense 5-HT innervation
of the XII nucleus (7, 8, 28,
92, 263, 264, 341),
and 3) the abnormally high level of the 5-HT metabolite
5-HIAA measured in the cerebrospinal fluid of victims of sudden infant
death syndrome (SIDS) (54). The latter report suggests
that an abnormal increase in 5-HT biosynthesis may be responsible for
inducing drastic obstructive apnea just before death. C. Catecholaminergic Modulation
The brain stem contains numerous catecholaminergic neurons
gathered in several interconnected medullary and pontine nuclei. They
constitute a complex network, sending and receiving information to and
from the raphe 5-HT nuclei. In vitro experiments on the neonatal rat
have shown that the pontine catecholaminergic A5 area exerts a
permanent modulatory inhibition of the medullary respiratory rhythm
generator (114-116, 192). This inhibition was first suggested by experiments in which pharmacological and electrical stimulations were applied to A5, which inhibited respiration, and by
others involving pontomedullary transection or A5 electrolytic lesions,
which increased the respiratory frequency. Applying norepinephrine to
either the A5 area alone or the whole pons inhibited the A5 noradrenergic neurons and withdrew the inhibitory effects of the A5
neurons on the medullary respiratory rhythm generator, which in turn
increased the respiratory frequency. Norepinephrine applied to the
medulla mimicked the A5 modulation and depressed the respiratory frequency. The A5 modulatory process involves
In rat fetuses, the A5 inhibitory modulation exerted on the respiratory
rhythm generator already exists by E20 but is not yet functional at E18
(85). In adult animals, because catecholamines may induce
respiratory and cardiovascular changes via several types of receptors
and several types of peripheral and central targets, in vivo studies
have often led to conflicting results (for review, see Ref. 79). In
view of the proximity of catecholaminergic and respiratory nuclei, the
question has been raised as to whether the same neuron might be both
catecholaminergic and respiratory, but this was not found to be the
case (375). The respiratory neurons do, however, possess
adrenergic receptors, and their activity and their excitability are
depressed by catecholamines (60, 79). In addition to their pontomedullary D. Neuropeptides
1. Opioid receptors
Endogenous opioid peptides play an important role in modulating
cardiorespiratory function via at least three classes of receptors, namely, the µ-, 2. Substance P
Substance P (SP) belongs to the tachykinin family and displays a
particularly high affinity for tachykinin NK1
receptor, which is a member of the G protein-linked group of
metabotropic receptors (321). Substance P is found in the
cranial nerves innervating the arterial baroreceptors and
chemoreceptors, located at their endings within the dorsal medulla
(147, 218), the ventrolateral medulla, and
the nucleus ambiguus (196, 248). In the rabbit pup brain stem, considerable activation of the SP gene
occurs at birth (236, 442), and SP applied to
the dorsal part of the medulla increases the tidal volume
(492). In in vitro newborn rat brain stem preparations, SP
added to the aCSF increases the respiratory frequency via the
activation of tachykinin NK1 receptors, although the
possibility that NK3 receptors may be involved cannot be
ruled out (295, 493). The frequency changes clearly show the involvement of the Pre-I neurons of the RVLM (493). When applied to the cervical spinal cord alone, SP
increases the amplitude of the Phr bursts. In human infant victims of
SIDS, high concentrations of SP have been detected in the medulla
(34). In rodent fetuses, no data are yet available on the
respiratory effects of SP. In adult animals, SP has been thought to
mediate the baro- and chemoreceptor inputs to the medulla
(147). The amount of SP released increases during hypoxia
(249) and applying SP antagonist inhibits the increase in
respiratory frequency to hypoxia (492). When tested in
vivo, SP increased both respiratory frequency and tidal volume (for
reviews, see Refs. 35, 59, 80). The fact that SP receptor antagonists
applied to the medulla affect the respiratory frequency suggests that
endogenous SP may exert a facilitatory modulation on the respiratory
rhythm generator (62). However, this was not confirmed in
the neonatal medulla in vitro (295), but this discrepancy
may be due to the occurrence of an intense degradation of endogenous SP
in vitro. The in vivo effects of SP may have resulted from central
mechanisms, since similar respiratory changes to those mentioned above
can be elicited by applying SP to the medulla (63,
492), as well as from peripheral effects, especially at
the level of the carotid body (379). Hypoxia may be
responsible for SP release in the medulla (249), in which case, the high concentrations of SP in the medulla of victims of SIDS
(34) might result from drastic hypoxia before death. Indeed, several substances and factors might affect respiration at
birth, such as prostaglandins (327), massive sensory
stimulation caused by labor and delivery (2), and the
transition to lung gas exchange in the newborn (451).
E18) however, this experimental procedure
elicited no significant respiratory changes, which suggests that the
central chemosensitivity is still immature.
P3), hypoxia only
lengthened the duration of the cycle without inducing apnea
(385). In neonatal rat preparations, the preliminary
excitatory effects of hypoxia are not obvious; an initial increase in
the frequency occurred in ~50% of all the cases studied, but a
decrease in the respiratory frequency and even apneic periods of up to
3 min also sometimes occurred at the beginning of the hypoxia test.
Thereafter, anoxia depressed respiration, although the rhythmicity
persisted under CO2/bicarbonate aCSF but disappeared under
HEPES medium, which suggests that CO2 is an efficient
stimulus for maintaining respiratory activity under O2
depletion (467). Replacing the normal aCSF by aCSF gassed with 95% N2-5% CO2 decreases the respiratory
frequency and silences ~50% of the respiratory cells via a sustained
hyperpolarization and/or a blockade of their synaptic respiratory drive
(25). In neonatal rat brain stem preparations,
theophylline (a presumed respiratory stimulant, the efficiency of which
as a blocker of hypoxic ventilatory depression is under debate)
increases the Phr burst amplitude without affecting the respiratory
frequency and attenuates the respiratory depression induced by hypoxic
aCSF, possibly via the blockade of adenosine receptors
(221). Recent in vivo studies suggested that the
hypoxia-induced depression of breathing is unlikely to originate
only from a decrease of carotid body receptor discharge, or from
depressive central effects, but might involve an active inhibition
originating from the red nucleus (1, 469).
E21,
it has reached the newborn range. In utero, fetal breathing movements
increase in number and amplitude in response to the 5-HT precursor
5-HTP (381, 400, 470).
P7) but rather low (28) and
even null in the young adult (341). The 5-HT presynaptic
modulation of XII-Mns is not present before birth (86)
and may be viewed (as for Phr-Mns, Ref. 84) as a means of
reconfiguring the respiratory network, consisting of gating the central
drive to the respiratory Mns to allow them to become engaged in other
networks such as those responsible for swallowing and suckling
(433).
2-adrenoceptors located in the RVLM, where local
application of norepinephrine depressed the respiratory frequency. This
finding has been confirmed using medullary slices from neonatal rats
(14) and is likely to occur in the neonatal mouse
(180, 206). The inhibition of the respiratory
generator exerted by A5 might also exist in vivo in neonatal rats
(114), but this was not observed in kittens (102, 220). The functional significance of
the A5 modulation is not yet fully understood. A5 is known to integrate
various inputs, such as those conveyed by cardiovascular and
nociceptive afferents. In addition, noradrenergic turnover is
influenced by hypoxia (441) and occurrence of the first
breaths (237). The high levels of catecholamine
degradation products observed in infants suffering from hypoventilation
syndrome reflect an increased catecholamine turnover (37,
176, 452), which might be the cause of the hypoventilation.
2-effects,
catecholamines directly facilitate Phr-Mn firing via activation of
cervical
1-adrenoceptors (116). In the rat
XII-Mns, a moderately dense innervation of the XII nucleus by brain
stem noradrenergic groups including A5 has been reported, where
norepinephrine-containing axon terminals contact XII-Mns
(4-6). The XII nucleus contains both
1-receptors and mRNA
1-receptors
(215, 216, 372). In juvenile and
young adult rats, norepinephrine depolarizes the Mns, increases their
excitability, and alters their pattern of discharge, via
1-receptors located on XII-Mns
(359).
-, and
-opioid receptors, all of which are
blocked by naloxone. At birth, both µ- and
-opioid receptors are
present, but
-opioid receptors are very scarce. The number of
binding sites increases with age, but the developing patterns depend on the nucleus and the type of binding site. The brain stem has turned out
to be a µ-receptor region, although
-opioid receptors are present.
In the XII nucleus, the number of binding sites increased from P1 to
P5, then peaked at P10 (µ-opioid receptors) and again on P21
(
-opioid receptors) and decreased to adult values, which are low but
higher than at birth (487). The authors of in vitro studies performed on brain stem slices and brain stem-spinal cord preparations reported that opioid receptor activation affected the
respiratory frequency but not the amplitude of the XII bursts. Activation of µ-opioid receptors depressed the respiratory frequency, whereas that of
- and
-receptors had no effects on breathing up
to P14 (153). Endogenous opioids have been suspected of
being responsible for SIDS, since elevated plasma opioid levels were found in victims of SIDS (225, 226,
276). In utero, morphine induces a shift from REM to quiet
sleep, and apnea then occurs for ~20 min. Apnea is followed by a
period of hyperpnea, which in turn coincides with a shift from quiet
sleep to REM. The period of hyperpnea can be abolished by naloxone,
which does not alter the morphine-induced apnea (170,
171), and by midcollicular transection, which lengthens
apnea (169). In the adult rat, opioids decrease the
respiratory frequency and tidal volume (231,
316) via µ- and
-opioid receptors, which mediate
decrease in the amplitude and frequency, respectively
(305, 417). Medullary respiratory neurons
possess both µ- and
-opioid receptors, and their respiratory modulated firing is depressed by local application of opioid agents (311) acting on the glutamatergic excitatory inputs they
receive (for review, see Refs. 35, 59, 80). In the isolated respiratory network of newborn rats, the opioid-induced respiratory depression is reversed upon elevation of endogenous cAMP levels (24).
In the piglet, the
- and µ-systems might modulate sleep/wake
states and respiration, respectively, at birth, but this specific
neuromodulation might diminish with age (315,
317, 318, 479).
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VI. IN VITRO APPROACHES AND RESULTS |
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|
|
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The validity of the results gained using in vitro approaches can never be taken for granted, due to the limited O2 diffusion to the central respiratory network and the extremely special experimental conditions used. The decisive question seems to be in this context whether the overall state of an in vitro network is sufficiently normal to justify extrapolating the results obtained to in vivo situations.
A. Hypoxia and the In Vitro Central Respiratory Network
1. Mechanisms of in vitro survival
It was established long ago that neonatal rats can survive
exposure to pure nitrogen (443) and that the fetal blood
O2 level is three to four times lower than that of the
mother's arterial blood (167). At all the ambient
O2 concentrations, the O2 level was higher in
the neonatal than in the adult central nervous system, and a
O2 diffusion gradient was found to exist within the
preparation. Both tissue thickness and age are therefore major
determinants of the O2 level; zero level is reached in
slices thicker than 600 µm in adults and 1,500 µm in neonates.
Aerobic conditions exist in the vicinity of the neonatal VRG, but a
restricted O2 supply is likely to lead to an anoxic core
and a tissue gradient of extracellular pH and K+ in deeper
parts (44, 466, 467). Studies
based on NMR methods have confirmed that the relative patterns of
high-energy phosphate and pH present in in vitro preparations are
very similar to the normal ones (46). High bath glucose
levels are necessary in the aCSF for the anaerobic metabolism to
operate efficiently (26, 489), and although
the glucose transporter mRNA levels are lower in the newborn than in
the adult rat, they are increased by hypoxia in fetal and newborn rats
(490). Blocking the aerobic mechanisms does not seem to
severely perturb the K+ and Ca2+ homeostasis in
the region of the VRG (467). 2. Heterogeneity of neural responses to hypoxia
In adults, anoxia induced various responses, depending on the cell
type and location (for review, see Ref. 162). Reducing the
O2 level hyperpolarized CA1 hippocampal neurons but
depolarized XII neurons more than neocortical neurons. The XII-Mns
may be inherently more vulnerable to anoxia (356a), and this might help to explain their silencing under circumstances leading to obstructive apnea. Anoxia-induced depolarization is common in brain stem
neurons, and the underlying mechanisms of action are not well
understood so far (161, 164). It has been
hypothesized that a massive Ca2+ influx into neurons may be
involved, which may be partly mediated by glutamate (64),
but anoxia-induced damage may occur without any increase in the
intracellular Ca2+ and persists after a glutamate receptor
block (136, 161, 162). Anoxia
increases the intracellular Na+ levels in adult rat central
neurons in vitro (137, 138) and, depending on
its severity and duration, activates mechanisms that can lead either to
profoundly deleterious neuronal changes or to adaptation
(163, 211-213). Under hypoxia, the inherent
cellular properties are better preserved in newborn than in adult cells (159); a short hypoxia induces a 30-mV depolarization and
a large increase in the spontaneous firing frequency of adult
XII-Mns but only a 10-mV depolarization and little effect on the
excitability of neonatal XII-Mns (159,
210). The adult perfused brain stem is less tolerant to
hypoxia than the in vitro neonatal respiratory network
(23, 495), but it has been stated that
"there is a considerable oxygen consumption but no hypoxic or anoxic
core in the isolated perfused brain stem at the level of the
respiratory related neurons" (418). The hypoxic respiratory depression may result from a depression of
cellular metabolism (112, 325) and, in
summary, the in vitro survival of the neonatal respiratory network is
likely to be due to the small size of the brain stem, the superficial
location of the VRG, and the faculty of the newborn rat to reduce its
metabolic rate during O2 deprivation via an increased
glycolytic capacity. It is worth noting that adding norepinephrine and
5-HT precursors to aCSF elicited respiratory changes showing that the
precursors had been taken up and transformed into norepinephrine or
5-HT. These biosynthesis pathways in which O2 serves as
cofactor are therefore likely to be functional in vitro, including even
the 5-HT neurons of the raphe nuclei located deep within the
preparation. The persistence of a rhythmic activity in VRG neurons,
Phr- and XII-Mns, the fact that they show normal resting potential
values, the maintenance of the physiological regulations known to occur in vivo, the persistence of functional biosynthetic pathways, therefore
all argue in favor of the idea that the central respiratory network
continues to function fairly faithfully in vitro. Numerous neurons
within the deep structures of the brain stem might have been affected
by hypoxia, however, and this may indirectly affect the activity of the
respiratory network by changing the background level. The hypoxia
possibly occurring in the in vitro-like adult perfused brain stem
preparation has been less fully documented, and the validity of these
results may require confirmation, although they are completely in
agreement with the neonatal results. B. Respiratory Network and the Respiratory Circuits
This section can be said to be a speculative paragraph written to
counterbalance the conclusion that RVLM respiratory bursting pacemaker
neurons are the kernel of the respiratory network at all developmental
ages. On the basis of lobster network studies (55,
83, 201, 278), we propose the
alternative thought-provoking antithesis that the adult central
respiratory network, rather than being a stereotyped network, might be
taken to be a flexible part of the main medullary reticular network
that can be dynamically reconfigured in vivo in response to signals
arising from several other coexisting pattern-generating circuits. In the stomatogastric nervous system of the lobster, functional
membership of neurons in central networks is not fixed, and neurons can
be switched from one network to another as the result of
neuromodulatory processes. For example, neurons from the pyloric network may fire with the cardiac sac network (201). The
network producing swallowing behavior is constructed de novo from
neurons belonging to other networks (265) and "neurons
operating independently as members of different circuits may be
reconfigured into a new pattern-generating circuit that operates
differently from the original circuits." Numerous examples have been
reported of neurons switching their allegiance from one pattern
generator to another and of networks merging to generate a new pattern
(83). Finally, the various adult lobster networks develop
from a single embryonic network rather than from dismantled redundant
embryonic networks (55). In mammals, the medullary reticular formation contains several
intermingled networks containing pacemaker neurons (78,
151, 445-447, 454). These
networks subserve several functions such as respiration, swallowing,
vomiting, and cardiovascular regulation. As in the lobster networks,
the networks of the mammalian medullary reticular formation share
interneurons and Mns that may switch their allegiance from one pattern
generator to another, i.e., depending on the circumstances, respiratory
network neurons might belong to nonrespiratory networks, and
conversely, neurons from nonrespiratory networks may be involved in the
respiratory network. Indeed, respiratory neurons participate in
swallowing, vomiting, coughing, and sneezing activities
(156, 472), and RVLM Pre-I neurons can
even fire during nonrespiratory activities (499). In
addition, respiratory neuron discharges may undergo a cardiac modulation, and vice versa, i.e., cardiovascular neuronal firing may be
subject to respiratory modulation (172). Consequently, the
respiratory network cannot be viewed as a separate functional entity
but is part of the diffuse reticular formation consisting of several
functional networks that interact permanently via common neural
elements. In this framework, if the inner part of the reticular formation has been affected by hypoxia and total deafferentation, then
these impairments may have repercussions on the activity of the
respiratory network. Indeed, the various respiratory patterns we have described above (the
neonatal pattern in vitro, and the eupneic, apneustic, and polypneic
patterns in vivo) might originate from different neural circuits. The
idea that the circuit generating the respiratory patterns is not a
single predetermined structure may be suggested by the silencing or the
recruitment of respiratory neurons when the CO2 levels and
the sleep-awake states are changing (130, 260, 432). In these cases, it may be only the
number of active respiratory neurons that changes, and not the
intrinsic circuitry. However, it is likely that the intrinsic circuitry
may also change, for example, during sneezing, which "involves a
specific reconfiguration or remodeling of the respiratory network"
(472). This may also occur during a shift from eupneic to
polypneic patterns (185-189, 286-290,
292), since during polypnea 1) the inspiratory
medullary neurons (287, 290) and the
inspiratory Mns (185, 286, 288) acquire a decreasing discharge frequency within the bursts,
2) most of the expiratory medullary neurons
(287, 290) and all the expiratory Mns
(286, 288) become silent, and 3)
the CO2 level is so low that respiration should have
stopped (289, 290). Moreover, when polypnea
is just starting, both eupneic and polypneic patterns coexist for a
while (see Fig. 7 from Ref. 289), as if two pattern-generating
circuits function transiently. Coexisting pattern-generating
circuits can also be observed when attempts are made to generate
apneustic breathing, and short inspirations occur intermingled with
long-lasting apneustic inspirations (see Fig. 3 from Ref. 285).
Several circuits might therefore be responsible for the various
respiratory patterns, and switching from one circuit to another
requires various conditions. To be activated, the apneustic pattern-generating circuit needs anesthesia plus the abolition of
all vagal (bivagotomy) and pneumotaxic inputs. The polypneic pattern-generating circuit requires a very low CO2
level plus activation of thermoregulatory hypothalamic areas. On these lines, the respiratory pattern recorded in vitro in neonatal
and adult rodent preparations might originate from a circuit that is
switched on only under specific conditions, such as moderate hypoxia in
the deeper part of the reticular formation, low temperature, and
near-complete deafferentation from the upper structures, carotid
body, pulmonary stretch receptors, cardiovascular inputs, as well as
muscular and cutaneous afferents. This does not mean that this circuit
is present only under these experimental conditions but that other
circuits might predominate under other conditions. It can therefore be
hypothesized that an embryonic rhythmic circuit develops from E18 to
E20, which is responsible for respiration during delivery and for the
first few days after birth. This circuit is still operational
thereafter, but it may be dominated by the other active circuits until
it is unmasked under special circumstances. Therefore, the in vitro
respiratory pattern circuit we have been dealing with above may simply
correspond to an archaic embryonic circuit on the basis of which the
various respiratory pattern-generating circuits possibly existing
in the adult have developed, as in the lobster stomatogastric network (55). The above comments are of course purely speculative and have been added
to counterbalance the most plausible hypothesis suggested by the latest
experimental data, i.e., that the RVLM respiratory bursting pacemaker
neurons might be the actual kernel of the respiratory network in both
neonate and adult mammals.
| |
VII. SUMMARY |
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|
|
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The aim of this review was to analyze the maturational changes in the mammalian central respiratory network. In vivo studies of the neonatal respiratory act have described maturational changes that are at least partly central in origin, but these studies have shed little light on the central respiratory network. Practically no in vivo electrophysiological studies have been carried out on the neonatal respiratory network. Most of the studies on which we have focused in the present review have therefore been those performed in vitro on isolated respiratory network preparations of the kind developed by Suzue (449) and on brain stem slices and in vitro-like perfused brain stems. These data all argue in favor of the idea that respiratory bursting pacemaker neurons located within the RVLM play a key role in respiratory rhythmogenesis; these neurons may constitute the kernel of the respiratory network at most developmental ages.
The most obvious maturational changes in the medullary network occur between gestational days E18 and E20. At E18, the fetal network is unable to produce a stable central command in terms of its amplitude and frequency. At this early age, the involvement of the RVLM in respiratory rhythmicity seems to be unlikely. No respiratory bursting pacemaker neurons have yet been encountered, and some of the pathways modulating the activity of the respiratory rhythm generator, which exist at birth, are not yet functional. However, endogenous 5-HT exerts a very potent facilitatory modulation on the fetal respiratory rhythm generator, and although this result has not been yet confirmed, 5-HT might be a prerequisite for fetal respiratory rhythm to be expressed at E18.
From E20 up to birth, the respiratory motor output is stabilized. The RVLM contains respiratory pacemaker neurons and seems to be a crucial site as far as respiration is concerned, whereas it has turned out that inhibitory mechanisms within the medullary network are not essential to respiratory rhythmogenesis. Several endogenous substances modulate respiratory activity by acting directly on the RVLM neurons. Endogenous 5-HT still facilitates the respiratory frequency, but the strength of the modulation has decreased in comparison with E18. At birth, SP acquired a facilitatory role, but endogenous catecholamines exert an inhibitory modulation on the respiratory frequency. Both CO2 and pH levels regulate the respiratory activity, probably via a cholinergic relay, and some studies on the central chemosensitivity, for which the ventral surface of the medulla was thought to be responsible, now suggest that deeper structures may be involved.
In adults, inhibitory connections within the medullary network acquire a more important role in respiratory rhythmogenesis, but it is questionable whether they are indispensable for rhythmogenesis in maturing rodents. It seems likely that the adult RVLM continues to be a crucial area, but the existence of adult respiratory bursting pacemaker neurons still requires more convincing confirmation. Most of the modulatory mechanisms reported to occur in neonates probably continue to exist in adults, but the in vivo experimental conditions make it difficult to analyze this point in adults, and therefore, no definite conclusions have yet been reached.
The morphological and electrophysiological data on hypoglossal and Phr-Mn maturation have been reviewed from the fetal age to adulthood. Respiratory Mns undergo cell death only during prenatal life, and although Phr-Mns are not fully mature at E18, they are already able to fire sustained bursts of spikes when depolarized. At birth, the activity of the respiratory Mns is directly affected by several endogenous substances that modulate their responsiveness (catecholamines, SP, and 5-HT).
Special attention has been devoted here to 5-HT, which may on the one hand facilitate respiratory Mn firing via postsynaptic receptors but may, on the other hand, gate the central drive they receive via presynaptic receptors. This may be viewed as a means of reconfiguring the respiratory network so that the respiratory Mns can participate in nonrespiratory activities. Furthermore, 5-HT exerts potent facilitatory effects on both the medullary respiratory rhythm generator and the respiratory Mns before birth. This means that the 5-HT levels at least partly determine the level of activity of the whole respiratory network very early during development, and hence, it can be said that 5-HT may control the maturation of the respiratory network.
The physiological validity of the in vitro results presented here has been extensively discussed, and they seem to be reasonably true, especially in the case of newborn preparations. The RVLM respiratory bursting pacemaker neurons may therefore play a crucial role in respiratory rhythmogenesis in both neonates and adults. The question is discussed however as to whether they are really involved in the eupneic pattern in vivo or whether they may belong to a quiescent archaic network that can be activated only under specific circumstances. Further efforts are now required to convincingly prove whether these neurons exist under in vivo conditions and whether they are actually involved in both the neonate and adult eupneic patterns.
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ACKNOWLEDGMENTS |
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We thank our relatives, friends, and colleagues for their patience and their help during the writing of this review, with a special attention to Marie Gardette (figures) and Jessica Blanc (English revision).
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D. Morin and D. Viala Coordinations of Locomotor and Respiratory Rhythms In Vitro Are Critically Dependent on Hindlimb Sensory Inputs J. Neurosci., June 1, 2002; 22(11): 4756 - 4765. [Abstract] [Full Text] [PDF] |
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D. M Robinson, K. C Peebles, H. Kwok, B. M Adams, L.-L. Clarke, G. A Woollard, and G. D Funk Prenatal nicotine exposure increases apnoea and reduces nicotinic potentiation of hypoglossal inspiratory output in mice J. Physiol., February 1, 2002; 538(3): 957 - 973. [Abstract] [Full Text] [PDF] |
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S. M. Johnson, J. E. R. Wilkerson, D. R. Henderson, M. R. Wenninger, and G. S. Mitchell Serotonin elicits long-lasting enhancement of rhythmic respiratory activity in turtle brain stems in vitro J Appl Physiol, December 1, 2001; 91(6): 2703 - 2712. [Abstract] [Full Text] [PDF] |
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H. Burnet, M. Bevengut, F. Chakri, C. Bou-Flores, P. Coulon, S. Gaytan, R. Pasaro, and G. Hilaire Altered Respiratory Activity and Respiratory Regulations in Adult Monoamine Oxidase A-Deficient Mice J. Neurosci., July 15, 2001; 21(14): 5212 - 5221. [Abstract] [Full Text] [PDF] |
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K. Kobayashi, R. P. Lemke, and J. J. Greer Ultrasound measurements of fetal breathing movements in the rat J Appl Physiol, July 1, 2001; 91(1): 316 - 320. [Abstract] [Full Text] [PDF] |
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R. Kinkead, L. Dupenloup, N. Valois, and R. Gulemetova Stress-induced attenuation of the hypercapnic ventilatory response in awake rats J Appl Physiol, May 1, 2001; 90(5): 1729 - 1735. [Abstract] [Full Text] [PDF] |
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C. Bou-Flores, A.-M. Lajard, R. Monteau, E. De Maeyer, I. Seif, J. Lanoir, and G. Hilaire Abnormal Phrenic Motoneuron Activity and Morphology in Neonatal Monoamine Oxidase A-Deficient Transgenic Mice: Possible Role of a Serotonin Excess J. Neurosci., June 15, 2000; 20(12): 4646 - 4656. [Abstract] [Full Text] [PDF] |
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D. M. Robinson, H. Kwok, B. M. Adams, K. C. Peebles, and G. D. Funk Development of the ventilatory response to hypoxia in Swiss CD-1 mice J Appl Physiol, May 1, 2000; 88(5): 1907 - 1914. [Abstract] [Full Text] [PDF] |
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J.-R. Cazalets, M. Gardette, and G. Hilaire Locomotor Network Maturation Is Transiently Delayed in the MAOA-Deficient Mouse J Neurophysiol, April 1, 2000; 83(4): 2468 - 2470. [Abstract] [Full Text] [PDF] |
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H. Burnet and G. Hilaire Pulmonary stretch receptor discharges and vagal regulation of respiration differ between two mouse strains J. Physiol., September 1, 1999; 519(2): 581 - 590. [Abstract] [Full Text] [PDF] |
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G. B. Miles, M. A. Parkis, J. Lipski, and G. D. Funk Modulation of phrenic motoneuron excitability by ATP: consequences for respiratory-related output in vitro J Appl Physiol, May 1, 2002; 92(5): 1899 - 1910. [Abstract] [Full Text] [PDF] |
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S. DAUGER, F. GUIMIOT, S. RENOLLEAU, B. LEVACHER, B. BODA, C. MAS, V. NEPOTE, M. SIMONNEAU, C. GAULTIER, and J. GALLEGO MASH-1/RET pathway involvement in development of brain stem control of respiratory frequency in newborn mice Physiol Genomics, December 21, 2001; 7(2): 149 - 157. [Abstract] [Full Text] [PDF] |
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