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Control of Breathing Activity in the Fetus and Newborn

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Abstract

Breathing movements have been demonstrated in the fetuses of every mammalian species investigated and are a critical component of normal fetal development. The classic sheep preparations instrumented for chronic fetal monitoring determined that fetal breathing movements (FBMs) occur in aggregates interspersed with long periods of quiescence that are strongly associated with neurophysiological state. The fetal sheep model also provided data regarding the neurochemical modulation of behavioral state and FBMs under a variety of in utero conditions. Subsequently, in vitro rodent models have been developed to advance our understanding of cellular, synaptic, network, and more detailed neuropharmacological aspects of perinatal respiratory neural control. This includes the ontogeny of the inspiratory rhythm generating center, the preBötzinger complex (preBötC), and the anatomical and functional development of phrenic motoneurons (PMNs) and diaphragm during the perinatal period. A variety of newborn animal models and studies of human infants have provided insights into age‐dependent changes in state‐dependent respiratory control, responses to hypoxia/hypercapnia and respiratory pathologies. © 2012 American Physiological Society. Compr Physiol 2:1873‐1888, 2012.

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Figure 1. Figure 1.

Direct recording from a chronically prepared near‐term fetal lamb showing diaphragmatic activity. Fetal breathing movements (FBMs) occur largely during rapid eye movement (REM) sleep, recognized by low‐voltage ECoG: rapid activity of lateral rectus (eye electromyogram [EMG]) and absence of nuchal muscle tone (neck EMG). Non‐REM sleep is primarily recognized by high‐voltage slow ECoG: slow or absent eye movements and variable nuchal tone. Adapted, with permission, from ().

Figure 2. Figure 2.

Mean incidence of FBMs (min/h) during a 2‐h control period, a 24‐h period of hypoxia or normoxia (shown by bar), and a 2‐h recovery period. Values are means +/−SE. *significantly different from control (P < 0.05). Adapted, with permission, from ().

Figure 3. Figure 3.

In vitro and in vivo recordings of fetal respiratory activity. (A) Rectified and integrated suction electrode recordings of C4 ventral root activity from prenatal brainstem‐spinal cord preparations. (B) Rectified and integrated suction electrode recordings made from the preBötC (PBC) and XII motoneuron pool of prenatal rat medullary slice preparations. Rhythmic respiratory discharge commenced at E17 and the frequency and amplitude of inspiratory bursting increased in an age‐dependent manner in both types of in vitro preparations. (C) Combined calcium imaging and electrophysiological recording of respiratory rhythmic activity in E15 mouse medullary slice; fluorescence to initial fluorescence (ΔF/F), preBötzinger complex (preBötC). (D) Graph depicting the age‐dependent increase in FBMs from E16 to E20. FBMs occurred as isolated single movements or as episodes of clustered movements lasting 40 to 180 s. Abbreviations: H, heart; D, diaphragm; S, stomach; SC, spinal cord. Adapted, with permission, from ().

Figure 4. Figure 4.

Anatomical identification of the preBötC. (A) Illustration in sagittal view of the primary structures in the ventrolateral medulla along the rostral‐caudal (R‐C) axis (left). Immunolabeling for NK1R (green) in E17 and E16 sagittal section of the rat ventrolateral medulla (middle and right). The dotted circle demarcates the approximate area of the preBötC (calibration bar = 100 μm). (B) Immunolabeling for NK1R (red) and Islet1,2 (green, motoneuronal population marker) in E15 mouse sagittal (left) and transversal sections of the ventrolateral medulla (middle and right). At E15, NK1R is significantly expressed in the preBötC located ventral to the nucleus ambiguus (NA), as well as in other respiration‐related regions such as the retrotrapezoid nucleus (RTN)/parafacial respiratory group (pFRG). Right shows, at a higher magnification, the area highlighted with the white rectangle in the middle. White arrowheads indicate the localization of the preBötC. Dotted white lines indicate the limits of the preparations. Abbreviations: VII, facial nucleus; NAc, nucleus ambiguus, pars compacta; NAsc, nucleus ambiguus, semicompact BötC, Bötzinger complex; preBötC, preBötzinger complex; rVRG, rostral ventral respiratory group; LRN, lateral reticular nucleus; XII, hypoglossal motor nucleus. Adapted, with permission, from ().

Figure 5. Figure 5.

Age‐dependent changes in the effects of chloride‐mediated conductances. (A) Rectified and integrated suction electrode recordings of XII nerve roots of rat brainstem‐spinal cord preparations during the perinatal period. Muscimol (a GABAA receptor agonist) induced an increase, no significant change, and decrease of respiratory frequency at ages E17, E18, and E20, respectively. (B) Population data for changes in respiratory frequency relative to control of brainstem‐spinal cord preparations in response to bath application of muscimol. The transition from an excitatory to inhibitory action occurred at approximately E19. Adapted, with permission, from ().

Figure 6. Figure 6.

Developmental changes in PMN properties pre‐ and postinception of FBMs. (A) Typical action potentials recorded from E16, E18, and P0 PMNs. From E16 to P0, the action potential became shorter in duration and larger in amplitude. A medium‐duration afterdepolarization (ADP) and a fast afterhyperpolarization (AHP) are present in P0 PMNs. (B) PMN firing properties. Left panel shows examples of repetitive firing patterns generated in E16, E18, and P0 PMNs. Right panel shows representative current frequency plot for PMNs at various ages studied. With increasing age, there are increases in the amount of current necessary to initiate firing, the maximal attainable firing frequencies, and the slope of the current‐frequency relationships; lowest stimulation current able to evoke repetitive firing threshold (I thr)] Adapted, with permission, from ().

Figure 7. Figure 7.

Migration of phrenic axons and muscle precursors to the primordial diaphragm. (A) Schematic of early phrenic nerve‐diaphragm development in an embryonic rat. Phrenic nerve exits cervical roots and follows a track of cells along the medial aspect of the body wall to innervate pleuroperitoneal folds (PPFs). (B) Growth‐associated protein (GAP‐43) immunolabeling of a transverse section of an E13 fetal rat illustrates the migratory path of phrenic axons (Ph) beyond brachial plexus toward PPF. CV, cardinal vein; Br, brachial axons; DRG, dorsal root ganglion; FL, forelimb. (C) Leading phrenic axons have just separated from the brachial plexus and are located at ventral end of a well‐defined track (arrow) of p75 receptor‐expressing tissue, situated along the migratory path toward the PPF (*). (D) Transverse section from an E13.5 rat cut at the level of the midcervical spinal cord and stained with H&E. The area within the box contains the developing lung tissue and the bilateral PPFs (*). (E) Photomicrograph from an E13.5 rat embryo immunolabeled with an antibody to MyoD to delineate muscle precursors concentrated within the PPFs. (F) Left PPF immunolabeled for Pax3/7, which labels the nerve (arrow) and muscle precursors that have reached the PPF. SC, spinal cord; Lu, lung; H, heart. Scale bars = 100 μm. Adapted, with permission, from ().

Figure 8. Figure 8.

Correlation between the extent of phrenic nerve intramuscular branching and myotube formation. Whole mounts of diaphragms isolated from 4 fetal rats aged E14.5, E15.5, E16.5, and E17.5 illustrating the developing intramuscular branching of phrenic nerve and diaphragmatic myotube formation (both axons and myotubes are visualized via immunolabeling for polysialylated neural cell adhesion molecule). Note that primary myotube formation (mediolateral running striations) are restricted to regions within the vicinity of intradiaphragmatic phrenic nerve branches (right sternal branch indicated by arrows). E, esophagus; VC, vena cava; A, aorta. Scale bars = 500 μm. Adapted, with permission, from ().

Figure 9. Figure 9.

Congenital diaphragmatic hernia (CDH) is characterized by defects in the dorsolateral region of the diaphragm and subsequent invasion of abdominal contents into the thoracic cavity. (A) Drawing adapted, with permission, from (). (B) Representative example of the most common type of CDH‐related defect of the diaphragm, with the left dorsolateral regions missing from a nitrofen‐treated E17 rat. Muscle fibers and nerve immunolabeled with MyoD and GAP43, respectively. Adapted, with permission, from ().

Figure 10. Figure 10.

Change in perinatal rat diaphragm muscle fiber contractile properties. (A) Schematic of in vitro phrenic nerve‐diaphragm preparation used to record end‐plate potentials (EPPs) from E18 and P1 muscle fibers. (B) The ability to maintain neuromuscular transmission at increased frequency of nerve firing improves markedly prior to birth. Adapted, with permission, from ().

Figure 11. Figure 11.

Time line illustrating key events in the development of respiratory neuronal activity in fetal rats. Adapted, with permission, from ().

Figure 12. Figure 12.

Central apnea, as indicated by lack of breathing movements and air flow, quickly results in marked drops in oxygen saturation and blood pressure. Adapted, with permission, from ().



Figure 1.

Direct recording from a chronically prepared near‐term fetal lamb showing diaphragmatic activity. Fetal breathing movements (FBMs) occur largely during rapid eye movement (REM) sleep, recognized by low‐voltage ECoG: rapid activity of lateral rectus (eye electromyogram [EMG]) and absence of nuchal muscle tone (neck EMG). Non‐REM sleep is primarily recognized by high‐voltage slow ECoG: slow or absent eye movements and variable nuchal tone. Adapted, with permission, from ().



Figure 2.

Mean incidence of FBMs (min/h) during a 2‐h control period, a 24‐h period of hypoxia or normoxia (shown by bar), and a 2‐h recovery period. Values are means +/−SE. *significantly different from control (P < 0.05). Adapted, with permission, from ().



Figure 3.

In vitro and in vivo recordings of fetal respiratory activity. (A) Rectified and integrated suction electrode recordings of C4 ventral root activity from prenatal brainstem‐spinal cord preparations. (B) Rectified and integrated suction electrode recordings made from the preBötC (PBC) and XII motoneuron pool of prenatal rat medullary slice preparations. Rhythmic respiratory discharge commenced at E17 and the frequency and amplitude of inspiratory bursting increased in an age‐dependent manner in both types of in vitro preparations. (C) Combined calcium imaging and electrophysiological recording of respiratory rhythmic activity in E15 mouse medullary slice; fluorescence to initial fluorescence (ΔF/F), preBötzinger complex (preBötC). (D) Graph depicting the age‐dependent increase in FBMs from E16 to E20. FBMs occurred as isolated single movements or as episodes of clustered movements lasting 40 to 180 s. Abbreviations: H, heart; D, diaphragm; S, stomach; SC, spinal cord. Adapted, with permission, from ().



Figure 4.

Anatomical identification of the preBötC. (A) Illustration in sagittal view of the primary structures in the ventrolateral medulla along the rostral‐caudal (R‐C) axis (left). Immunolabeling for NK1R (green) in E17 and E16 sagittal section of the rat ventrolateral medulla (middle and right). The dotted circle demarcates the approximate area of the preBötC (calibration bar = 100 μm). (B) Immunolabeling for NK1R (red) and Islet1,2 (green, motoneuronal population marker) in E15 mouse sagittal (left) and transversal sections of the ventrolateral medulla (middle and right). At E15, NK1R is significantly expressed in the preBötC located ventral to the nucleus ambiguus (NA), as well as in other respiration‐related regions such as the retrotrapezoid nucleus (RTN)/parafacial respiratory group (pFRG). Right shows, at a higher magnification, the area highlighted with the white rectangle in the middle. White arrowheads indicate the localization of the preBötC. Dotted white lines indicate the limits of the preparations. Abbreviations: VII, facial nucleus; NAc, nucleus ambiguus, pars compacta; NAsc, nucleus ambiguus, semicompact BötC, Bötzinger complex; preBötC, preBötzinger complex; rVRG, rostral ventral respiratory group; LRN, lateral reticular nucleus; XII, hypoglossal motor nucleus. Adapted, with permission, from ().



Figure 5.

Age‐dependent changes in the effects of chloride‐mediated conductances. (A) Rectified and integrated suction electrode recordings of XII nerve roots of rat brainstem‐spinal cord preparations during the perinatal period. Muscimol (a GABAA receptor agonist) induced an increase, no significant change, and decrease of respiratory frequency at ages E17, E18, and E20, respectively. (B) Population data for changes in respiratory frequency relative to control of brainstem‐spinal cord preparations in response to bath application of muscimol. The transition from an excitatory to inhibitory action occurred at approximately E19. Adapted, with permission, from ().



Figure 6.

Developmental changes in PMN properties pre‐ and postinception of FBMs. (A) Typical action potentials recorded from E16, E18, and P0 PMNs. From E16 to P0, the action potential became shorter in duration and larger in amplitude. A medium‐duration afterdepolarization (ADP) and a fast afterhyperpolarization (AHP) are present in P0 PMNs. (B) PMN firing properties. Left panel shows examples of repetitive firing patterns generated in E16, E18, and P0 PMNs. Right panel shows representative current frequency plot for PMNs at various ages studied. With increasing age, there are increases in the amount of current necessary to initiate firing, the maximal attainable firing frequencies, and the slope of the current‐frequency relationships; lowest stimulation current able to evoke repetitive firing threshold (I thr)] Adapted, with permission, from ().



Figure 7.

Migration of phrenic axons and muscle precursors to the primordial diaphragm. (A) Schematic of early phrenic nerve‐diaphragm development in an embryonic rat. Phrenic nerve exits cervical roots and follows a track of cells along the medial aspect of the body wall to innervate pleuroperitoneal folds (PPFs). (B) Growth‐associated protein (GAP‐43) immunolabeling of a transverse section of an E13 fetal rat illustrates the migratory path of phrenic axons (Ph) beyond brachial plexus toward PPF. CV, cardinal vein; Br, brachial axons; DRG, dorsal root ganglion; FL, forelimb. (C) Leading phrenic axons have just separated from the brachial plexus and are located at ventral end of a well‐defined track (arrow) of p75 receptor‐expressing tissue, situated along the migratory path toward the PPF (*). (D) Transverse section from an E13.5 rat cut at the level of the midcervical spinal cord and stained with H&E. The area within the box contains the developing lung tissue and the bilateral PPFs (*). (E) Photomicrograph from an E13.5 rat embryo immunolabeled with an antibody to MyoD to delineate muscle precursors concentrated within the PPFs. (F) Left PPF immunolabeled for Pax3/7, which labels the nerve (arrow) and muscle precursors that have reached the PPF. SC, spinal cord; Lu, lung; H, heart. Scale bars = 100 μm. Adapted, with permission, from ().



Figure 8.

Correlation between the extent of phrenic nerve intramuscular branching and myotube formation. Whole mounts of diaphragms isolated from 4 fetal rats aged E14.5, E15.5, E16.5, and E17.5 illustrating the developing intramuscular branching of phrenic nerve and diaphragmatic myotube formation (both axons and myotubes are visualized via immunolabeling for polysialylated neural cell adhesion molecule). Note that primary myotube formation (mediolateral running striations) are restricted to regions within the vicinity of intradiaphragmatic phrenic nerve branches (right sternal branch indicated by arrows). E, esophagus; VC, vena cava; A, aorta. Scale bars = 500 μm. Adapted, with permission, from ().



Figure 9.

Congenital diaphragmatic hernia (CDH) is characterized by defects in the dorsolateral region of the diaphragm and subsequent invasion of abdominal contents into the thoracic cavity. (A) Drawing adapted, with permission, from (). (B) Representative example of the most common type of CDH‐related defect of the diaphragm, with the left dorsolateral regions missing from a nitrofen‐treated E17 rat. Muscle fibers and nerve immunolabeled with MyoD and GAP43, respectively. Adapted, with permission, from ().



Figure 10.

Change in perinatal rat diaphragm muscle fiber contractile properties. (A) Schematic of in vitro phrenic nerve‐diaphragm preparation used to record end‐plate potentials (EPPs) from E18 and P1 muscle fibers. (B) The ability to maintain neuromuscular transmission at increased frequency of nerve firing improves markedly prior to birth. Adapted, with permission, from ().



Figure 11.

Time line illustrating key events in the development of respiratory neuronal activity in fetal rats. Adapted, with permission, from ().



Figure 12.

Central apnea, as indicated by lack of breathing movements and air flow, quickly results in marked drops in oxygen saturation and blood pressure. Adapted, with permission, from ().

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John J. Greer. Control of Breathing Activity in the Fetus and Newborn. Compr Physiol 2015, 2: 1873-1888. doi: 10.1002/cphy.c110006