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Review
. 2017 Jan;67(1):45-62.
doi: 10.1007/s12576-016-0475-y. Epub 2016 Aug 17.

The respiratory control mechanisms in the brainstem and spinal cord: integrative views of the neuroanatomy and neurophysiology

Keiko Ikeda  1 , Kiyoshi Kawakami  2 , Hiroshi Onimaru  3 , Yasumasa Okada  4 , Shigefumi Yokota  5 , Naohiro Koshiya  6 , Yoshitaka Oku  7 , Makito Iizuka  8 , Hidehiko Koizumi  9
Affiliations
Review

The respiratory control mechanisms in the brainstem and spinal cord: integrative views of the neuroanatomy and neurophysiology

Keiko Ikeda et al. J Physiol Sci. 2017 Jan.

Abstract

Respiratory activities are produced by medullary respiratory rhythm generators and are modulated from various sites in the lower brainstem, and which are then output as motor activities through premotor efferent networks in the brainstem and spinal cord. Over the past few decades, new knowledge has been accumulated on the anatomical and physiological mechanisms underlying the generation and regulation of respiratory rhythm. In this review, we focus on the recent findings and attempt to elucidate the anatomical and functional mechanisms underlying respiratory control in the lower brainstem and spinal cord.

Keywords: Medulla; Parafacial respiratory group (pFRG); Pons; Pre-Bötzinger complex (preBötC); Respiratory rhythm; Spinal cord.

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Conflict of interest statement

The authors declare no conflicts of interest in association with this study.

Figures

Fig. 1
Fig. 1
Level of the transverse section used for the optical recordings (e.g., Fig. 2) and Phox2b immunoreactive cells in the most rostral medulla. a Phox2b immunoreactivity (Alexa Fluor 546). An arrow denotes a Phox2b cell cluster in the ventral parafacial region. b A NeuroTrace (435/455 blue fluorescence, Invitrogen) for Nissl staining. c A merged view of a and b. d A ventral view of a brainstem-spinal cord preparation. The preparation was cut at the level of the dotted line. AICA anterior inferior cerebellar artery, FN facial nucleus, pFRG parafacial respiratory group, preBötC pre-Bötzinger complex, VII–XII cranial nerves, C4 the fourth cervical ventral root, D dorsal, M medial. At the level of the most rostral medulla, close to the rostral end of the facial nucleus, Phox2b-ir cells formed one of the highest density clusters in the limited region ventrolateral to the facial nucleus. The cell density of the cluster was high enough to be clearly recognized, even in the Nissl-stained preparations (b)
Fig. 2
Fig. 2
Voltage imaging of the respiratory neuron activity in the ventral medulla of the rostral cut surface. The results are the averages of 40 respiratory cycles triggered by C4 inspiratory activity. a An optical image of the rostral cut surface; its time point is represented by the dotted vertical line on b. b C4 activity and the change in fluorescence at one location (red open circle). The approximate inspiratory phase is indicated by the horizontal blue bar under the C4 trace. c Optical images of respiratory neuron activity. The images are arranged in a time course from left to right and top to bottom, as indicated by the numeric values, where time 0 is a and the subsequent images c correspond to time points represented by the arrows in b. d An image of the cut surface of the rostral medulla at lower magnification. The red square denotes the area of the optical recording. e Nissl staining of the rostral cut surface after the experiment. Note that the photo clearly indicates the facial nucleus (FN) and the ventral cell cluster corresponding to the parafacial respiratory group (pFRG). Note that the optical records show the neuronal activity preceding the inspiratory activity by 500–600 ms in the area ventral to the facial nucleus (i.e., the rostral part of the pFRG). The activity reached its peak immediately before the peak of C4 inspiratory activity and then decreased slightly during the inspiratory phase. After the inspiratory period, the activity continued for 2–3 s during the post-inspiratory phase
Fig. 3
Fig. 3
Expression of enhanced-yellow-fluorescent protein (EYFP) signals driven by the mouse Phox2b enhance/promoter in the brainstem of transgenic Phox2b-EYFP/CreERT2 rats [28] from the rostral to the caudal region. In all of the micrographs, the upper side is the dorsal side. The experimental procedures are described by Ikeda et al. [28]. The experiments were performed in neonatal transgenic rats (P0–03). Su5 supratrigeminal nucleus, mlf medial longitudinal fasciculus, Py pyramidal tract, 5M motor trigeminal nucleus, Rt reticular nucleus, FN facial nucleus, pFRG parafacial respiratory group, 4V ventricle, nTS nucleus of the solitary tract, dnmX dorsal motor nucleus of the vagus nerve, Amb ambiguus nucleus, preBötC pre-Bötzinger complex, IO inferior olive, AP area postrema, 10N nucleus of vagus, 12N hypoglossal nucleus. Scale a–e, 1.0 mm; f 500 µm
Fig. 4
Fig. 4
Localization of the respiratory-related regions in the brainstem (the parafacial respiratory group/retrotrapezoid nucleus [pFRG/RTN], Bötzinger complex [BötC], pre-Bötzinger complex [preBötC] and the high cervical spinal cord respiratory group [HCRG]), projected on schematic illustrations of the brainstem and spinal cord of the neonatal rat. a Ventral view. b Sagittal view. c–e Transverse view. VII facial nucleus, XII 12th cranial nerve, C1 and C4 1st and 4th ventral roots of the cervical spinal cord, respectively, BA basilar artery, VA vertebral artery, VRG ventral respiratory group
Fig. 5
Fig. 5
Localization of anatomically identified putative rhythmogenic neurons in the pre-Bötzinger complex (preBötC). a Line drawings showing the distribution of neurokinin 1 receptor (NK1R)-immunoreactive neurons (green dots), preprotachykinin A (PPTA) mRNA-positive neurons (black dots), and double-labeled neurons (red dots) in the medulla. b, c Confocal images showing the appearance of PPTA mRNA-positive neurons (red) and NK1R-immunoreactive neurons (green) in the preBötC. The asterisks indicate double-labeled neurons. d The preBötC region where retrograde tracer fluorogold (FG) was injected (shaded area). e The distribution of FG-labeled neurons (blue dots), PPTA mRNA-positive neurons (black dots), and PPTA mRNA-positive neurons simultaneously labeled with FG (red dots) in the contralateral medulla. The open arrows in (a) and (e) indicate the preBötC region. f–h PPTA mRNA-positive preBötC neurons with projection to the contralateral preBötC. Confocal images of FG-labeled (f) and PPTA mRNA-positive (g) neurons. The merged image is shown in h. The arrow indicates a double-labeled neuron. 10 dorsal motor nucleus of vagus, 12 hypoglossal nucleus, Amb nucleus ambiguus, ECu external cuneate nucleus, icp inferior cerebellar peduncle, IO inferior olive, MVe medial vestibular nucleus, NTS nucleus of the solitary tract, py pyramidal tract, Sp5 spinal trigeminal nucleus, sp5 spinal trigeminal tract, SpVe spinal vestibular nucleus, st solitary tract
Fig. 6
Fig. 6
Colocalization of neurons and astrocytes in the ventrolateral medulla. Neurons and astrocytes are identified as neuron-specific marker NeuN-positive cells (green) and astrocyte-specific marker S100b-positive cells (red), respectively. a Ventrolateral medullary region. The square indicates the preBötC region, and corresponds to the area in b. b An enlarged image of the preBötC. The square indicates the area in c. c A high-magnification picture showing colocalized cell bodies of neurons and astrocytes. Amb nucleus ambiguus
Fig. 7
Fig. 7
Functional connectomics of the preBötC [36]. Panels corresponding to the present paragraphs: functional localization (pan-slice activity mapping); instantaneous activity (dt = 500 µs) and COA (black ball); Single-breath recruitment chaos of the preBötC population; Inter-preBötC tract’s action potential conduction under CNQX (Glu-blocked); and Glutamatergic premotor relays (Glu-dependent). See the open-access online graphic abstract of the paper for further details: http://www.sciencedirect.com/science/article/pii/S0306452214002085
Fig. 8
Fig. 8
The possible neuronal mechanisms underlying the organizing pattern wherein the inspiratory motor activities in the rostral thoracic segments are larger than those in the caudal thoracic segments. a The pattern is organized at the level of medulla where descending neurons exist. The descending neurons project richly to the motoneurons positioned at more rostral thoracic cord. b An example showing that the pattern is organized at the level of the spinal cord. In this example, the number of inspiratory excitatory interneurons is larger than that in the rostral segments, and these neurons amplify the excitatory inputs to the motoneurons in the rostral segments
Fig. 9
Fig. 9
a Possible neuronal mechanism in which inhibitory spinal interneurons are involved in the rostrocaudal gradient of the inspiratory motor activity. The inspiratory depolarizing optical signals in the motoneuron and interneuron areas of the rostral thoracic segments are larger than those in the caudal thoracic segments (b, e) [101]. Many of the thoracic respiratory interneurons had an axon descending a few segments, which would be inhibitory [97, 100]. Based on these studies, it is possible that the inhibitory synaptic inputs to motoneurons gradually increase to reach the caudal segments (d). In order for the motoneurons to be activated during the inspiratory phase, it is necessary to receive excitatory synaptic inputs (c). Thus, in this model, the combination of inhibitory and excitatory synaptic inputs to motoneurons forms the rostrocaudal gradient of the thoracic inspiratory motor activity
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