The chemical neuroanatomy of breathing
Introduction
This essay provides an overview of the transmitters and, to some extent, the receptors associated with mammalian respiratory circuits within the context of functionally defined brainstem respiratory “compartments.” Respiratory neurons (i.e. neurons phasically firing in synchrony with the respiratory cycle) are concentrated in three main brainstem areas (Fig. 1): the dorsal respiratory group within the nucleus of the solitary tract, the ventrolateral medulla from the level of the spinal–medullary junction through the level of the facial nucleus (i.e. the ventral respiratory column, VRC), and in the pontine respiratory group within the dorsolateral pons. These aggregates of brainstem respiratory neurons are interconnected, and together with respiratory-related sensory afferents, are collectively responsible for the automatic control of breathing as well as adaptive changes in breathing to homeostatic and environmental challenges.
A variety of additional neuronal groups in the brainstem and forebrain contribute to the innervation of brainstem respiratory compartments. These include serotonergic and catecholaminergic neurons, neurons in the mesencephalic periaqueductal gray (PAG), and forebrain neurons in hypothalamus, amygdala and cortex. PAG neurons directly target respiratory neurons in caudal medulla and also modulate respiration indirectly via relays in dorsolateral and ventrolateral pons (Hayward et al., 2004). Forebrain neurons targeting respiratory circuits are particularly evident in hypothalamus, with modest contributions from amygdala, and from frontal and insular cortices. These additional respiratory-related regions are not discussed separately but are included, where appropriate, in the context of afferents to respiratory neurons or compartments. Serotonergic and catecholamine influences on respiration are additionally discussed elsewhere in this issue, as are the influence of orexinergic hypothalamic neurons and sex hormones.
The present survey is based on data mainly derived from the adult rat, with supplemental observations derived from the mouse, cat, and dog. As with any functional-anatomical system, the neurochemistry of the respiratory network is subject to dramatic developmental changes. This extensive topic is frequently addressed elsewhere in this volume. The neurochemistry of breathing also encompasses the differential expression of specific ion channels, signal transduction pathways, and various transcription factors, as normal components of respiratory circuits and elements modified developmentally, in response to environmental changes, and as mutations in genetic based diseases impacting respiration. These topics have been the target of increasing scrutiny and are addressed by a variety of papers in this volume.
Section snippets
The nucleus of the solitary tract and the dorsal respiratory group
The caudal third of the nucleus of the solitary tract (cNTS; Fig. 1A) is the principal site of termination for sensory afferents conveying respiratory-related information from the lungs and peripheral chemoreceptors. The cNTS is also the site of one of three principal concentrations of brainstem respiratory neurons, the “dorsal respiratory group” (see below).
The portion of the cNTS related to breathing includes the areas alongside and extending caudal to the most posterior limits of the area
The ventral respiratory column; serial respiratory compartments in the medulla
The VRC occupies the ventrolateral medulla along its entire length and is populated by various types of respiratory neurons identified by their activation during the inspiratory or expiratory phases of the respiratory cycle (Fig. 2). Respiratory rhythm generation occurs mainly as a result of circuit interactions in the rostral half of the VRC. Bulbospinal neurons in the caudal half of the VRC transmit this rhythm unchanged but their activity modulates the amplitude of respiratory motor output
Pontine respiratory regions
In a sense, the VRC extends rostrally into the lateral pons as a nearly uninterrupted corridor of neurons interconnected with the VRC (Fig. 1B) (Alheid et al., 2004). As with the medullary VRC, segments of the neuronal populations traversing the pons appear to form functionally distinct groups. Just rostral to the RTN/pFRG, these aggregates include neurons of the ventrolateral pons, and the paratrigeminal area, including the laterally located intertrigeminal area (I5; Fig. 1) that is sandwiched
Conclusions
The CNS network controlling respiration is a complex array of neurons stretching from the cortex to the lower thoracic/upper lumbar spinal cord. Respiratory neurons in the NTS and in a column formed by a series of brainstem compartments in the medulla represent the core structures responsible for the automatic control of breathing.
It is evident that the neurochemistry of respiration has made great strides over the past decade. It is worth noting that the germinal observation of the preferential
Acknowledgements
This work was supported by NIH grants, HL 72415, HL 73474, HL 80208.
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