Medullary serotonin neurons and central CO2 chemoreception

doi:10.1016/j.resp.2009.04.014

Respiratory Physiology & Neurobiology

Volume 168, Issues 1–2, 31 August 2009, Pages 49-58

https://doi.org/10.1016/j.resp.2009.04.014 Get rights and content

Abstract

Serotonergic (5-HT) neurons are putative central respiratory chemoreceptors, aiding in the brain's ability to detect arterial changes in $P_{C O_{2}}$ and implement appropriate ventilatory responses to maintain blood homeostasis. These neurons are in close proximity to large medullary arteries and are intrinsically chemosensitive in vitro, characteristics expected for chemoreceptors. 5-HT neurons of the medullary raphé are stimulated by hypercapnia in vivo, and their disruption results in a blunted hypercapnic ventilatory response. More recently, data collected from transgenic and knockout mice have provided further insight into the role of 5-HT in chemosensitivity. This review summarizes current evidence in support of the hypothesis that 5-HT neurons are central chemoreceptors, and addresses arguments made against this role. We also briefly explore the relationship between the medullary raphé and another chemoreceptive site, the retrotrapezoid nucleus, and discuss how they may interact during hypercapnia to produce a robust ventilatory response.

Introduction

It has been several years since a comprehensive review on the role of serotonin (5-hydroxytryptamine, 5-HT) neurons in central chemoreception has been published (Richerson, 2004, Richerson et al., 2005). In that period, a number of studies have been carried out that contribute to the body of evidence supporting the hypothesis that 5-HT neurons are central respiratory chemoreceptors. Novel techniques have recently been employed, including the use of transgenic mouse models to study the relative importance of 5-HT neurons in the hypercapnic ventilatory response (HCVR). These data are consistent with the hypothesis that there are multiple sites that contain central chemoreceptors, and the set that is dominant may differ depending on the specific conditions. In addition, new evidence points to an important interaction between the medullary raphé and another putative chemoreceptor region, the retrotrapezoid nucleus (RTN). The current review aims to couple recent data with past results in an effort to synthesize the substantial and compelling evidence that 5-HT neurons are central respiratory chemoreceptors. We also discuss and dispute two arguments made recently that challenge the role of 5-HT neurons as central respiratory chemoreceptors.

Section snippets

Evidence that serotonergic neurons are respiratory chemosensors

There is a subset of 5-HT neurons located in the rostral ventrolateral medulla (VLM) in the region classically defined as the rostral chemosensitive zone (Mitchell et al., 1963). 5-HT neurons are also located in the caudal chemosensitive zone in the caudal VLM (Loeschcke, 1982). However, the majority of 5-HT neurons on the ventral surface are found in the midline—a region that was not examined in early in vivo experiments localizing the central chemoreceptors because of the risk of bleeding

Arguments against a role of 5-HT neurons as chemoreceptors

Although there is strong evidence for a role of 5-HT neurons in central respiratory chemoreception, this hypothesis has recently been challenged. Here we evaluate the two main lines of evidence that have been cited as support for the conclusion that 5-HT neurons are not chemoreceptors, and discuss their validity.

Evidence for other central chemoreceptors

There is compelling evidence that there are additional central chemoreceptors located in other brainstem nuclei, including the RTN, locus coeruleus, nucleus tractus solitarius (NTS), lateral hypothalamus and cerebellum. The idea of a chemoreceptor system with more than one site is supported by data that has been discussed in several recent reviews (Nattie, 1998, Nattie, 1999, Feldman et al., 2003, Nattie and Li, 2008).

The RTN has long been recognized as being important in respiratory control (

Relationship between the RTN and medullary raphé

As discussed above, evidence for widespread distribution of chemosensitivity lends support to the hypothesis that central chemoreception is the result of interaction between many sites, with some more dominant under certain conditions (e.g., arousal state, gender, pathology). There is good evidence in favour of both the RTN and 5-HT neurons being chemoreceptors. Comparison of this evidence (Table 1) reveals many similarities, and some differences.

While it is likely that both nuclei, along with

Conclusions

In evaluating the existing data, we find considerable support of the hypothesis that 5-HT neurons are central respiratory chemoreceptors. Novel genetic methods have made a large contribution to this conclusion and lend further support to the concept that there are gender differences in the role of 5-HT and CO₂ sensitivity. Additionally, increasing evidence points to a functional interaction between the RTN and raphé 5-HT neurons, supporting the growing theory that RTN neurons act to integrate

Acknowledgements

Supported by the NICHD, the VAMC, and the Bumpus Foundation.

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Citation Excerpt :
Indeed, one problem encountered by this field of research is the plethora of acid-responsive proteins and neurons and the difficulty to prove or disprove the contribution of such pH sensitivity to the HCVR. Countless neurons besides the locus coeruleus and orexin neurons (solitary tract nucleus, retrotrapezoid nucleus, preBötzinger complex) respond to acid changes, typically substantial (0.1 to 0.5 pH) and in vitro (acute slices or cell cultures) (Corcoran et al., 2009; Erlichman et al., 2009; Guyenet et al., 2019; Mulkey et al., 2004; Pineda and Aghajanian, 1997). There is no disputing that the HCVR is altered when the regions containing such neurons are artificially acidified or when these neurons or regions are ablated, inhibited or activated by a genetically encoded actuator (Gargaglioni et al., 2010; Hodges and Richerson, 2010; Liu et al., 2021; Nattie and Li, 2012).
The rostral half of the ventrolateral medulla (RVLM) and adjacent ventrolateral retropontine region (henceforth RVLMRP) have been divided into various sectors by neuroscientists interested in breathing or autonomic regulations. The RVLMRP regulates respiration, glycemia, vigilance and inflammation, in addition to blood pressure. It contains interoceptors that respond to acidification, hypoxia and intracranial pressure and its rostral end contains the retrotrapezoid nucleus (RTN) which is the main central respiratory chemoreceptor. Acid detection by the RTN is an intrinsic property of the principal neurons that is enhanced by paracrine influences from surrounding astrocytes and CO₂-dependent vascular constriction. RTN mediates the hypercapnic ventilatory response via complex projections to the respiratory pattern generator (CPG). The RVLM contributes to autonomic response patterns via differential recruitment of several subtypes of adrenergic (C1) and non-adrenergic neurons that directly innervate sympathetic and parasympathetic preganglionic neurons. The RVLM also innervates many brainstem and hypothalamic nuclei that contribute, albeit less directly, to autonomic responses. All lower brainstem noradrenergic clusters including the locus coeruleus are among these targets.
Sympathetic tone to the circulatory system is regulated by subsets of presympathetic RVLM neurons whose activity is continuously restrained by the baroreceptors and modulated by the respiratory CPG. The inhibitory input from baroreceptors and the excitatory input from the respiratory CPG originate from neurons located in or close to the rhythm generating region of the respiratory CPG (preBötzinger complex).

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Frontiers reviewMedullary serotonin neurons and central CO2 chemoreception

Abstract

Introduction

Section snippets

Evidence that serotonergic neurons are respiratory chemosensors

Arguments against a role of 5-HT neurons as chemoreceptors

Evidence for other central chemoreceptors

Relationship between the RTN and medullary raphé

Conclusions

Acknowledgements

Respir. Physiol. Neurobiol.

Neurosci. Lett.

Respir. Physiol.

Respir. Physiol. Neurobiol.

Respir. Physiol.

Sleep Med.

Respir. Physiol.

Neuron

Eur. J. Pharmacol.

Respir. Physiol. Neurobiol.

Respir. Physiol. Neurobiol.

Neurosci. Lett.

Mol. Cell Neurosci.

Am. J. Med.

J. Physiol. (Paris)

Respir. Physiol. Neurobiol.

Respir. Physiol. Neurobiol.

Eur. J. Pharmacol.

Neurosci. Lett.

Eur. J. Pharmacol.

Brain Res.

Respir. Physiol.

Prog. Neurobiol.

Am. J. Pathol.

Respir. Physiol. Neurobiol.

Respir. Physiol. Neurobiol.

J. Biol. Chem.

Respir. Physiol.

Raphé neurons stimulate respiratory circuit activity by endogenously released serotonin and substance P which are critical for respiratory rhythm generation

Soc. Neurosci. Abstr.

Evidence for central chemoreception in the midline raphé

J. Appl. Physiol.

Chemosensitive serotonergic neurons are intimately associated with large arteries of the ventral medulla

Nat. Neurosci.

Serotonergic modulation of inspiratory hypoglossal motoneurons in decerebrate dogs

J. Neurophysiol.

Deficiency in hypercapnia-induced arousal in mice with genetic deletion of 5-HT neurons

Soc. Neurosci. Abstr.

Contribution of chemosensitive serotonergic neurons to interactions between the sleep-wake cycle and respiratory control

Development of chemosensitivity in neurons from the nucleus tractus solitarii (NTS) of neonatal rats

Respir. Physiol. Neurobiol.

RTN TRH causes prolonged respiratory stimulation

J. Appl. Physiol.

TRH microdialysis into the RTN of the conscious rat increases breathing, metabolism, and temperature

J. Appl. Physiol.

Destruction of serotonergic neurons in the neonatal rat brainstem decreases breathing and exacerbates apnea-induced bradycardia: evidence for a role for 5-HT signalling in Sudden Infant Death Syndrome (SIDS)

Soc. Neurosci. Abstr.

Nucleus raphé obscurus modulates CO2-drive to breathing

Postnatal developmental changes in CO2 sensitivity in rats

J. Appl. Physiol.

Raphé magnus nucleus is involved in ventilatory but not hypothermic response to CO2

J. Appl. Physiol.

Focal CO2 dialysis in raphé obscurus does not stimulate ventilation but enhances the response to focal CO2 dialysis in the retrotrapezoid nucleus

J. Appl. Physiol.

Lmx1b is essential for the development of serotonergic neurons

Nat. Neurosci.

Breathing: rhythmicity, plasticity, chemosensitivity

Ann. Rev. Neurosci.

Effects on breathing of ventrolateral medullary cooling in awake goats

J. Appl. Physiol.

Apneic oxygenation in man

Anesthesiology

Modifications of the serotonergic system in mice lacking serotonin transporters: an in vivo electrophysiological study

J. Pharm. Exp. Ther.

Retrotrapezoid nucleus: a litmus test for the identification of central chemoreceptors

Exp. Physiol.

Retrotrapezoid nucleus and central chemoreception

J. Physiol.

The 2008 Carl Ludwig Lecture: retrotrapezoid nucleus, CO2 homeostasis and breathing automaticity

J. Appl. Physiol.

Frontiers review
Medullary serotonin neurons and central CO₂ chemoreception

Nucleus raphé obscurus modulates CO₂-drive to breathing

Postnatal developmental changes in CO₂ sensitivity in rats

Raphé magnus nucleus is involved in ventilatory but not hypothermic response to CO₂

Focal CO₂ dialysis in raphé obscurus does not stimulate ventilation but enhances the response to focal CO₂ dialysis in the retrotrapezoid nucleus

The 2008 Carl Ludwig Lecture: retrotrapezoid nucleus, CO₂ homeostasis and breathing automaticity