Chemosensitivity of Phox2b‐expressing retrotrapezoid neurons is mediated in part by input from 5‐HT neurons

Abstract

Key pointsr Neurons of the retrotrapezoid nucleus (RTN) and medullary serotonin (5-HT) neurons are both candidates for central CO 2 /pH chemoreceptors, but it is not known how interactions between them influence their responses to pH.r We found that RTN neurons in brain slices were stimulated by exogenous 5-HT and by heteroexchange release of endogenous 5-HT, and these responses were blocked by antagonists of 5-HT 7 receptors.r The pH response of RTN neurons in brain slices was markedly reduced by the same antagonists of 5-HT 7 receptors.r Similar results were obtained in dissociated, primary cell cultures prepared from the ventral medulla, where it was also found that the pH response of RTN neurons was blocked by preventing 5-HT synthesis and enhanced by blocking 5-HT reuptake. Exogenous 5-HT did not enable latent intrinsic RTN chemosensitivity.r RTN neurons may play more of a role as relays from other central and peripheral chemoreceptors than as CO 2 sensors.Abstract Phox2b-expressing neurons in the retrotrapezoid nucleus (RTN) and serotonin (5-HT) neurons in the medullary raphe have both been proposed to be central respiratory chemoreceptors. How interactions between these two sets of neurons influence their responses to acidosis is not known. Here we recorded from mouse Phox2b+ RTN neurons in brain slices, and found that their Yuanming Wu, MD, received his MD from Hubei Medical College Xianning Branch, China, and his MS from Tongji Medical University, China. He joined the laboratory of George B Richerson, MD, PhD, in the neurology department at Yale University from 1997 to 2010. He then moved to the University of Iowa in 2010, where he has risen to the rank of Research Scientist. He is highly experienced and skilled at patch clamp recordings from neurons in cell culture and brain slices, and has a deep interest in synaptic transmission, chemoreception, respiratory control and epilepsy. Katherine Proch received her BS in Neuroscience and German in 2008 from Allegheny College, Meadville, PA, where her senior thesis introduced her to CO 2 chemosensation. She continued research in that field as a member of the Medical Scientist Training Program at the University of Iowa, and defended her thesis, Effects of serotonergic input on Phox2b neuron chemosensitivity in the RTN, in March 2018. She is expected to receive her medical degree and PhD in May 2019. * These authors contributed equally. Y. Wu and others J Physiol 597.10response to moderate hypercapnic acidosis (pH 7.4 to ß7.2) was markedly reduced by antagonists of 5-HT 7 receptors. RTN neurons were stimulated in response to heteroexchange release of 5-HT, indicating that RTN neurons are sensitive to endogenous 5-HT. This electrophysiological behaviour was replicated in primary, dissociated cell cultures containing 5-HT and RTN neurons grown together. In addition, pharmacological inhibition of 5-HT synthesis in culture reduced RTN neuron chemosensitivity, and blocking 5-HT reuptake enhanced chemosensitivity. The effect of 5-HT on RTN neuron chemosensitivity was ...

Astrocytes modulate baroreceptor reflex sensitivity at the level of the nucleus of the solitary tract

“…Additionally, repeated activation of chemosensory inputs has been shown to chronically inhibit the baroreflex and is thought to contribute to the pathology of conditions such as sleep apnoea (see Mifflin et al, 2015). Activation of chemosensory inputs increases extracellular 5-HT concentration within the NTS via vagal/hypoglossal afferent release, and also by inputs from central chemosensory nuclei (Kellett et al, 2005; Wu et al, 2019). This would have the effect of amplifying the activation of astrocytes and further decreasing baroreflex sensitivity.…”

Your input is a breath of fresh air! A chemosensory microcircuit of medullary raphe and RTN neurons

“…demonstrate that the chemosensitive response of juvenile to young adult RTN neurons is largely dependent on serotonergic input from the medullary raphe (Wu et al . ). Furthermore, they were able to recapitulate the in vivo connectivity of the raphe and RTN (Mulkey et al .…”

“…This provides a novel reduced model for studying this important microcircuit without confounding afferents from other regions; following antagonism of serotonergic signalling the residual response to hypercapnic acidosis of RTN neurons in culture was considerably lower than that of RTN neurons in the more intact circuitry of brain slices (Wu et al . ).…”

“…Following antagonism of both 5‐HT 2 and 5‐HT 7 receptors at room temperature, and 5‐HT 7 at a more physiologically relevant temperature, there was a residual response to hypercapnic acidosis in RTN neurons in cultures of 20% and 17%, respectively (Wu et al . ). As these antagonists were not able to fully prevent the response of RTN neurons to exogenously applied 5‐HT, it may be that the remaining response to hypercapnic acidosis comes from other serotonergic pathways that do not involve these 5‐HT receptor subtypes.…”

“…Given the response of serotonergic neurons to hypercapnic acidosis and their influence on RTN neurons (Wu et al . ), it is not surprising that loss of serotonergic neurons leads to a 50% reduction in the HCVR of adult mice (Hodges et al . ).…”