Respiratory chemoreceptor activity encoding arterial Pco and Po is a critical determinant of ventilation. Currently, the relative importance of several putative chemoreceptor mechanisms for maintaining eupneic breathing and respiratory homeostasis is debated. Transcriptomic and anatomic evidence suggests that bombesin-related peptide Neuromedin-B () expression identifies chemoreceptor neurons in the retrotrapezoid nucleus (RTN) that mediate the hypercapnic ventilatory response, but functional support is missing. In this study, we generated a transgenic -Cre mouse and used Cre-dependent cell ablation and optogenetics to test the hypothesis that RTN neurons are necessary for the CO-dependent drive to breathe in adult male and female mice. Selective ablation of ∼95% of RTN neurons causes compensated respiratory acidosis because of alveolar hypoventilation, as well as profound breathing instability and respiratory-related sleep disruption. Following RTN lesion, mice were hypoxemic at rest and were prone to severe apneas during hyperoxia, suggesting that oxygen-sensitive mechanisms, presumably the peripheral chemoreceptors, compensate for the loss of RTN neurons. Interestingly, ventilation following RTN -lesion was unresponsive to hypercapnia, but behavioral responses to CO (freezing and avoidance) and the hypoxia ventilatory response were preserved. Neuroanatomical mapping shows that RTN neurons are highly collateralized and innervate the respiratory-related centers in the pons and medulla with a strong ipsilateral preference. Together, this evidence suggests that RTN neurons are dedicated to the respiratory effects of arterial Pco/pH and maintain respiratory homeostasis in intact conditions and suggest that malfunction of these neurons could underlie the etiology of certain forms of sleep-disordered breathing in humans. Respiratory chemoreceptors stimulate neural respiratory motor output to regulate arterial Pco and Po, thereby maintaining optimal gas exchange. Neurons in the retrotrapezoid nucleus (RTN) that express the bombesin-related peptide Neuromedin-B are proposed to be important in this process, but functional evidence has not been established. Here, we developed a transgenic mouse model and demonstrated that RTN neurons are fundamental for respiratory homeostasis and mediate the stimulatory effects of CO on breathing. Our functional and anatomic data indicate that -expressing RTN neurons are an integral component of the neural mechanisms that mediate CO-dependent drive to breathe and maintain alveolar ventilation. This work highlights the importance of the interdependent and dynamic integration of CO- and O-sensing mechanisms in respiratory homeostasis of mammals.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10376939 | PMC |
http://dx.doi.org/10.1523/JNEUROSCI.0386-23.2023 | DOI Listing |
J Neurosci
January 2025
Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908
The homeostatic regulation of pulmonary ventilation, and ultimately arterial PCO, depends on interactions between respiratory chemoreflexes and arousal state. The ventilatory response to CO is triggered by neurons in the retrotrapezoid nucleus (RTN) that function as sensors of central pH, which can be identified in adulthood by the expression of Phox2b and neuromedin B. Here, we examine the dynamic response of genetically defined RTN neurons to hypercapnia and arousal state in freely behaving adult male and female mice using the calcium indicator jGCaMP7 and fiber photometry.
View Article and Find Full Text PDFNeuroSci
September 2024
InAm Neuroscience Research Center, Sanbon Medical Center, College of Medicine, Wonkwang University, 321, Sanbon-ro, Gunpo-si 15865, Republic of Korea; (H.K.); (D.N.).
Exp Neurol
October 2024
Department of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, SP, 05508 Sao Paulo, SP, Brazil. Electronic address:
Parkinson's disease (PD) involves the degeneration of dopaminergic neurons in the substantia nigra (SNpc) and manifests with both classic and non-classic motor symptoms, including respiratory failure. Our study aims to investigate the involvement of the commissural and intermediate nucleus of the solitary tract (cNTS and iNTS) in the attenuated respiratory response to hypoxia in PD. Using a PD rat model induced by bilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum of male Wistar rats, we explored potential alterations in the population of Phox2b neurons or hypoxia-activated neurons in the NTS projecting to the retrotrapezoid nucleus (RTN).
View Article and Find Full Text PDFJ Neurosci
September 2024
Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22903
An interoceptive homeostatic reflex monitors levels of CO/H to maintain blood gas homeostasis and rapidly regulate tissue acid-base balance by driving lung ventilation and CO excretion-this CO-evoked increase in respiration is the hypercapnic ventilatory reflex (HCVR). Retrotrapezoid nucleus (RTN) neurons provide crucial excitatory drive to downstream respiratory rhythm/pattern-generating circuits, and their activity is directly modulated by changes in CO/H RTN neurons express GPR4 and TASK-2, global deletion of which abrogates CO/H activation of RTN neurons and the HCVR. It has not been determined if the intrinsic pH sensitivity of these proton detectors is required for these effects.
View Article and Find Full Text PDFAm J Physiol Lung Cell Mol Physiol
October 2024
Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brazil.
Considering that the retrotrapezoid nucleus/respiratory parafacial region (RTN/pFRG) would be an important center in the central nervous system involved in the maintenance and modulation of respiratory activity, we hypothesized that neurons in this nucleus would also be involved in the postinspiratory (post-I) phase of the respiratory cycle through a connection with the pontine Kölliker-Fuse (KF) region. Here, we performed pharmacogenetic manipulation (AAV-hM3D(Gq)-mCherry or AAV-hM4D(Gi)-mCherry) in VGlut2-cre, Ai6 conscious mice to evaluate breathing parameters through whole body plethysmography under baseline conditions (normoxia: [Formula: see text] = 0.21) or under hypercapnia or hypoxia challenges ([Formula: see text] = 0.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!