Serotonergic Neurons Activate Chemosensitive Retrotrapezoid Nucleus Neurons by a pH-Independent Mechanism

Abstract

Serotonin activates respiration and enhances the stimulatory effect of CO 2 on breathing. The present study tests whether the mechanism involves the retrotrapezoid nucleus (RTN), a group of medullary glutamatergic neurons activated by extracellular brain pH and presumed to regulate breathing. We show that the RTN is innervated by both medullary and pontine raphe and receives inputs from thyrotropin-releasing hormone (TRH) and substance P-expressing neurons. Coexistence of serotonin and substance P in terminals within RTN confirmed that lower medullary serotonergic neurons innervate RTN. In vivo, unilateral injection of serotonin into RTN stimulated inspiratory motor activity, and pH-sensitive RTN neurons were activated by iontophoretic application of serotonin or substance P. In brain slices, pH-sensitive RTN neurons were activated by serotonin, substance P, and TRH. The effect of serotonin in slices was ketanserin sensitive and persisted in the presence of glutamate, GABA, glycine, and purinergic ionotropic receptor antagonists. Serotonin and pH had approximately additive effects on the discharge rate of RTN neurons, both in slices and in vivo. In slices, serotonin produced an inward current with little effect on conductance and had no effect on the pH-induced current. We conclude that (1) RTN receives input from multiple raphe nuclei, (2) serotonin, substance P, and TRH activate RTN chemoreceptors, and (3) excitatory effects of serotonin and pH are mediated by distinct ionic conductances. Thus, RTN neurons presumably contribute to the respiratory stimulation caused by serotonergic neurons, but serotonin seems without effect on the cellular mechanism by which RTN neurons detect pH.

Pulmonary Neuroendocrine Cell-Secreted Factors May Alter Fetal Lung Liquid Clearance

“…Others have reported that serotonin and GRP from the same manufacturers are biologically active when used in other unrelated models (32,33). Our results contrast with other reports investigating the effects of these compounds on lung epithelia.…”

Defects in Breathing and Thermoregulation in Mice with Near-Complete Absence of Central Serotonin Neurons

“…This, however, would likely enhance respiratory output under all conditions, including during a hypoxic challenge. Conversely, 5-HT may specifically enhance the HCVR by either increasing the gain of respiratory neurons to input from chemoreceptors, or by enhancing the activity of nonserotonergic chemoreceptors (Putnam et al, 2004;Li et al, 2006;Mulkey et al, 2007). The effects of 5-HT on breathing demonstrated here could also potentially be mediated in part by trophic effects (Golder and Mitchell, 2005), or by 5-HT-dependent respiratory plasticity (Feldman et al, 2003).…”

Intermittent hypoxia-induced sensitization of central chemoreceptors contributes to sympathetic nerve activity during late expiration in rats

“…These inputs allow the system to maintain the appropriate homeostatic levels of O 2 and CO 2 and adaptively respond to various metabolic demands (Fortuna et al 2008;Guyenet et al 2005Guyenet et al , 2008Guyenet et al , 2009Mulkey et al 2007;Nattie 1999;Nattie and Li 2009;Richerson 2004). These drives have been conditionally modeled as excitatory "tonic drives" from multiple sources distributed within the brain stem (pons, RTN, raphé; see Fig.…”

“…Among the drive sources mentioned above, the RTN/pFRG is considered to be a major central chemoreceptor site whose drive is sensitive to CO 2 Guyenet et al 2005Guyenet et al , 2008Guyenet et al , 2009Mulkey et al 2007). To explicitly simulate this property, the RTN tonic drive was considered not constant, as other tonic drives in the model, but dependent on the CO 2 level.…”

“…However, the suggestion of the involvement of peripheral chemoreceptor drive would contradict our previous data showing that the carotid body denervation after CIH exposure did not eliminate the late-E discharges from sympathetic activity (Zoccal et al 2008). Nevertheless, peripheral-central chemoreceptor interaction may be involved in the development of plastic changes in the excitability of central chemoreceptors after CIH conditioning via activation of neuromodulators that enhance the activity of RTN chemosensitive neurons, such as serotonin (Mulkey et al 2007), ATP , or locally produced oxidative stress (Jurado-Gamez et al 2011). These or other, currently unknown mechanisms may be involved in the observed CIH-evoked sensitization of RTN/ pFRG chemoreceptors, which requires additional studies.…”