The role of medullary serotonin (5-HT) neurons in respiratory control: contributions to eupneic ventilation, CO2 chemoreception, and thermoregulation

Abstract

The functional roles of the medullary raphé, and specifically 5-HT neurons, are not well understood. It has previously been stated that the role of 5-HT has been so difficult to understand, because "it is implicated in virtually everything, but responsible for nothing"(Cowen PJ. Foreword. In: Serotonin and Sleep: Molecular, Functional and Clinical Aspects, edited by Monti JM, Prandi-Perumal SR, Jacobs BL, Nutt DJ. Switzerland: Birkhauser, 2008). Are 5-HT neurons important, and can we assign a general, or even specific, function to them given their diffuse projections? Recent data obtained from transgenic animals and other model systems indicate that the 5-HT system is not expendable, particularly during postnatal development, and likely plays specific roles in vital functions such as respiratory and thermoregulatory control. We recently provided a detailed and updated review of one specific function of 5-HT neurons, as central respiratory chemoreceptors contributing to the brain's ability to detect changes in pH/CO2 and stimulate adjustments to ventilation accordingly (9). Here, we turn our focus to recent data demonstrating that 5-HT neurons provide an essential excitatory drive to the respiratory network. We then further discuss their role in the CO2 chemoreflex, as well as other homeostatic functions that are closely related to ventilatory control. Last, we provide additional hypotheses/concepts that are worthy of further study, and how 5-HT neurons may be involved in human disease.

Fig. 1.

Raphé-specific stimulation increases hypoglossal (XII) and phrenic motor outputs in vitro and in situ. Individual raphé unit activity (A) and integrated XII motor activity (B) both increase during midline raphé application of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) in rhythmic slices. C: the increase in XII motor output can be reduced with bath application of the 5-HT_2A receptor antagonist MDL-11,939 (MDL), and further reduced with coapplication of the NK-1 receptor antagonist SR 140333 (SR). CTRL, control. D: similarly, focal application of AMPA into the raphé of perfused brain (in situ) preparations increases raphé unit activity, and phrenic (PN) and XII motor outputs. E: the stimulatory effect of raphé AMPA is blunted or nearly eliminated in situ with SR or methysergide (MeSG) + SR, respectively. [Adapted from Ptak et al. (49) with permission from the Society for Neuroscience.]

Fig. 2.

Mice lacking 5-HT neurons display severe apnea in early development. A: raw traces of baseline ventilation in wild-type (WT; top trace) and Lmx1b^f/f/p mice (middle trace) at 4 days of age. Note the long apnea in the Lmx1b^f/f/p mouse. Apneas are eliminated after intraperitoneal injection of the 5-HT_2A agonist 2,5-dimethoxy-iodoamphetamine (DOI; bottom trace). B: schematic of the isolated brain stem-spinal cord (en bloc) preparation, showing raw and integrated inspiratory motor output from the XII and cervical (C) nerve roots. C: XII motor output is reduced in en bloc preparations from postnatal day 2 (P2) Lmx1b^f/f/p mice under control conditions (left) but is restored to the level of WT preparations by bath application of DOI or substance P (SP). [Adapted from Hodges et al. (27) with permission from the Society for Neuroscience.]