Figure 6.

Serotonergic neurons and breathing. (A) Selective expression of ChR2-mCherry fusion protein by raphe obscurus serotonergic neurons in an e-PET Cre mouse [adapted, with permission, after (86)]. (B) Photostimulation of ChR2-expressing raphe obscurus serotonergic neurons in such a mouse (ketamine/dexmedetomidine initial anesthesia with 0.3% to 0.6% isoflurane supplementation) increases diaphragm EMG amplitude (top trace) and respiratory rate (fR, second from top). Bottom traces shows a single raphe serotonergic unit being photoactivated every time the laser light was pulsed [adapted, with permission, after (86)]. (C) Selective optogenetic photostimulation of ChR2-expressing raphe obscurus serotonergic neurons in a conscious mouse (whole body plethysmography). The response has the same slow ON-slow OFF kinetics as in the anesthetized mouse [adapted, with permission, after (155)]. (D) Robust acid sensitivity of a serotonergic neuron in culture [reprinted from Richerson (353)] adapted with permission from Macmillan Publishers Ltd., Nature Neuroscience (5), 2004). (E1) In an arterially perfused rat preparation, serotonergic neurons are either modestly inhibited or modestly excited by CO₂. (E2) In this preparation, hypercapnia had no effect on the mean activity of the serotonergic population at large (all 5-HT) [from Iceman et al. (188) with permission]. (F) Putative serotonergic neuron recorded in conscious cats showing a modest but dose-dependent increase in discharge rate (2.7 to 3.9 Hz; +44% at 6% FiCO₂). The effect of CO₂ essentially disappeared during non-REM sleep [reproduced from Veasey et al. (440) with permission]. (G) Serotonin2A receptor antagonism dramatically slows the pre-Bötzinger complex rhythm in a slice (top traces, mass activity of pre-Bötzinger complex neurons, bottom traces whole cell recording of a presumed rhythmogenic neuron) [reproduced from Peña and Ramirez (337) with permission]. (H1–2) Iontophoretic application of serotonin activates RTN neurons by a constant amount regardless of the level of end-expiratory CO₂ [H1, representative example, H2 average results; adapted, with permission, from (299)]. (I) Selective global inhibition of CNS serotonergic neurons (DREADD methodology) attenuates the hypercapnic ventilatory reflex of a conscious mouse [after Ray et al. (349) reprinted with permission from AAAS]. (J) Interpretations: serotonergic neurons activate breathing via innumerable mechanisms (e.g., direct projection to RTN, the RPG, dorsolateral pons, motoneurons, and indirect effects via changes in vigilance). The integrity of serotonergic neurons is required for full expression of the hypercapnic ventilatory reflex, possibly because a fraction of serotonergic neuron is directly responsive to acidification in vivo.