Abstract
Cardiorespiratory recovery from apneas requires dynamic responses of brainstem circuitry. One implicated component is the raphe system of Pet1-expressing (largely serotonergic) neurons, however their precise requirement neonatally for homeostasis is unclear, yet central toward understanding newborn cardiorespiratory control and dysfunction. Here we show that acute in vivo perturbation of Pet1-neuron activity, via triggering cell-autonomously the synthetic inhibitory receptor hM4Di, resulted in altered baseline cardiorespiratory properties and diminished apnea survival. Respiratory more than heart rate recovery was impaired, uncoupling their normal linear relationship. Disordered gasp recovery from the initial apnea distinguished mice that would go on to die during subsequent apneas. Further, the risk likelihood of apnea-related mortality associated with suppression of Pet1 neurons was higher for animals with baseline elevated ventilatory equivalents for oxygen. These findings establish that Pet1 neurons play an active role in neonatal cardiorespiratory homeostasis and provide mechanistic plausibility for the serotonergic abnormalities associated with SIDS.
Highlights
Tissue oxygen levels are maintained within a narrow, life-sustaining range through the coordinated actions of oxygen flux through breathing, red blood cell loading-unloading, and circulation via heart pumping
Double transgenic Pet1-Flpe, RC-FDi pups allow for acute, inducible perturbation of Pet1 neurons for neonatal, whole-animal functional study before and following intraperitoneal (i.p.) CNO administration
The raphe location, proportion, and intensity of HA-Di immunodetection signal was qualitatively similar across Pet1-Di pups from independent litters (Figure 1—figure supplement 1). (D–F) Representative fields from negative-control single transgenics harboring the unrecombined RC-FDi allele, showing no detectable HA-Di, in line with prior validation that Di-expression from RC-FDi requires Flpe-recombination
Summary
Tissue oxygen levels are maintained within a narrow, life-sustaining range through the coordinated actions of oxygen flux through breathing, red blood cell loading-unloading, and circulation via heart pumping. This vital cardiorespiratory homeostasis is subserved by the interplay of neural circuits that must reliably function for the duration of an organism’s ex utero life. Neonatal mammals have an especially robust, protective homeostatic response – referred to as autoresuscitation – which utilizes gasping after an apnea to increase blood oxygen levels to facilitate restoration of heart rate and eupneic breathing (Gershan et al, 1992; Guntheroth and Kawabori, 1975; Jacobi et al, 1991; Saiki et al, 2001). We present progress in delineating aspects of the underlying neurobiology, querying the neonatal importance for Pet1-lineage neurons, largely serotonergic (5-hydroxytryptamine-, 5-HT-producing), in the apnea recovery response
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