The Role of Raphe‐derived Neuromodulation of the Retrotrapezoid Nucleus (RTN) in Ventilatory Chemoreflexes

Abstract

Excitatory neuromodulators such as serotonin (5‐HT) and Substance P are synthesized in and released from raphe 5‐HT neurons and increase the excitability of neurons within the brainstem nuclei responsible for controlling breathing. These neuromodulators have also been shown to increase the excitability of respiratory chemoreceptors, including the CO2‐sensitive Phox2b‐expressing (Phox2b+) neurons in the retrotrapezoid nucleus (RTN). However, the importance of this raphe‐derived neuromodulation of the RTN for the hypoxic and hypercapnic ventilatory chemoreflexes has not been tested in vivo. We hypothesize that unilateral ablation of serotonergic terminals within the RTN will attenuate the ventilatory chemoreflexes in vivo. To test this hypothesis, 8 week‐old female Sprague‐Dawley rats received stereotaxic injections of 5,7‐Dihydroxytryptamine (5,7‐DHT; 2 mg/ml, 2 μl vol.) unilaterally targeting the RTN to selectively lesion axon terminals from serotonergic neurons under anesthesia. Desipramine (30mg/kg, intraperitoneal) was administered 30 min prior to toxin injection to prevent axon terminal lesions of other aminergic neurons and limit the off‐target effects of 5,7‐DHT. Breathing was measured in room air, hypercapnia (7% CO2 challenge), and hypoxia (12% O2 challenge) before the lesions and then 3, 5, 7, 10, and 14 days after injection. Three days after injection, we observed a 41% decrease in the ventilatory response to hypercapnia and a 45% decrease in the ventilatory response to hypoxia, driven by a decrease in breathing frequency in both cases (N=4). However, the reduced chemoreflexes normalized over the two weeks after injection. There was no consistent effect following sham injection (N=2) of saline (2 μl vol.). These preliminary data suggest that the serotonergic terminals surrounding the RTN play a vital role in facilitating both hypercapnic and hypoxic ventilatory chemoreflexes in vivo, and support our overall hypothesis that raphe‐derived excitatory neuromodulation of the RTN is essential for ventilatory chemoreflexes in vivo.Support or Funding InformationThis work was supported by NIH HL122358.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.