Activity ofTachykinin1-ExpressingPet1Raphe Neurons Modulates the Respiratory Chemoreflex

Abstract

Homeostatic control of breathing, heart rate, and body temperature relies on circuits within the brainstem modulated by the neurotransmitter serotonin (5-HT). Mounting evidence points to specialized neuronal subtypes within the serotonergic neuronal system, borne out in functional studies, for the modulation of distinct facets of homeostasis. Such functional differences, read out at the organismal level, are likely subserved by differences among 5-HT neuron subtypes at the cellular and molecular levels, including differences in the capacity to coexpress other neurotransmitters such as glutamate, GABA, thyrotropin releasing hormone, and substance P encoded by the Tachykinin-1 (Tac1) gene. Here, we characterize in mice a 5-HT neuron subtype identified by expression of Tac1 and the serotonergic transcription factor gene Pet1, referred to as the Tac1-Pet1 neuron subtype. Transgenic cell labeling showed Tac1-Pet1 soma resident largely in the caudal medulla. Chemogenetic [clozapine-N-oxide (CNO)-hM4Di] perturbation of Tac1-Pet1 neuron activity blunted the ventilatory response of the respiratory CO 2 chemoreflex, which normally augments ventilation in response to hypercapnic acidosis to restore normal pH and PCO 2 . Tac1-Pet1 axonal boutons were found localized to brainstem areas implicated in respiratory modulation, with highest density in motor regions. These findings demonstrate that the activity of a Pet1 neuron subtype with the potential to release both 5-HT and substance P is necessary for normal respiratory dynamics, perhaps via motor outputs that engage muscles of respiration and maintain airway patency. These Tac1-Pet1 neurons may act downstream of Egr2-Pet1 serotonergic neurons, which were previously established in respiratory chemoreception, but do not innervate respiratory motor nuclei.

Breathing regulation and blood gas homeostasis after near complete lesions of the retrotrapezoid nucleus in adult rats

“…The serotonergic neurons located within the parapyramidal region and the raphe (magnus and pallidus), some of which contribute to the hypercapnic ventilatory reflex (Brust et al . 2014; Hennessy et al . 2017), were unaffected as were the Phox2b‐negative (non‐RTN) Nmb neurons located in the ventromedial medulla (Shi et al .…”

Anatomical, Physiological, and Functional Heterogeneity of the Dorsal Raphe Serotonin System

“…Accumulating evidence points to electrophysiological, neurochemical, and molecular heterogeneity within the DR serotonin system (Calizo et al, 2011;Cohen et al, 2015;Fernandez et al, 2016;Hennessy et al, 2017;Okaty et al, 2015). Previous retrograde labeling studies also suggest that DR subregions may preferentially project to different target regions (reviewed in Waselus et al, 2011).…”

Role of Propriospinal Neurons in Control of Respiratory Muscles and Recovery of Breathing Following Injury

“…In fact, detailed gene expression analyses can divide V1 neurons into over 50 inferred neuron subtypes and V2a neurons into at least 11 subtypes (Bikoff et al, 2016;Gabitto et al, 2016;Hayashi et al, 2018;Sweeney et al, 2018). Once markers of specific subtypes are identified, intersectional genetic tools may be used to elucidate specific roles for different neural subtypes in breathing or other motor functions (Ray et al, 2011;Brust et al, 2014;Hennessy et al, 2017).…”