Functional and Developmental Identification of a Molecular Subtype of Brain Serotonergic Neuron Specialized to Regulate Breathing Dynamics

•Functional specializations map to distinct 5HT neuron developmental lineages•Life-sustaining breathing reflex is specifically driven by Egr2-Pet1 5HT neurons•Egr2-Pet1 5HT neurons function as frontline PCO2/pH chemoreceptor•5HT neuronal system is found to have sensory and motor subdivisions

SummarySerotonergic neurons modulate behavioral and physiological responses from aggression and anxiety to breathing and thermoregulation. Disorders involving serotonin (5HT) dysregulation are commensurately heterogeneous and numerous. We hypothesized that this breadth in functionality derives in part from a developmentally determined substructure of distinct subtypes of 5HT neurons each specialized to modulate specific behaviors. By manipulating developmentally defined subgroups one by one chemogenetically, we find that the Egr2-Pet1 subgroup is specialized to drive increased ventilation in response to carbon dioxide elevation and acidosis. Furthermore, this subtype exhibits intrinsic chemosensitivity and modality-specific projections—increasing firing during hypercapnic acidosis and selectively projecting to respiratory chemosensory but not motor centers, respectively. These findings show that serotonergic regulation of the respiratory chemoreflex is mediated by a specialized molecular subtype of 5HT neuron harboring unique physiological, biophysical, and hodological properties specified developmentally and demonstrate that the serotonergic system contains specialized modules contributing to its collective functional breadth.

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