Interdependence of cellular and network properties in respiratory rhythmogenesis

Abstract

ABSTRACTHow breathing is generated by the preBötzinger Complex (preBötC) remains divided between two ideological frameworks, and the persistent sodium current (INaP) lies at the heart of this debate. AlthoughINaPis widely expressed, thepacemaker hypothesisconsiders it essential because it endows a small subset of neurons with intrinsic bursting or “pacemaker” activity. In contrast,burstlet theoryconsidersINaPdispensable because rhythm emerges from “pre-inspiratory” spiking activity driven by feed-forward network interactions. Using computational modeling, we discover that changes in spike shape can dissociateINaPfrom intrinsic bursting. Consistent with many experimental benchmarks, conditional effects on spike shape during simulated changes in oxygenation, development, extracellular potassium, and temperature alter the prevalence of intrinsic bursting and pre-inspiratory spiking without altering the role ofINaP. Our results support a unifying hypothesis whereINaPand excitatory network interactions, but not intrinsic bursting or pre-inspiratory spiking, are critical interdependent features of preBötC rhythmogenesis.SIGNIFICANCE STATEMENTBreathing is a vital rhythmic process originating from the preBötzinger complex. Since its discovery in 1991, there has been a spirited debate about whether respiratory rhythm generation emerges as a network property or is driven by a subset of specialized neurons with rhythmic bursting capabilities, endowed by intrinsic currents. Here, using computational modeling, we propose a unifying data-driven model of respiratory rhythm generation which bridges the gap between these competing theories. In this model, both intrinsic cellular properties (a persistent sodium current) and network properties (recurrent excitation), but not intrinsic bursting, are essential and interdependent features of respiratory rhythm generation.