Sigh breathing rhythm depends on intracellular calcium oscillations in a population of inspiratory rhythmogenic preBötzinger complex neurons in mice

Abstract

The preBötzinger Complex (preBötC) of the lower brainstem generates two breathing-related rhythms: one for inspiration on a timescale of seconds and another that produces larger amplitude sighs on the order of minutes. Their underlying mechanisms and cellular origins remain incompletely understood. We resolve these problems via a joint experiment and modeling approach. Blocking purinergic gliotransmission does not perturb either rhythm and imaging experiments show that both rhythms emanate from the same glutamatergic neuron population. We hypothesized that these two disparate rhythms emerge in tandem wherein recurrent excitation gives rise to inspiratory rhythm while a calcium oscillator generates sighs; there is no obligatory role for gliotransmission, hyperpolarization activated mixed cationic current (Ih) in neurons, or synaptic inhibition-mediated coupling of separate populations. We developed a mathematical model that instantiates our working hypothesis. Tests of model predictions validate the single-population rhythmogenic framework, reproducing disparate breathing-related frequencies and the ability for inspiratory and sigh rhythms to be separately regulated in support of respiration under a wide array of conditions. Here we show how a single neuron population exploits two cellular tool-kits: one involving voltage-dependent membrane properties and synaptic excitation for inspiratory breathing (eupnea) and an intracellular biochemical oscillator for sighs, which ventilate and maintain optimal function in the compliant mammalian lung.