The preBötzinger Complex (preBötC) gives rise to two types of breathing behavior under normal physiological conditions: eupnea and sighing. Here, we examine the neural mechanisms that couple their underlying rhythms. We measured breathing in awake intact adult mice and recorded inspiratory rhythms from the preBötC in neonatal mouse brainstem slice preparations. We show previously undocumented variability in the temporal relationship between sigh breaths or bursts and their preceding eupneic breaths or inspiratory bursts. Investigating the synaptic mechanisms for this variability in vitro, we further show that pharmacological blockade of chloride-mediated synaptic inhibition strengthens inspiratory-to-sigh temporal coupling. These findings contrast with previous literature, which suggested glycinergic inhibition linked sigh bursts to their preceding inspiratory bursts with minimal time intervals. Furthermore, we verify that pharmacological disinhibition did not alter the duration of the prolonged interval that follows a sigh burst prior to resumption of the inspiratory rhythm. These results demonstrate that synaptic inhibition does not enhance coupling between sighs and preceding inspiratory events or contribute to post-sigh apneas. Instead, we conclude that excitatory synaptic mechanisms coordinate inspiratory (eupnea) and sigh rhythms. 4 SIGNIFICANCE STATEMENT Normal breathing consists of eupnea and sigh breaths, which differ in their magnitude, frequency, and function. Both breath types emerge from a brainstem microcircuit that coordinates their timing. Here, we advance understanding of these rhythms by assessing the nature and strength of their coordination, and by showing that synaptic inhibition does not constrain their temporal coupling in contrast to conventional understanding. This study elucidates synaptic mechanisms linking oscillations of different amplitude and frequency within one core oscillator microcircuit.
The preBötzinger complex 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. We hypothesize that these two disparate rhythms emerge in tandem wherein recurrent excitation gives rise to the inspiratory rhythm while a calcium oscillator generates sighs; distinct neuronal populations are not required. We present several mathematical models that instantiate our working hypothesis including: (1) an activity (firing rate) model and (2) a minimal spiking network model. Both modeling frameworks corroborate the single-population rhythmogenic hypothesis.
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