Phasic inhibition as a mechanism for generation of rapid respiratory rhythms

Abstract

Central neural networks operate continuously throughout life to control respiration, yet mechanisms regulating ventilatory frequency are poorly understood. Inspiration is generated by the pre-Bötzinger complex of the ventrolateral medulla, where it is thought that excitation increases inspiratory frequency and inhibition causes apnea. To test this model, we used an in vitro optogenetic approach to stimulate select populations of hindbrain neurons and characterize how they modulate frequency. Unexpectedly, we found that inhibition was required for increases in frequency caused by stimulation of Phox2b-lineage, putative CO-chemosensitive neurons. As a mechanistic explanation for inhibition-dependent increases in frequency, we found that phasic stimulation of inhibitory neurons can increase inspiratory frequency via postinhibitory rebound. We present evidence that Phox2b-mediated increases in frequency are caused by rebound excitation following an inhibitory synaptic volley relayed by expiration. Thus, although it is widely thought that inhibition between inspiration and expiration simply prevents activity in the antagonistic phase, we instead propose a model whereby inhibitory coupling via postinhibitory rebound excitation actually generates fast modes of inspiration.

Differential impact of two critical respiratory centres in opioid‐induced respiratory depression in awake mice

“…It is becoming increasingly evident that inhibition plays an important role in respiratory frequency (Cregg et al . ; Baertsch et al . ; Ramirez & Baertsch, ).…”

“…Supporting evidence from other studies indicates that the KF plays a role in regulating the rate and stability of the respiratory rhythm (Dutschmann & Herbert, ; Pattinson, ; Guyenet & Bayliss, ; Cregg et al . ; Dhingra et al . ).…”

Effects of persistent sodium current blockade in respiratory circuits depend on the pharmacological mechanism of action and network dynamics

“…In the intact network, the pre-I population receives transient inhibition from post-I 442 neurons during the expiratory phase of respiration [13,17,18,19,20], which, our results 443…”

“…As g N aP is lowered, the model remains in the bursting 116 regime until the part of the V m -nullcline near the left knee intersects the h N aP -nullcline. 117 The bifurcation that results creates a stable equilibrium point that corresponds to the 118 stabilization of a constant, hyperpolarized membrane potential, marking a transition 119 from bursting to silence (Fig 4 B, In in vivo conditions, the pre-BötC receives strong inhibition during the interburst 153 interval from other nuclei involved in respiratory rhythm and pattern formation 154 [13,17,18,19,20]. During this interval the transient hyperpolarization is 155 approximately 10 mV in magnitude and 2 s in duration.…”

Evaluating the burstlet theory of inspiratory rhythm and pattern generation

“…C. Rekling, 305 Champagnat, and Denavit-Saubie 1996;Rubin et al 2009). However, disinhibition of the preBötC (Baertsch, Baertsch, and Ramirez 2018;Brockhaus and Ballanyi 1998;Cregg et al 2017;Janczewski et al 2013;Marchenko et al 2016;Shao and Feldman 1997;Sherman et al 2015), as well as attenuation of pacemaker conductances (Del Negro et al 2002, 2005Koizumi and Smith 2008;Pace et al 2007;) and mixed-cationic conductances Picardo et al 2019) neither perturbs the 310 frequency in the predicted manner nor stops breathing in vivo or inspiratory rhythms in vitro, which therefore falsifies all three rhythmogenic mechanisms. Nevertheless, the key to understanding rhythmogenesis may be found in what these theories get wrong: inextricable neural bursts that culminate the inspiratory phase of the cycle.…”