Evaluating the Burstlet Theory of Inspiratory Rhythm and Pattern Generation

Abstract

The preBötzinger complex (preBötC) generates the rhythm and rudimentary motor pattern for inspiratory breathing movements. Here, we test "burstlet" theory (Kam et al., 2013a), which posits that low amplitude burstlets, subthreshold from the standpoint of inspiratory bursts, reflect the fundamental oscillator of the preBötC. In turn, a discrete suprathreshold process transforms burstlets into full amplitude inspiratory bursts that drive motor output, measurable via hypoglossal nerve (XII) discharge in vitro. We recap observations by Kam and Feldman in neonatal mouse slice preparations: field recordings from preBötC demonstrate bursts and concurrent XII motor output intermingled with lower amplitude burstlets that do not produce XII motor output. Manipulations of excitability affect the relative prevalence of bursts and burstlets and modulate their frequency. Whole-cell and photonic recordings of preBötC neurons suggest that burstlets involve inconstant subsets of rhythmogenic interneurons. We conclude that discrete rhythm-and pattern-generating mechanisms coexist in the preBötC and that burstlets reflect its fundamental rhythmogenic nature.

KCNQ Current Contributes to Inspiratory Burst Termination in the Pre-Bötzinger Complex of Neonatal Rats in vitro

“…The profile and duration of the XII motor output are reliable indicators of collective activity in the preBötC (Del Negro et al, 2001), although the absence of XII motor output does not indicate lack of collective activity in the preBötC (Kam et al, 2013;Ashhad and Feldman, 2020;Kallurkar et al, 2020).…”

“…Its rhythm emanates from the pre-Bötzinger complex (preBötC) of the ventrolateral medulla (Smith et al, 1991;Del Negro et al, 2018). The most recent models of inspiratory rhythm generation favor synaptic mechanisms where burstlets or bursts derive from the progressive recruitment and excitation of a critical subpopulation of Dbx1-derived, glutamatergic neurons and their increased synchronization in the pre-inspiratory and ultimately inspiratory phases (Del Negro et al, 2018;Ashhad and Feldman, 2020;Kallurkar et al, 2020).…”

Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network

“…We also noted that many bursts failed to fully form in DAMGO. These failed bursts were characterized by small-amplitude activity occurring in only subsets of the population typically active during successful bursts (Figure 3D, E; Supplemental Figure 4), potentially analogous to “burstlets” (Kam et al, 2013a, Kallurkar et al, 2020). As a fraction of the total burst attempts, such burst failures became more prevalent with increasing concentrations of DAMGO (Figure 3E) with 43±5% of bursts attempts failing in 300 nM DAMGO.…”

To model or not to model – the physiologist's dilemma

“…While no model perfectly captures the subtlety of cellular physiology, Flor and her team have done an excellent job of testing their models with real physiology. This paper serves as a blueprint for all of us within the world of breathing control as we strive to integrate new concepts such as 'burstlet theory' (Kallurkar et al 2020) and the use of massively parallel high performance clusters for real-time simulation of neurophysiological networks in our own work.…”

“…This paper serves as a blueprint for all of us within the world of breathing control as we strive to integrate new concepts such as ‘burstlet theory’ (Kallurkar et al . 2020) and the use of massively parallel high performance clusters for real‐time simulation of neurophysiological networks in our own work.…”