Inspiratory rhythmogenic activity is burst-independent and opioid-sensitive

Abstract

SummaryHow mammalian neural circuits generate rhythmic activity in motor behaviors, such as breathing, walking, and chewing, remains elusive. For breathing, rhythm generation can be localized to a brainstem nucleus called the preBötzinger Complex (preBötC). Rhythmic preBötC population activity consists of small amplitude burstlets, which we hypothesize are rhythmogenic, and larger inspiratory bursts, which drive motoneuronal activity. If burstlets are rhythmogenic, opioids, analgesics that can cause profound respiratory depression, should similarly reduce burstlet frequency. In conditions where burstlets were separated from bursts in medullary slices from neonatal mice, the μ-opioid receptor (μOR) agonist DAMGO decreased burstlet frequency. DAMGO-mediated depression was abolished by genetic deletion of μORs in a glutamatergic preBötC subpopulation and was reduced by Substance P, but not blockade of inhibitory synaptic transmission. Our findings suggest that rhythmogenesis need not rely on strong bursts of activity associated with motor output and point to strategies for ameliorating opioid-induced depression of breathing.

Evaluating the burstlet theory of inspiratory rhythm and pattern generation

“…uncaging (Kam, Worrell, Ventalon, et al 2013; J. C. Rekling, Champagnat, and Denavit-Saubie 1996;J. C. Smith et al 1990;Sun et al 2019), can effectively trigger a preBötC network burst after a latency of 100-400 ms, similar to the duration of preinspiratory activity, shown in our Fig. 5 and by others.…”

“…That seemingly large range can explain why burstlet amplitude is voltage-dependent: increasing excitability can recruit potentially hundreds of additional constituent neurons to the burstlet-active subpopulation in the preBötC. Whether or not the fraction of burstlet-active preBötC neurons is closer to 20% or 89%, very few (<10) coactive preBötC neurons can trigger full bursts and motor output (Kam, 350 Worrell, Ventalon, et al 2013;Sun et al 2019) so the relative fraction of burstlet-active neurons may not be a critical parameter governing network activity.…”

“…The magnitude of inspiratory bursts (in the preBötC 40 and motor output) can be diminished while only minimally affecting their frequency (Del Negro et al 2002;Shereé M. Johnson, Koshiya, and Smith 2001;Pace et al 2007;Peña et al 2004). Also, manipulating excitability in the preBötC affects the frequency, but not the magnitude of preBötC inspiratory bursts and motor output Sun et al 2019). It thus appears that two discrete phenomena emanate from the preBötC: a fundamental rhythm (whose frequency is adjustable) and a rudimentary 45 pattern consisting of bursts that drive motor output.…”

Evaluating the Burstlet Theory of Inspiratory Rhythm and Pattern Generation

“…The magnitude of inspiratory bursts (in the pre-BötC and motor output) can be diminished while only minimally affecting their frequency (Johnson et al, 2001;Del Negro et al, 2002;Peña et al, 2004;Pace et al, 2007). Also, manipulating network excitability affects the frequency, but not the magnitude of preBötC inspiratory bursts and motor output (Del Negro et al, 2009;Sun et al, 2019). It thus appears that two discrete phenomena emanate from the preBötC: a fundamental rhythm (whose frequency is adjustable) and a rudimentary pattern consisting of bursts that drive motor output.…”

Network synchronization and synchrony propagation: emergent elements of inspiration

“…2g1-i, S2d1-e). Given that the excitation-inhibition balance in a network is a critical determinant of its output 24 , including for breathing 5,8,25,26 , we hypothesize that that net impact of increased [K + ] ACSF is to shift the excitation-inhibition balance towards higher excitation, which favors preBötC synchronization. To test this hypothesis, we disinhibited the network by antagonizing gamma-aminobutyric acid type A (GABA A ) or glycinergic receptors.…”