Role of NaV1.6-mediated persistent sodium current and bursting-pacemaker properties in breathing rhythm generation

Silva, Carlos Aparecido da; Grover, Cameron J.; Picardo, Maria Cristina D.; Negro, Christopher A. Del

doi:10.1016/j.celrep.2023.113000

Cited by 5 publications

(5 citation statements)

References 82 publications

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“…4) support this view. This interpretation is also supported by experimental observations that the preBötC rhythm can persist even after intrinsic bursting is apparently abolished by pharmacological or genetic attenuation of I NaP (Del Negro et al, 2002b;da Silva et al, 2019). Due to the conflation of I NaP and intrinsic bursting, these findings have reinforced the idea that I NaP is not obligatory for preBötC rhythm generation.…”

Section: Discussionsupporting

confidence: 60%

Interdependence of cellular and network properties in respiratory rhythmogenesis

Phillips,

Baertsch

2023

Preprint

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How breathing is generated by the preBötzinger Complex (preBötC) remains divided between two ideological frameworks, and the persistent sodium current (INaP) lies at the heart of this debate. AlthoughINaPis widely expressed, thepacemaker hypothesisconsiders it essential because it endows a small subset of neurons with intrinsic bursting or “pacemaker” activity. In contrast,burstlet theoryconsidersINaPdispensable because rhythm emerges from “pre-inspiratory” spiking activity driven by feed-forward network interactions. Using computational modeling, we discover that changes in spike shape can dissociateINaPfrom intrinsic bursting. Consistent with many experimental benchmarks, conditional effects on spike shape during simulated changes in oxygenation, development, extracellular potassium, and temperature alter the prevalence of intrinsic bursting and pre-inspiratory spiking without altering the role ofINaP. Our results support a unifying hypothesis whereINaPand excitatory network interactions, but not intrinsic bursting or pre-inspiratory spiking, are critical interdependent features of preBötC rhythmogenesis.SIGNIFICANCE STATEMENTBreathing is a vital rhythmic process originating from the preBötzinger complex. Since its discovery in 1991, there has been a spirited debate about whether respiratory rhythm generation emerges as a network property or is driven by a subset of specialized neurons with rhythmic bursting capabilities, endowed by intrinsic currents. Here, using computational modeling, we propose a unifying data-driven model of respiratory rhythm generation which bridges the gap between these competing theories. In this model, both intrinsic cellular properties (a persistent sodium current) and network properties (recurrent excitation), but not intrinsic bursting, are essential and interdependent features of respiratory rhythm generation.

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Section: Discussionsupporting

confidence: 60%

Interdependence of cellular and network properties in respiratory rhythmogenesis

Phillips,

Baertsch

2023

Preprint

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“…Both g leak and g NaP contribute to cellular excitability (resting membrane potential), and the voltage-dependent properties of g NaP allow some neurons with appropriate g leak to exhibit intrinsic bursting or "pacemaker" activity (Koizumi & Smith, 2008). Whether such neurons with intrinsic bursting capabilities have a specialized role in network rhythmogenesis is a matter of ongoing debate (da Silva et al, 2023;Feldman & Del Negro, 2006;Ramirez & Baertsch, 2018a;Ramirez & Baertsch, 2018b;Smith et al, 2000) that we do not address here. Instead, we aimed to understand how opioids alter the intrinsic activities 20…”

Section: Discussionmentioning

confidence: 98%

Modeling Effects of Variable preBötzinger Complex Network Topology and Cellular Properties on Opioid-Induced Respiratory Depression and Recovery

Chou,

Bush,

Phillips

et al. 2024

eNeuro

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The pre-Botzinger complex (preBotC), located in the medulla, is the essential rhythm-generating neural network for breathing. The actions of opioids on this network impair its ability to generate robust, rhythmic output, contributing to life-threatening opioid-induced respiratory depression (OIRD).The occurrence of OIRD varies across individuals and internal and external states, increasing the risk of opioid use, yet the mechanisms of this variability are largely unknown. In this study, we utilize a computational model of the preBotC to perform severalin silicoexperiments exploring how differences in network topology and the intrinsic properties of preBotC neurons influence the sensitivity of the network rhythm to opioids. We find that rhythms produced by preBotC networksin silicoexhibit variable responses to simulated opioids, similar to the preBotC networkin vitro.This variability is primarily due to random differences in network topology and can be manipulated by imposed changes in network connectivity and intrinsic neuronal properties. Our results identify features of the preBootC network that may regulate its susceptibility to opioids.Significance StatementThe neural network in the brainstem that generates the breathing rhythm is disrupted by opioid drugs. However, this response can be surprisingly unpredictable. By constructing computational models of this rhythm-generating network, we illustrate how random differences in the distribution of biophysical properties and connectivity patterns within individual networks can predict their response to opioids, and we show how modulation of these network features can make breathing more susceptible or resistant to the effects of opioids.

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“…We formulated a minimal model of inspiratory rhythmogenesis based on emergent network properties (Ashhad & Feldman, 2020;Ashhad et al, 2023;Carroll & Ramirez, 2013;da Silva et al, 2023;Del Negro, Morgado-Valle, et al, 2002;Del Negro et al, 2005;Kallurkar et al, 2020;Kam, Worrell, Ventalon, et al, 2013). That model is consistent with contemporary views of preBötC function, namely that it is fundamentally a network oscillator (Grillner, 2006;Grillner & El Manira, 2020), which additionally features a subset of neurons with bursting-pacemaker properties that can augment recurrent excitation leading to burst generation (Ausborn et al, 2018;Smith et al, 2000) particularly in the context of development (da Silva et al, 2023). Our minimal activity model is coarse-grained regarding cellular and synaptic properties; it does not explicitly model cellular pacemakers or any other type of intrinsic membrane property.…”

Section: Discussionmentioning

confidence: 99%

“…However, if there are discrete eupnoea-and sigh-dedicated cell populations, then one population may be non-neural, consisting instead of astrocytes (Severs et al, 2023). Second, an inspiratory rhythmogenic role for I NaP is still a matter of considerable debate, with a branch of genetic knockout, and knockdown perturbations (da Silva et al, 2023) and pharmacological experiments (Del Negro, Morgado-Valle, et al, 2002;Del Negro et al, 2005;Pace et al, 2007a;Peña et al, 2004) unsupportive, and a parallel branch of modelling, pharmacology, and optogenetic experiments supportive (Ausborn et al, 2018;Koizumi & Smith, 2008;Phillips & Rubin, 2019;Yamanishi et al, 2018). Third, blocking I h stops sigh rhythm in the embryonic preBötC (Toporikova et al, 2015), but this observation has not been corroborated in the preBötC postnatally (Thoby-Brisson et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Inspiratory and sigh breathing rhythms depend on distinct cellular signalling mechanisms in the preBötzinger complex

Borrus,

Stettler,

Grover

et al. 2024

The Journal of Physiology

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Breathing behaviour involves the generation of normal breaths (eupnoea) on a timescale of seconds and sigh breaths on the order of minutes. Both rhythms emerge in tandem from a single brainstem site, but whether and how a single cell population can generate two disparate rhythms remains unclear. We posit that recurrent synaptic excitation in concert with synaptic depression and cellular refractoriness gives rise to the eupnoea rhythm, whereas an intracellular calcium oscillation that is slower by orders of magnitude gives rise to the sigh rhythm. A mathematical model capturing these dynamics simultaneously generates eupnoea and sigh rhythms with disparate frequencies, which can be separately regulated by physiological parameters. We experimentally validated key model predictions regarding intracellular calcium signalling. All vertebrate brains feature a network oscillator that drives the breathing pump for regular respiration. However, in air‐breathing mammals with compliant lungs susceptible to collapse, the breathing rhythmogenic network may have refashioned ubiquitous intracellular signalling systems to produce a second slower rhythm (for sighs) that prevents atelectasis without impeding eupnoea. imageKey points A simplified activity‐based model of the preBötC generates inspiratory and sigh rhythms from a single neuron population. Inspiration is attributable to a canonical excitatory network oscillator mechanism. Sigh emerges from intracellular calcium signalling. The model predicts that perturbations of calcium uptake and release across the endoplasmic reticulum counterintuitively accelerate and decelerate sigh rhythmicity, respectively, which was experimentally validated. Vertebrate evolution may have adapted existing intracellular signalling mechanisms to produce slow oscillations needed to optimize pulmonary function in mammals.

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Role of NaV1.6-mediated persistent sodium current and bursting-pacemaker properties in breathing rhythm generation

Cited by 5 publications

References 82 publications

Interdependence of cellular and network properties in respiratory rhythmogenesis

Interdependence of cellular and network properties in respiratory rhythmogenesis

Modeling Effects of Variable preBötzinger Complex Network Topology and Cellular Properties on Opioid-Induced Respiratory Depression and Recovery

Inspiratory and sigh breathing rhythms depend on distinct cellular signalling mechanisms in the preBötzinger complex

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