Exploring the role of the Kölliker–Fuse nucleus in breathing variability by mathematical modelling DOI

Sharon John,

William H. Barnett, Ana P. Abdala

и другие.

The Journal of Physiology, Год журнала: 2023, Номер 602(1), С. 93 - 112

Опубликована: Дек. 8, 2023

Abstract The Kölliker–Fuse nucleus (KF), which is part of the parabrachial complex, participates in generation eupnoea under resting conditions and control active abdominal expiration when increased ventilation required. Moreover, dysfunctions KF neuronal activity are believed to play a role emergence respiratory abnormalities seen Rett syndrome (RTT), progressive neurodevelopmental disorder associated with an irregular breathing pattern frequent apnoeas. Relatively little known, however, about intrinsic dynamics neurons within how their synaptic connections affect contribute irregularities. In this study, we use reduced computational model consider several dynamical regimes paired different input sources determine combinations compatible known experimental observations. We further build on these findings identify possible interactions between other components neural circuitry. Specifically, present two models that both simulate eupnoeic as well RTT‐like phenotypes. Using nullcline analysis, types inhibitory inputs leading patterns suggest local circuit organizations. When identified properties present, also exhibit quantal acceleration late‐expiratory activity, hallmark featuring forced exhalation, increasing inhibition KF, reported experimentally. Hence, instantiate plausible hypotheses forms network interactions, thus providing general framework specific predictions for future testing. image Key points involved regulating normal controlling during ventilation. Dysfunction thought (RTT). This study utilizes modelling explore compatibility By analysing configurations, identifies lead proposes potential Two presented patterns. These provide testable investigations, offering understanding interactions.

Язык: Английский

Inspiratory and sigh breathing rhythms depend on distinct cellular signalling mechanisms in the preBötzinger complex DOI Creative Commons
Daniel S. Borrus,

Marco K. Stettler,

Cameron J. Grover

и другие.

The Journal of Physiology, Год журнала: 2024, Номер 602(5), С. 809 - 834

Опубликована: Фев. 14, 2024

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

Язык: Английский

Процитировано

8
Degenerate Neuronal and Circuit Mechanisms Important for Generating Rhythmic Motor Patterns DOI
Ronald L. Calabrese, Eve Marder

Physiological Reviews, Год журнала: 2024, Номер 105(1), С. 95 - 135

Опубликована: Июнь 13, 2024

In 1996, we published a review article (Marder E, Calabrese RL.

Язык: Английский

Процитировано

6
Interdependence of cellular and network properties in respiratory rhythm generation DOI Creative Commons
Ryan S. Phillips, Nathan A. Baertsch

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(19)

Опубликована: Май 1, 2024

How breathing is generated by the preBötzinger complex (preBötC) remains divided between two ideological frameworks, and a persistent sodium current (I

Язык: Английский

Процитировано

4
The multifunctionality of the brainstem breathing control circuit DOI Creative Commons
Kevin Yackle, Jeehaeh Do

Current Opinion in Neurobiology, Год журнала: 2025, Номер 90, С. 102974 - 102974

Опубликована: Янв. 28, 2025

Subconscious breathing is generated by a network of brainstem nodes with varying purposes, like pacing or patterning certain breath phase. Decades anatomy, pharmacology, and physiology studies have identified characterized the system's fundamental properties that produce robust breathing, we now well-conceived computational models are based on detailed descriptions neuronal connectivity, biophysical properties, functions in breathing. In total, considerable understanding control circuit. But, last five years, utilization molecular genetic approaches to study neural subtypes within each node has led new era circuit research explains how integrated more complex behaviors speaking running connected other physiological systems our state-of-mind. This review will describe basic role key components then highlight transformative discoveries broaden these brain areas. These serve illustrate creativity exciting future research.

Язык: Английский

Процитировано

0
Microcircuit Synchronization and Heavy-Tailed Synaptic Weight Distribution Augment preBötzinger Complex Bursting Dynamics DOI Creative Commons
Sufyan Ashhad, Valentin M. Slepukhin, Jack L. Feldman

и другие.

Journal of Neuroscience, Год журнала: 2022, Номер 43(2), С. 240 - 260

Опубликована: Ноя. 18, 2022

The preBötzinger Complex (preBötC) encodes inspiratory time as rhythmic bursts of activity underlying each breath. Spike synchronization throughout a sparsely connected preBötC microcircuit initiates that ultimately drive the motor patterns. Using minimal models to explore burst initiation dynamics, we examined variability in probability and latency following exogenous stimulation small subset neurons, mimicking experiments. Among various physiologically plausible graphs 1000 excitatory neurons constructed using experimentally determined synaptic connectivity parameters, directed Erdős-Rényi with broad (lognormal) distribution weights best captured observed dynamics. leading was regulated by efferent spiking are optimally tuned amplify modest preinspiratory through input convergence. graph-theoretic machine learning-based analyses, found convergence at next-nearest neighbor order strong predictor incipient synchronization. Our analyses revealed crucial role heterogeneity imparting exceptionally robust yet flexible attractor Given pervasiveness lognormally distributed strengths nervous system, postulate these mechanisms represent ubiquitous template for temporal processing decision-making computational motifs. SIGNIFICANCE STATEMENT Mammalian breathing is robust, virtually continuous life, inherently labile: adapt rapid metabolic shifts (e.g., fleeing predator or chasing prey); airway reflexes; enable nonventilatory behaviors vocalization, breathholding, laughing). Canonical theoretical frameworks—based on pacemakers intrinsic bursting—cannot account robustness flexibility rhythm. Experiments reveal network key initiate cycle. We investigated dynamics neuronal parameters. discovered fat-tailed (non-Gaussian) weight distribution—a manifestation heterogeneity—augments this vital rhythmogenic network, contributing its extraordinary reliability responsiveness.

Язык: Английский

Процитировано

14
Inhibitory subpopulations in preBötzinger Complex play distinct roles in modulating inspiratory rhythm and pattern DOI Open Access

Zheng Chang,

Jordan Skach,

Kaiwen Kam

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Авг. 8, 2023

Abstract Inhibitory neurons embedded within mammalian neural circuits shape breathing, walking, chewing, and other rhythmic motor behaviors. At the core of circuit controlling breathing is preBötzinger Complex (preBötC), a nucleus in ventrolateral medulla necessary for generation inspiratory rhythm. In preBötC, recurrently connected network glutamatergic Dbx1-derived (Dbx1 + ) generates drive. Functionally anatomically intercalated among preBötC Dbx1 are GABAergic (GAD1/2 glycinergic (GlyT2 neurons, whose roles remain unclear. To elucidate inhibitory microcircuits we first characterized spatial distribution molecularly-defined subpopulations double reporter mice expressing either red fluorescent protein tdTomato or EGFP GlyT2 , GAD1 GAD2 neurons. We found that, neonatal mice, majority expressed combination while much smaller subpopulation also GAD1. determine functional role these subpopulations, used holographic photostimulation, patterned illumination technique with high spatiotemporal resolution, rhythmically active medullary slices from ;GlyT2 ;GAD1 mice. Stimulation 4 8 during endogenous rhythm prolonged interburst interval phase-dependent manner increased latency to burst initiation when bursts were evoked by stimulation contrast, did not affect initiation. Instead, photoactivation duration decreased amplitude. conclude that express both modulate delaying shapes patterning altering

Язык: Английский

Процитировано

6
Predictions and experimental tests of a new biophysical model of the mammalian respiratory oscillator DOI Creative Commons
Ryan S. Phillips, Hidehiko Koizumi, Yaroslav I. Molkov

и другие.

eLife, Год журнала: 2022, Номер 11

Опубликована: Июль 5, 2022

Previously our computational modeling studies (Phillips et al., 2019) proposed that neuronal persistent sodium current (INaP) and calcium-activated non-selective cation (ICAN) are key biophysical factors that, respectively, generate inspiratory rhythm burst pattern in the mammalian preBötzinger complex (preBötC) respiratory oscillator isolated vitro. Here, we experimentally tested confirmed three predictions of model from new simulations concerning roles INaP ICAN: (1) ICAN blockade have opposite effects on relationship between network excitability preBötC rhythmic activity; (2) is essential for rhythmogenesis; (3) generating amplitude output but not generation. These were via optogenetic manipulations during graded or by pharmacological slices vitro containing rhythmically active medulla oblongata neonatal mice. Our results support advance hypothesis mechanistically underlie generation, preBötC.

Язык: Английский

Процитировано

10
Inspiratory rhythm generation is stabilized by Ih DOI
Nicholas Burgraff, Ryan S. Phillips, Liza J. Severs

и другие.

Journal of Neurophysiology, Год журнала: 2022, Номер 128(1), С. 181 - 196

Опубликована: Июнь 8, 2022

Cellular and network properties must be capable of generating rhythmic activity that is both flexible stable. This particularly important for breathing, a behavior dynamically adapts to environmental, behavioral, metabolic changes from the first last breath. The pre-Bötzinger complex (preBötC), located within ventral medulla, responsible producing inspiration. Its cellular tunable, as well stabilizing. Here, we explore role hyperpolarization-activated, nonselective cation current (Ih) stabilizing PreBötC during opioid exposure reduced excitatory synaptic transmission. Introducing Ih into an in silico preBötC predicts loss this depolarizing should significantly slow inspiratory rhythm. By contrast, vitro vivo experiments revealed minimally affected breathing frequency, but destabilized rhythmogenesis through generation incompletely synchronized bursts (burstlets). Associated with was increased susceptibility opioid-induced respiratory depression or weakened interactions, paradoxical depolarization at level, suppression tonic spiking. Tonic spiking generated by nonrhythmic inhibitory neurons, which large percentage express Ih. Together, our results suggest maintaining spiking, rhythmogenesis, protecting against perturbations state.NEW & NOTEWORTHY plays multiple roles preBötC. promoting intrinsic neurons preserving function conditions dampen excitability, such context depression. We therefore propose expands dynamic range buffers perturbations, stabilizes preventing unsynchronized bursts.

Язык: Английский

Процитировано

7
Inhibitory subpopulations in preBötzinger Complex play distinct roles in modulating inspiratory rhythm and pattern DOI

Zheng Chang,

Jordan Skach,

Kaiwen Kam

и другие.

Journal of Neuroscience, Год журнала: 2024, Номер 44(25), С. e1928232024 - e1928232024

Опубликована: Май 10, 2024

Inhibitory neurons embedded within mammalian neural circuits shape breathing, walking, and other rhythmic motor behaviors. At the core of circuit controlling breathing is preBtzinger Complex (preBtC), where GABAergic (GAD1/2 + ) glycinergic (GlyT2 are functionally anatomically intercalated among glutamatergic Dbx1-derived (Dbx1 that generate inspiratory drive. The roles these preBtC inhibitory in remain unclear. We first characterized spatial distribution molecularly defined subpopulations male female neonatal double reporter mice expressing either tdTomato or EGFP GlyT2 , GAD1 GAD2 neurons. found majority expressed both while a much smaller subpopulation also GAD1. To determine functional role subpopulations, we used holographic photostimulation, patterned illumination technique, rhythmically active medullary slices from Dbx1 ;GlyT2 ;GAD1 sex. Stimulation 4 8 during endogenous rhythm prolonged interburst interval phase-dependent manner increased latency to burst initiation when bursts were evoked by stimulation In contrast, did not affect initiation. Instead, photoactivation duration decreased amplitude. conclude /GAD2 modulate delaying shapes patterning altering

Язык: Английский

Процитировано

1
A novel mechanism for ramping bursts based on slow negative feedback in model respiratory neurons DOI
Sushmita Rose John, Ryan S. Phillips, Jonathan Rubin

и другие.

Chaos An Interdisciplinary Journal of Nonlinear Science, Год журнала: 2024, Номер 34(6)

Опубликована: Июнь 1, 2024

Recordings from pre-Bötzinger complex neurons responsible for the inspiratory phase of respiratory rhythm reveal a ramping burst pattern, starting around time that transition expiration to inspiration begins, in which spike rate gradually rises until into high-frequency occurs. The increase along is accompanied by gradual depolarization plateau potential underlies spikes. These effects may be functionally important inducing onset and hence maintaining effective respiration; however, most mathematical models bursting do not capture this activity pattern. Here, we study how modulation height afterhyperpolarization via slow inactivation an inward current can support various patterns including bursts. We use dynamical systems methods designed multiple timescale systems, such as bifurcation analysis based on decomposition averaging over fast oscillations, generate understanding predictions about specific dynamic lead also analyze transitions between other occur with parameter changes, could associated experimental manipulations, environmental conditions, and/or development.

Язык: Английский

Процитировано

1