Computational models of the neural control of breathing

Molkov, Yaroslav I.; Rubin, Jonathan E.; Rybak, Ilya A.; Smith, Jeffrey C.

doi:10.1002/wsbm.1371

Cited by 73 publications

(138 citation statements)

References 96 publications

(337 reference statements)

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“…We have extended our previous firing-rate based model of the respiratory central pattern generator to account for differential respiratory responses to perturbations of glycinergic and GABAergic transmission within the BötC (Figure 5). The respiratory circuitry in this model was based on the respiratory circuitry presented in a series of previous models that examined the emergence of active expiration as well as gas-exchange and pulmonary feedback (Rubin et al, 2009, Rubin et al, 2011, Molkov et al, 2014, Molkov et al, 2016). The network connectivity in these models was informed by brainstem transection experiments presented in Smith et al (2007).…”

Section: Methodsmentioning

confidence: 99%

“…Pharmacological or optogenetic suppression of the pFRG neurons eliminates the abdominal expiratory activity evoked by hypercapnia or stimulation of peripheral chemoreceptors (Zoccal et al, 2018, de Britto and Moraes, 2017, Marina et al, 2010, Moraes et al, 2012a, Lemes et al, 2016), indicating that pFRG neurons are necessary for the emergence of active expiratory pattern. How pFRG oscillator interacts with other respiratory compartments within the brainstem, especially with the core of respiratory network, was theoretically hypothesized (Molkov et al, 2016, Molkov et al, 2014, Rubin et al, 2011, Molkov et al, 2010), but largely remains an unresolved question.…”

Section: Introductionmentioning

confidence: 99%

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Inhibitory control of active expiration by the Bötzinger complex in rats

Flor

Barnett

Karlen‐Amarante

et al. 2019

Preprint

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26The expiratory neurons of the Bötzinger complex (BötC) provide inhibitory inputs to 27 the respiratory network, which, during eupnea, are critically important for respiratory phase 28 transition and duration control. Herein, we investigated how the BötC neurons interact with the 29 expiratory oscillator located in the parafacial respiratory group (pFRG) and control the 30 abdominal activity during active expiration. Using the decerebrated, arterially perfused in situ 31 rat preparations, we recorded the neuronal activity and performed pharmacological 32 manipulations of the BötC and pFRG during hypercapnia or after the exposure to short-term 33 sustained hypoxia -conditions that generate active expiration. The experimental data were 34 integrated in a mathematical model to gain new insights in the inhibitory connectome within 35 the respiratory central pattern generator. Our results reveal a complex inhibitory circuitry within 36 the BötC that provides inhibitory inputs to the pFRG thus restraining abdominal activity under 37 resting conditions and contributing to abdominal expiratory pattern formation during active 38 expiration. 39 40 41 Keywords: abdominal activity, hypercapnia, hypoxia, parafacial respiratory group, ventral 42 respiratory column. 48 et al., 2015, Harris-Warrick, 2010, Ramirez and Baertsch, 2018. In mammals, rhythmical 49 contraction and relaxation of respiratory muscles emerges from interacting excitatory and 50 inhibitory neurons with specific cellular properties, distributed within the pons and the medulla 51 oblongata (Richter and Smith, 2014, Del Negro et al., 2018, Lindsey et al., 2012. Coupled 52 oscillators embedded in this brainstem respiratory network are essential to generate and 53 distribute synaptic inputs for the initiation of respiratory rhythmicity and the control of pattern 54 formation (Anderson and Ramirez, 2017, Del Negro et al., 2018). Defining the arrangement 55 and connections of the respiratory oscillators and circuitries are essential to understand how 56 breathing is generated and adjusted to attend metabolic and behavior demands.57

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibitory control of active expiration by the Bötzinger complex in rats

Flor

Barnett

Karlen‐Amarante

et al. 2019

Preprint

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“…; Molkov et al . ). With the latter omission, we felt it was not appropriate to explore recruitment of abdominal outputs and forced expiration such as in hypercapnia, as has been discussed by others (Molkov et al .…”

Section: Discussionmentioning

confidence: 97%

Reduced computational modelling of Kölliker‐Fuse contributions to breathing patterns in Rett syndrome

Wittman

Abdala

Rubin

2019

The Journal of Physiology

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Key pointsr Reduced computational models are used to test effects of loss of inhibition to the Kölliker-Fuse nucleus (KFn).r Three reduced computational models that simulate eupnoeic and vagotomized respiratory rhythms are considered.r All models exhibit the emergence of respiratory perturbations associated with Rett syndrome as inhibition to the KFn is diminished.r Simulations suggest that application of 5-HT 1A agonists can mitigate the respiratory pathology. r The three models can be distinguished and tested based on their predictions about connections and dynamics within the respiratory circuit and about effects of perturbations on certain respiratory neuron populations.Abstract Rett syndrome (RTT) is a developmental disorder that can lead to respiratory disturbances featuring prolonged apnoeas of variable durations. Determining the mechanisms underlying these effects at the level of respiratory neural circuits would have significant implications for treatment efforts and would also enhance our understanding of respiratory rhythm generation and control. While experimental studies have suggested possible factors contributing to the respiratory patterns of RTT, we take a novel computational approach to the investigation of RTT, which allows for direct manipulation of selected system parameters and testing of specific hypotheses. Specifically, we present three reduced computational models, developed using an established framework, all of which successfully simulate respiratory outputs across eupnoeic and vagotomized conditions. All three models show that loss of inhibition to the Kölliker-Fuse nucleus reproduces the key respiratory alterations associated with RTT and, as suggested experimentally, that effects of 5-HT 1A agonists on the respiratory neural circuit suffice Sam Wittman graduated from the University of Pittsburgh in 2017 with BS degrees in mathematical biology and neuroscience. As an undergraduate, he performed modelling research on the neural basis of Rett syndrome under Dr Jonathan Rubin, and he worked in the vestibular electrophysiology lab of Dr Bill Yates and Dr Andrew McCall. He is currently pursuing a MS in S. Wittman and others J Physiol 597.10to alleviate this respiratory pathology. Each of the models makes distinct predictions regarding the neuronal populations and interactions underlying these effects, suggesting natural directions for future experimental testing.

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“…In spite of the fact that the ventral medullary neurons are responsible for generating the respiratory rhythm (Richter & Smith, 2014;Smith et al, 1991), the stimulation of sensory afferents, c 2018 The Authors. Experimental Physiology c 2018 The Physiological Society including baroreceptor inputs, leads to significant changes in the breathing pattern (Dick et al, 2005;Molkov, Rubin, Rybak, & Smith, 2017). Baekey, Molkov, Paton, Rybak, and Dick (2010) reported that baroreceptor stimulation during expiration prolongs the expiratory duration.…”

Section: Introductionmentioning

confidence: 99%

Firing properties of ventral medullary respiratory neurons in sino‐aortic denervated rats

Amorim

Pena

Souza

et al. 2018

Experimental Physiology

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New Findings What is the central question of this study?After sino‐aortic denervation (SAD), rats present normal levels of mean arterial pressure (MAP), high MAP variability and changes in breathing. However, mechanisms involved in SAD‐induced respiratory changes and their impact on the modulation of sympathetic activity remain unclear. Herein, we characterized the firing frequency of medullary respiratory neurons after SAD. What is the main finding and its importance?Sino‐aortic denervation‐induced prolonged inspiration was associated with a reduced interburst frequency of pre‐inspiratory/inspiratory neurons and an increased long‐term variability of late inspiratory neurons, but no changes were observed in the ramp‐inspiratory and post‐inspiratory neurons. This imbalance in the respiratory network might contribute to the modulation of sympathetic activity after SAD. Abstract In previous studies, we documented that after sino‐aortic denervation (SAD) in rats there are significant changes in the breathing pattern, but no significant changes in sympathetic activity and mean arterial pressure compared with sham‐operated rats. However, the neural mechanisms involved in the respiratory changes after SAD and the extent to which they might contribute to the observed normal sympathetic activity and mean arterial pressure remain unclear. Here, we hypothesized that after SAD, rats present with changes in the firing frequency of the ventral medullary inspiratory and post‐inspiratory neurons. To test this hypothesis, male Wistar rats underwent SAD or sham surgery and 3 days later were surgically prepared for an in situ experiment. The duration of inspiration significantly increased in SAD rats. During inspiration, the total firing frequency of ramp‐inspiratory, pre‐inspiratory/inspiratory and late‐inspiratory neurons was not different between groups. During post‐inspiration, the total firing frequency of post‐inspiratory neurons was also not different between groups. Furthermore, the data demonstrate a reduced interburst frequency of pre‐inspiratory/inspiratory neurons and an increased long‐term variability of late‐inspiratory neurons in SAD compared with sham‐operated rats. These findings indicate that the SAD‐induced prolongation of inspiration was not accompanied by alterations in the total firing frequency of the ventral medullary respiratory neurons, but it was associated with changes in the long‐term variability of late‐inspiratory neurons. We suggest that the timing imbalance in the respiratory network in SAD rats might contribute to the modulation of presympathetic neurons after removal of baroreceptor afferents.

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Computational models of the neural control of breathing

Cited by 73 publications

References 96 publications

Inhibitory control of active expiration by the Bötzinger complex in rats

Inhibitory control of active expiration by the Bötzinger complex in rats

Reduced computational modelling of Kölliker‐Fuse contributions to breathing patterns in Rett syndrome

Firing properties of ventral medullary respiratory neurons in sino‐aortic denervated rats

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