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Predictions and experimental tests of a new biophysical model of the mammalian respiratory oscillator

Previously our computational modeling studies (Phillips et al., 2019) proposed that neuronal persistent sodium current (I(NaP)) and calcium-activated non-selective cation current (I(CAN)) are key biophysical factors that, respectively, generate inspiratory rhythm and burst pattern in the mammalian p...

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Autores principales: Phillips, Ryan S, Koizumi, Hidehiko, Molkov, Yaroslav I, Rubin, Jonathan E, Smith, Jeffrey C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9262387/
https://www.ncbi.nlm.nih.gov/pubmed/35796425
http://dx.doi.org/10.7554/eLife.74762
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author Phillips, Ryan S
Koizumi, Hidehiko
Molkov, Yaroslav I
Rubin, Jonathan E
Smith, Jeffrey C
author_facet Phillips, Ryan S
Koizumi, Hidehiko
Molkov, Yaroslav I
Rubin, Jonathan E
Smith, Jeffrey C
author_sort Phillips, Ryan S
collection PubMed
description Previously our computational modeling studies (Phillips et al., 2019) proposed that neuronal persistent sodium current (I(NaP)) and calcium-activated non-selective cation current (I(CAN)) are key biophysical factors that, respectively, generate inspiratory rhythm and burst pattern in the mammalian preBötzinger complex (preBötC) respiratory oscillator isolated in vitro. Here, we experimentally tested and confirmed three predictions of the model from new simulations concerning the roles of I(NaP) and I(CAN): (1) I(NaP) and I(CAN) blockade have opposite effects on the relationship between network excitability and preBötC rhythmic activity; (2) I(NaP) is essential for preBötC rhythmogenesis; and (3) I(CAN) is essential for generating the amplitude of rhythmic output but not rhythm generation. These predictions were confirmed via optogenetic manipulations of preBötC network excitability during graded I(NaP) or I(CAN) blockade by pharmacological manipulations in slices in vitro containing the rhythmically active preBötC from the medulla oblongata of neonatal mice. Our results support and advance the hypothesis that I(NaP) and I(CAN) mechanistically underlie rhythm and inspiratory burst pattern generation, respectively, in the isolated preBötC.
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spelling pubmed-92623872022-07-08 Predictions and experimental tests of a new biophysical model of the mammalian respiratory oscillator Phillips, Ryan S Koizumi, Hidehiko Molkov, Yaroslav I Rubin, Jonathan E Smith, Jeffrey C eLife Neuroscience Previously our computational modeling studies (Phillips et al., 2019) proposed that neuronal persistent sodium current (I(NaP)) and calcium-activated non-selective cation current (I(CAN)) are key biophysical factors that, respectively, generate inspiratory rhythm and burst pattern in the mammalian preBötzinger complex (preBötC) respiratory oscillator isolated in vitro. Here, we experimentally tested and confirmed three predictions of the model from new simulations concerning the roles of I(NaP) and I(CAN): (1) I(NaP) and I(CAN) blockade have opposite effects on the relationship between network excitability and preBötC rhythmic activity; (2) I(NaP) is essential for preBötC rhythmogenesis; and (3) I(CAN) is essential for generating the amplitude of rhythmic output but not rhythm generation. These predictions were confirmed via optogenetic manipulations of preBötC network excitability during graded I(NaP) or I(CAN) blockade by pharmacological manipulations in slices in vitro containing the rhythmically active preBötC from the medulla oblongata of neonatal mice. Our results support and advance the hypothesis that I(NaP) and I(CAN) mechanistically underlie rhythm and inspiratory burst pattern generation, respectively, in the isolated preBötC. eLife Sciences Publications, Ltd 2022-07-07 /pmc/articles/PMC9262387/ /pubmed/35796425 http://dx.doi.org/10.7554/eLife.74762 Text en https://creativecommons.org/publicdomain/zero/1.0/This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication (https://creativecommons.org/publicdomain/zero/1.0/) .
spellingShingle Neuroscience
Phillips, Ryan S
Koizumi, Hidehiko
Molkov, Yaroslav I
Rubin, Jonathan E
Smith, Jeffrey C
Predictions and experimental tests of a new biophysical model of the mammalian respiratory oscillator
title Predictions and experimental tests of a new biophysical model of the mammalian respiratory oscillator
title_full Predictions and experimental tests of a new biophysical model of the mammalian respiratory oscillator
title_fullStr Predictions and experimental tests of a new biophysical model of the mammalian respiratory oscillator
title_full_unstemmed Predictions and experimental tests of a new biophysical model of the mammalian respiratory oscillator
title_short Predictions and experimental tests of a new biophysical model of the mammalian respiratory oscillator
title_sort predictions and experimental tests of a new biophysical model of the mammalian respiratory oscillator
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9262387/
https://www.ncbi.nlm.nih.gov/pubmed/35796425
http://dx.doi.org/10.7554/eLife.74762
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