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Ryan S Phillips

Hidehiko Koizumi

Yaroslav I Molkov

Jonathan E Rubin

Jeffrey C Smith

(2022)
Predictions and experimental tests of a new biophysical model of the mammalian respiratory oscillator

eLife 11:e74762.

https://doi.org/10.7554/eLife.74762
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Additional files

9 figures, 1 table and 2 additional files

Figures

Figure 1 with 1 supplement

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Model simulation predictions for the relationships between applied current (I_App) and population burst frequency and amplitude of synaptically coupled excitatory neurons (N=100) incorporating neuronal persistent sodium current (I_NaP) and calcium-activated non-selective cation current (I_CAN) over a range of conductances (calcium-activated non-selective cation conductance [g_CAN], neuronal persistent sodium conductance [g_NaP]).

Pharmacological block of I_NaP and I_CAN is simulated by a percent reduction of their respective conductances. (**A & B**) Model parameter space plots color-coded from simulations show effects on …

Figure 1—source data 1 Related to Figure 1A–D.: https://cdn.elifesciences.org/articles/74762/elife-74762-fig1-data1-v1.xlsx
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Figure 1—figure supplement 1

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Comparison of model simulation predictions with a lower synaptic connection probability of 13% (p_Syn=0.13), as experimentally approximated by Rekling et al., 2000, with those presented in Figure 1.

Simulations characterize the predicted relationships between applied current (I_App) and population burst frequency and amplitude of synaptically coupled excitatory neurons (N=100) incorporating …

Figure 1—figure supplement 1—source data 1 Related to Figure 1—figure supplement 1A-D.: https://cdn.elifesciences.org/articles/74762/elife-74762-fig1-figsupp1-data1-v1.xlsx
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Figure 2

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Channelrhodopsin-2 (ChR2)-mediated membrane depolarization of preBötzinger complex (preBötC) vesicular glutamate transporter type-2 (VgluT2)-positive inspiratory neurons in vitro.

(A) Two-photon microscopy single optical plane live images of the preBötC subregion in an in vitro neonatal medullary slice preparation from the VgluT2-tdTomato-ChR2-EYFP transgenic mouse line, …

Figure 2—source data 1 Related to Figure 2D.: https://cdn.elifesciences.org/articles/74762/elife-74762-fig2-data1-v1.xlsx
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Figure 3

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Photostimulation of the bilateral preBötzinger complex (preBötC) vesicular glutamate transporter type-2 (VgluT2)-positive neuron population caused laser-power-dependent increases of inspiratory burst frequency and decreases of burst amplitude.

(A) Overview of experimental in vitro rhythmically active slice preparation from neonatal VgluT2-tdTomato-channelrhodopsin-2 transgenic mouse with macro-patch electrodes on the preBötC region for …

Figure 3—source data 1 Related to Figure 3C.: https://cdn.elifesciences.org/articles/74762/elife-74762-fig3-data1-v1.xlsx
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Figure 4 with 1 supplement

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Perturbations of inspiratory burst frequency and amplitude by bilateral preBötzinger complex (preBötC) photostimulation during pharmacological block of neuronal persistent sodium current (I_NaP).

(A) Example recordings of integrated XII activity (∫XII) with bath application of low concentration of tetrodotoxin citrate (TTX; 5 nM), which gradually decreased inspiratory burst frequency and …

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Figure 4—figure supplement 1

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Pharmacological profile of block of neuronal persistent sodium current (I_NaP) in preBötzinger complex (preBötC) inspiratory glutamatergic neurons.

(A) Example of current-voltage (I-V) relationships measured from whole-cell voltage-clamp recording obtained by applying slow voltage ramps (30 mV/s; –100 to +10 mV) from optically identified …

Figure 4—figure supplement 1—source data 1 Related to Figure 4—figure supplement 1C.: https://cdn.elifesciences.org/articles/74762/elife-74762-fig4-figsupp1-data1-v1.xlsx
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Figure 5

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Power spectrum analyses of preBötzinger complex (preBötC) neuronal population activity in vitro before and after complete block of neuronal persistent sodium current (I_NaP).

(A) Examples of preBötC integrated population activity patterns and associated power spectra before and after block of I_NaP, which eliminates rhythmic preBötC population activity, leaving only a …

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Figure 6

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Elimination of inspiratory rhythm at the cellular level after complete block of neuronal persistent sodium current (I_NaP) in vitro.

(A) Whole-cell current-clamp recordings from td-tomato-labeled preBötzinger complex (preBötC) inspiratory neuron illustrating rhythmic bursting synchronized with inspiratory hypoglossal (XII) motor …

Figure 7

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Perturbations of inspiratory burst frequency and amplitude by bilateral photostimulation of the preBötzinger complex (preBötC) during transient receptor potential channel M4 (TRPM4) pharmacological blockade.

(A) Upper trace illustrates the time course of integrated XII inspiratory activity (∫XII) during bath application of the specific pharmacological inhibitor of TRPM4 channels (9-phenanthrol, 50 µM), …

Figure 7—source data 1 Related to Figure 7D.: https://cdn.elifesciences.org/articles/74762/elife-74762-fig7-data1-v1.xlsx
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Figure 8

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Comparison of experimental and simulated optogenetic photostimulation of the preBötzinger complex (preBötC) excitatory network under control conditions and after partial block of neuronal persistent sodium current (I_NaP) or transient receptor potential channel M4 (TRPM4)/calcium-activated non-selective cation current (I_CAN).

(A) Matched relationship between neuronal membrane depolarization from baseline (ΔV_M) as a function of laser power with photostimulation from experimental data (same as shown in Figure 2D) and model …

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Figure 9

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Channelrhodopsin-2 (ChR2) channel configuration.

The ChR2 channel activation dynamics are described with a four-state Markov model, based on Williams et al., 2013. Transition rates between states are represented by variables $γ_{1 - 5}$ and the …

Tables

Table 1

Updated model parameters.

Channel	Parameters
$I_{N a}$	$g_{N a} = 150.0 n S$ , $E_{N a} = 55.0 m V$ , $V_{m_{1 / 2}} = - 43.8 m V$ , $k_{m} = 6.0 m V$ , $V_{τ m_{1 / 2}} = - 43.8 m V$ , $k_{τ_{m}} = 14.0 m V$ , $τ_{m_{m a x}} = 0.25 m s$ , $V_{h_{1 / 2}} = - 67.5 m V$ , $k_{h} = - 10.8 m V$ , $V_{τ h_{1 / 2}} = - 67.5 m V$ , $k_{τ_{h}} = 12.8 m V$ , $τ_{h_{m a x}} = 8.46 m s$
$I_{K}$	$g_{K} = 160.0 n S$ , $E_{K} = - 94.0 m V$ , $A_{α} = 0.01$ , $B_{α} = 44.0 m V$ , $κ_{α} = 5.0 m V$ , $A_{β} = 0.17$ , $B_{β} = 49.0 m V$ , $κ_{β} = 40.0 m V$
$I_{L e a k}$	$g_{L e a k} = 2.5 n S$ , $E_{L e a k} = - 68.0 m V$
$I_{N a P}$	$g_{N a P} \in [0.0, 5.0] n S$ , $V_{m_{1 / 2}} = - 47.1 m V$ , $k_{m} = 3.1 m V$ , $V_{τ m_{1 / 2}} = - 47.1 m V$ , $k_{τ_{m}} = 6.2 m V$ , $τ_{m_{m a x}} = 1.0 m s$ , $V_{h_{1 / 2}} = - 60.0 m V$ , $k_{h} = - 9.0 m V$ , $V_{τ h_{1 / 2}} = - 60.0 m V$ , $k_{τ_{h}} = 9.0 m V$ , $τ_{h_{m a x}} = 5000 m s$
$I_{C A N}$	$g_{C A N} \in [0.5, 1.5] n S$ , $E_{C A N} = 0.0 m V,$ $C a_{1 / 2} = 0.00074 m M$ , $n = 0.97$
$I_{C a}$	$g_{C a} = 0.00175 n S$ , $E_{C a} = R \cdot T / F \cdot l n ({[C a]}_{o u t} / {[C a]}_{i n})$ , $R = 8.314 J / (m o l \cdot K)$ , $T = 308.0 K$ , $F = 96.485 k C / m o l$ , ${[C a]}_{o u t} = 4.0 m M$ , $V_{m_{1 / 2}} = - 27.5 m V$ , $k_{m} = 5.7 m V$ , $τ_{m} = 0.5 m s$ , $V_{h_{1 / 2}} = - 52.4 m V$ , $k_{h} = - 5.2 m V$ , $τ_{h} = 18.0 m s$
$C a_{i n}$	$α_{C a} = 2.5 \cdot 10^{- 5} m M / f C$ , $P_{C a} = 0.0225$ , $C a_{m i n} = 1.0 \cdot 10^{- 10} m M$ , $τ_{C a} = 50.0 m s$
$I_{S y n}$	$g_{T o n i c} = 0.304 n S$ , $E_{S y n} = - 10.0 m V$ , $τ_{S y n} = 5.0 m s$ , $P_{S y n} = 1$ , $W_{m a x} = 0.01412 n S$
$I_{C h R 2}$	$g_{C h R 2} = 1.19 n S$ , $E_{C h R 2} = 0.0 m V$ , $δ = 0.1$ , $I r r_{C h R 2} = [0, 2] m W$ , $σ_{r e t} = 1.0 \cdot 10^{- 20} m m^{2}$ , $λ = 470 n m$ , $ω_{l o s s} = 0.77$ , $h = 6.62607 \cdot 10^{- 34} m^{2} \cdot k g / s$ , $C = 3.0 \cdot 10^{8} m / s$ , $τ_{C h R 2} = 1.3 m s$

Additional files

Transparent reporting form: https://cdn.elifesciences.org/articles/74762/elife-74762-transrepform1-v1.pdf
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Source code 1 Model source code.: https://cdn.elifesciences.org/articles/74762/elife-74762-code1-v1.zip
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Figures

Figure 1—source data 1

Comparison of model simulation predictions with a lower synaptic connection probability of 13% (p_Syn=0.13), as experimentally approximated by Rekling et al., 2000, with those presented in Figure 1.

Figure 1—figure supplement 1—source data 1

Channelrhodopsin-2 (ChR2)-mediated membrane depolarization of preBötzinger complex (preBötC) vesicular glutamate transporter type-2 (VgluT2)-positive inspiratory neurons in vitro.

Figure 2—source data 1

Photostimulation of the bilateral preBötzinger complex (preBötC) vesicular glutamate transporter type-2 (VgluT2)-positive neuron population caused laser-power-dependent increases of inspiratory burst frequency and decreases of burst amplitude.

Figure 3—source data 1

Perturbations of inspiratory burst frequency and amplitude by bilateral preBötzinger complex (preBötC) photostimulation during pharmacological block of neuronal persistent sodium current (I_NaP).

Figure 4—source data 1

Pharmacological profile of block of neuronal persistent sodium current (I_NaP) in preBötzinger complex (preBötC) inspiratory glutamatergic neurons.

Figure 4—figure supplement 1—source data 1

Power spectrum analyses of preBötzinger complex (preBötC) neuronal population activity in vitro before and after complete block of neuronal persistent sodium current (I_NaP).

Figure 5—source data 1

Elimination of inspiratory rhythm at the cellular level after complete block of neuronal persistent sodium current (I_NaP) in vitro.

Perturbations of inspiratory burst frequency and amplitude by bilateral photostimulation of the preBötzinger complex (preBötC) during transient receptor potential channel M4 (TRPM4) pharmacological blockade.

Figure 7—source data 1

Figure 8—source data 1

Channelrhodopsin-2 (ChR2) channel configuration.

Tables

Updated model parameters.

Additional files

Transparent reporting form

Source code 1

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Figure 1—source data 1

Comparison of model simulation predictions with a lower synaptic connection probability of 13% (pSyn=0.13), as experimentally approximated by Rekling et al., 2000, with those presented in Figure 1.

Figure 1—figure supplement 1—source data 1

Channelrhodopsin-2 (ChR2)-mediated membrane depolarization of preBötzinger complex (preBötC) vesicular glutamate transporter type-2 (VgluT2)-positive inspiratory neurons in vitro.

Figure 2—source data 1

Photostimulation of the bilateral preBötzinger complex (preBötC) vesicular glutamate transporter type-2 (VgluT2)-positive neuron population caused laser-power-dependent increases of inspiratory burst frequency and decreases of burst amplitude.

Figure 3—source data 1

Perturbations of inspiratory burst frequency and amplitude by bilateral preBötzinger complex (preBötC) photostimulation during pharmacological block of neuronal persistent sodium current (INaP).

Figure 4—source data 1

Pharmacological profile of block of neuronal persistent sodium current (INaP) in preBötzinger complex (preBötC) inspiratory glutamatergic neurons.

Figure 4—figure supplement 1—source data 1

Power spectrum analyses of preBötzinger complex (preBötC) neuronal population activity in vitro before and after complete block of neuronal persistent sodium current (INaP).

Figure 5—source data 1

Elimination of inspiratory rhythm at the cellular level after complete block of neuronal persistent sodium current (INaP) in vitro.

Perturbations of inspiratory burst frequency and amplitude by bilateral photostimulation of the preBötzinger complex (preBötC) during transient receptor potential channel M4 (TRPM4) pharmacological blockade.

Figure 7—source data 1

Figure 8—source data 1

Channelrhodopsin-2 (ChR2) channel configuration.

Updated model parameters.

Transparent reporting form

Source code 1

Comparison of model simulation predictions with a lower synaptic connection probability of 13% (p_Syn=0.13), as experimentally approximated by Rekling et al., 2000, with those presented in Figure 1.

Perturbations of inspiratory burst frequency and amplitude by bilateral preBötzinger complex (preBötC) photostimulation during pharmacological block of neuronal persistent sodium current (I_NaP).

Pharmacological profile of block of neuronal persistent sodium current (I_NaP) in preBötzinger complex (preBötC) inspiratory glutamatergic neurons.

Power spectrum analyses of preBötzinger complex (preBötC) neuronal population activity in vitro before and after complete block of neuronal persistent sodium current (I_NaP).

Elimination of inspiratory rhythm at the cellular level after complete block of neuronal persistent sodium current (I_NaP) in vitro.