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Sigh and Eupnea Rhythmogenesis Involve Distinct Interconnected Subpopulations: A Combined Computational and Experimental Study(1,2,3).

Toporikova N, Chevalier M, Thoby-Brisson M - eNeuro (2015)

Bottom Line: One compartment generates sighs and the other produces eupneic bursts.Through a combination of in vitro and in silico approaches we find that (1) sigh events are less sensitive to network excitability than eupneic activity, (2) calcium-dependent mechanisms and the Ih current play a prominent role in sigh generation, and (3) specific parameters of Ih activation set the low sensitivity to excitability in the sigh neuronal subset.Altogether, our results strongly support the hypothesis that distinct subpopulations within the preBötC network are responsible for sigh and eupnea rhythmogenesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, Washington and Lee University , Lexington, Virginia 24450.

ABSTRACT
Neural networks control complex motor outputs by generating several rhythmic neuronal activities, often with different time scales. One example of such a network is the pre-Bötzinger complex respiratory network (preBötC) that can simultaneously generate fast, small-amplitude, monophasic eupneic breaths together with slow, high-amplitude, biphasic augmented breaths (sighs). However, the underlying rhythmogenic mechanisms for this bimodal discharge pattern remain unclear, leaving two possible explanations: the existence of either reconfiguring processes within the same network or two distinct subnetworks. Based on recent in vitro data obtained in the mouse embryo, we have built a computational model consisting of two compartments, interconnected through appropriate synapses. One compartment generates sighs and the other produces eupneic bursts. The model reproduces basic features of simultaneous sigh and eupnea generation (two types of bursts differing in terms of shape, amplitude, and frequency of occurrence) and mimics the effect of blocking glycinergic synapses. Furthermore, we used this model to make predictions that were subsequently tested on the isolated preBötC in mouse brainstem slice preparations. Through a combination of in vitro and in silico approaches we find that (1) sigh events are less sensitive to network excitability than eupneic activity, (2) calcium-dependent mechanisms and the Ih current play a prominent role in sigh generation, and (3) specific parameters of Ih activation set the low sensitivity to excitability in the sigh neuronal subset. Altogether, our results strongly support the hypothesis that distinct subpopulations within the preBötC network are responsible for sigh and eupnea rhythmogenesis.

No MeSH data available.


Related in: MedlinePlus

A persistent sodium current is critically involved in sigh and eupnea generation. A, In silico experiment showing the effects of reducing gNaP from 100% (2.5 nS for eupnea and 1 nS for sigh, top trace) to 80% (2 nS for eupnea and 0.8 nS for sigh, middle trace) and to 0% (bottom trace) on global network activity. B, In vitro: Extracellular recordings of preBötC activity in control conditions (top trace) and under increasing concentrations of riluzole (middle and bottom traces) to impair the persistent sodium current. C, Quantification of burst frequency changes under the partial and full blockade of gNaP for fictive eupnea (white bars) and sighs (gray bars) in the model (left) and in vitro (right). Orange stars indicate sigh events.
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Figure 4: A persistent sodium current is critically involved in sigh and eupnea generation. A, In silico experiment showing the effects of reducing gNaP from 100% (2.5 nS for eupnea and 1 nS for sigh, top trace) to 80% (2 nS for eupnea and 0.8 nS for sigh, middle trace) and to 0% (bottom trace) on global network activity. B, In vitro: Extracellular recordings of preBötC activity in control conditions (top trace) and under increasing concentrations of riluzole (middle and bottom traces) to impair the persistent sodium current. C, Quantification of burst frequency changes under the partial and full blockade of gNaP for fictive eupnea (white bars) and sighs (gray bars) in the model (left) and in vitro (right). Orange stars indicate sigh events.

Mentions: We acknowledge that both ICaN and INaP are important in respiratory rhythmogenesis (Del Negro et al., 2002; Peña et al., 2004; Del Negro et al., 2005; Pace et al., 2007a,b); however, in the present version of our model, we mainly examined the potential role of INaP in sigh generation only. Although INaP is expressed in the sigh compartment of our model, its value was set lower than the one required for stable oscillations. In contrast, the generation of rhythmic activity in the eupnea compartment relies mainly on the persistent sodium conductance (gNaP). Consequently, a reduction of gNaP should affect the eupnea rhythm more than the sigh rhythm. We therefore tested the involvement of INaP in rhythmic activity in silico by progressively reducing gNaP. As expected, a decrease in gNaP (gNaP = 80% of control) reduced the frequency of eupnea activity without much effect on the sigh frequency (Fig. 4A,C). Complete removal of INaP abolished oscillations in the eupnea compartment. Since in the sigh compartment, gNaP is activated only during Ca2+ oscillations, its removal decreased the size of sigh bursts that became indistinguishable in amplitude from typical eupneic bursts.


Sigh and Eupnea Rhythmogenesis Involve Distinct Interconnected Subpopulations: A Combined Computational and Experimental Study(1,2,3).

Toporikova N, Chevalier M, Thoby-Brisson M - eNeuro (2015)

A persistent sodium current is critically involved in sigh and eupnea generation. A, In silico experiment showing the effects of reducing gNaP from 100% (2.5 nS for eupnea and 1 nS for sigh, top trace) to 80% (2 nS for eupnea and 0.8 nS for sigh, middle trace) and to 0% (bottom trace) on global network activity. B, In vitro: Extracellular recordings of preBötC activity in control conditions (top trace) and under increasing concentrations of riluzole (middle and bottom traces) to impair the persistent sodium current. C, Quantification of burst frequency changes under the partial and full blockade of gNaP for fictive eupnea (white bars) and sighs (gray bars) in the model (left) and in vitro (right). Orange stars indicate sigh events.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4596094&req=5

Figure 4: A persistent sodium current is critically involved in sigh and eupnea generation. A, In silico experiment showing the effects of reducing gNaP from 100% (2.5 nS for eupnea and 1 nS for sigh, top trace) to 80% (2 nS for eupnea and 0.8 nS for sigh, middle trace) and to 0% (bottom trace) on global network activity. B, In vitro: Extracellular recordings of preBötC activity in control conditions (top trace) and under increasing concentrations of riluzole (middle and bottom traces) to impair the persistent sodium current. C, Quantification of burst frequency changes under the partial and full blockade of gNaP for fictive eupnea (white bars) and sighs (gray bars) in the model (left) and in vitro (right). Orange stars indicate sigh events.
Mentions: We acknowledge that both ICaN and INaP are important in respiratory rhythmogenesis (Del Negro et al., 2002; Peña et al., 2004; Del Negro et al., 2005; Pace et al., 2007a,b); however, in the present version of our model, we mainly examined the potential role of INaP in sigh generation only. Although INaP is expressed in the sigh compartment of our model, its value was set lower than the one required for stable oscillations. In contrast, the generation of rhythmic activity in the eupnea compartment relies mainly on the persistent sodium conductance (gNaP). Consequently, a reduction of gNaP should affect the eupnea rhythm more than the sigh rhythm. We therefore tested the involvement of INaP in rhythmic activity in silico by progressively reducing gNaP. As expected, a decrease in gNaP (gNaP = 80% of control) reduced the frequency of eupnea activity without much effect on the sigh frequency (Fig. 4A,C). Complete removal of INaP abolished oscillations in the eupnea compartment. Since in the sigh compartment, gNaP is activated only during Ca2+ oscillations, its removal decreased the size of sigh bursts that became indistinguishable in amplitude from typical eupneic bursts.

Bottom Line: One compartment generates sighs and the other produces eupneic bursts.Through a combination of in vitro and in silico approaches we find that (1) sigh events are less sensitive to network excitability than eupneic activity, (2) calcium-dependent mechanisms and the Ih current play a prominent role in sigh generation, and (3) specific parameters of Ih activation set the low sensitivity to excitability in the sigh neuronal subset.Altogether, our results strongly support the hypothesis that distinct subpopulations within the preBötC network are responsible for sigh and eupnea rhythmogenesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, Washington and Lee University , Lexington, Virginia 24450.

ABSTRACT
Neural networks control complex motor outputs by generating several rhythmic neuronal activities, often with different time scales. One example of such a network is the pre-Bötzinger complex respiratory network (preBötC) that can simultaneously generate fast, small-amplitude, monophasic eupneic breaths together with slow, high-amplitude, biphasic augmented breaths (sighs). However, the underlying rhythmogenic mechanisms for this bimodal discharge pattern remain unclear, leaving two possible explanations: the existence of either reconfiguring processes within the same network or two distinct subnetworks. Based on recent in vitro data obtained in the mouse embryo, we have built a computational model consisting of two compartments, interconnected through appropriate synapses. One compartment generates sighs and the other produces eupneic bursts. The model reproduces basic features of simultaneous sigh and eupnea generation (two types of bursts differing in terms of shape, amplitude, and frequency of occurrence) and mimics the effect of blocking glycinergic synapses. Furthermore, we used this model to make predictions that were subsequently tested on the isolated preBötC in mouse brainstem slice preparations. Through a combination of in vitro and in silico approaches we find that (1) sigh events are less sensitive to network excitability than eupneic activity, (2) calcium-dependent mechanisms and the Ih current play a prominent role in sigh generation, and (3) specific parameters of Ih activation set the low sensitivity to excitability in the sigh neuronal subset. Altogether, our results strongly support the hypothesis that distinct subpopulations within the preBötC network are responsible for sigh and eupnea rhythmogenesis.

No MeSH data available.


Related in: MedlinePlus