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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: 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.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.

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

Biphasic shape of sigh bursts requires inhibitory synaptic input. A−C, In vitro recordings of sigh and eupnea activities in control conditions and after blockade of glycinergic synapses. A, Integrated traces of preBötC recordings in control conditions (black, top) and in the presence of 1 µM strychnine (blue, bottom). Both recordings show two types of bursts corresponding to eupnea and sigh. B, Sequential slots of the amplitude (in arbitrary units) of inspiratory bursts versus time in control conditions (top) and under strychnine (bottom). Note that the amplitudes of both types of burst were significantly larger in the presence of strychnine. C, Averaged traces for eupneic bursts (n = 10; left) and sigh bursts (n = 8; right) in control (black) and strychnine (blue) conditions. D, In silico average voltage output of a two-compartment coupled model with (top trace) and without (bottom trace) synaptic inhibition (). E, Average profile of eupnea (left) and sigh bursts (right) obtained from traces in D. Orange stars indicate sigh events.
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Figure 2: Biphasic shape of sigh bursts requires inhibitory synaptic input. A−C, In vitro recordings of sigh and eupnea activities in control conditions and after blockade of glycinergic synapses. A, Integrated traces of preBötC recordings in control conditions (black, top) and in the presence of 1 µM strychnine (blue, bottom). Both recordings show two types of bursts corresponding to eupnea and sigh. B, Sequential slots of the amplitude (in arbitrary units) of inspiratory bursts versus time in control conditions (top) and under strychnine (bottom). Note that the amplitudes of both types of burst were significantly larger in the presence of strychnine. C, Averaged traces for eupneic bursts (n = 10; left) and sigh bursts (n = 8; right) in control (black) and strychnine (blue) conditions. D, In silico average voltage output of a two-compartment coupled model with (top trace) and without (bottom trace) synaptic inhibition (). E, Average profile of eupnea (left) and sigh bursts (right) obtained from traces in D. Orange stars indicate sigh events.

Mentions: In addition to frequency and amplitude differences, sigh motor output events differ from eupneic bursts in terms of shape (Figs. 1, 2A), (Lieske et al., 2000; Tryba et al., 2008; Chapuis et al., 2014). Whereas eupneic activity has a monophasic shape, sighs are defined as biphasic bursts with the initial phase being comparable to a eupneic event and the second phase having larger amplitude (Fig. 2C, black trace). However, as previously published (Lieske et al., 2000; Chapuis et al., 2014) and illustrated in Figure 2A, the two components of a sigh burst can be separated by blockade of inhibitory glycinergic synaptic connections within the preBötC network. We confirmed this finding in embryonic mouse brain stem preparation in vitro by bath application of strychnine (1 µM), which rendered the high-amplitude, low-frequency events monophasic in shape (Fig. 2C, blue trace). Blockade of glycinergic synapses also induced an increase in amplitude of both eupneic and sigh bursts (Fig. 2B,C), suggesting that inhibitory glycinergic inputs are able to limit the overall magnitude of bursting activity throughout the inspiratory neuronal population.


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)

Biphasic shape of sigh bursts requires inhibitory synaptic input. A−C, In vitro recordings of sigh and eupnea activities in control conditions and after blockade of glycinergic synapses. A, Integrated traces of preBötC recordings in control conditions (black, top) and in the presence of 1 µM strychnine (blue, bottom). Both recordings show two types of bursts corresponding to eupnea and sigh. B, Sequential slots of the amplitude (in arbitrary units) of inspiratory bursts versus time in control conditions (top) and under strychnine (bottom). Note that the amplitudes of both types of burst were significantly larger in the presence of strychnine. C, Averaged traces for eupneic bursts (n = 10; left) and sigh bursts (n = 8; right) in control (black) and strychnine (blue) conditions. D, In silico average voltage output of a two-compartment coupled model with (top trace) and without (bottom trace) synaptic inhibition (). E, Average profile of eupnea (left) and sigh bursts (right) obtained from traces in D. Orange stars indicate sigh events.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Biphasic shape of sigh bursts requires inhibitory synaptic input. A−C, In vitro recordings of sigh and eupnea activities in control conditions and after blockade of glycinergic synapses. A, Integrated traces of preBötC recordings in control conditions (black, top) and in the presence of 1 µM strychnine (blue, bottom). Both recordings show two types of bursts corresponding to eupnea and sigh. B, Sequential slots of the amplitude (in arbitrary units) of inspiratory bursts versus time in control conditions (top) and under strychnine (bottom). Note that the amplitudes of both types of burst were significantly larger in the presence of strychnine. C, Averaged traces for eupneic bursts (n = 10; left) and sigh bursts (n = 8; right) in control (black) and strychnine (blue) conditions. D, In silico average voltage output of a two-compartment coupled model with (top trace) and without (bottom trace) synaptic inhibition (). E, Average profile of eupnea (left) and sigh bursts (right) obtained from traces in D. Orange stars indicate sigh events.
Mentions: In addition to frequency and amplitude differences, sigh motor output events differ from eupneic bursts in terms of shape (Figs. 1, 2A), (Lieske et al., 2000; Tryba et al., 2008; Chapuis et al., 2014). Whereas eupneic activity has a monophasic shape, sighs are defined as biphasic bursts with the initial phase being comparable to a eupneic event and the second phase having larger amplitude (Fig. 2C, black trace). However, as previously published (Lieske et al., 2000; Chapuis et al., 2014) and illustrated in Figure 2A, the two components of a sigh burst can be separated by blockade of inhibitory glycinergic synaptic connections within the preBötC network. We confirmed this finding in embryonic mouse brain stem preparation in vitro by bath application of strychnine (1 µM), which rendered the high-amplitude, low-frequency events monophasic in shape (Fig. 2C, blue trace). Blockade of glycinergic synapses also induced an increase in amplitude of both eupneic and sigh bursts (Fig. 2B,C), suggesting that inhibitory glycinergic inputs are able to limit the overall magnitude of bursting activity throughout the inspiratory neuronal population.

Bottom Line: 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.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.

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