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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

Sigh and eupnea activity patterns in vitro and in silico. A, Schematic representation of an in vitro transverse brainstem slice preparation isolating the pre-Bötzinger complex respiratory network (preBötC). Raw (upper trace) and integrated (bottom trace) preBötC activity recordings were obtained with an extracellular macro-electrode positioned at the surface of the slice. B1, Diagrams of sigh (left) and eupnea (right) network models. Except for parameter values for the ER capacity (λ), INaP, and Ih, the sigh and eupnea models are identical. Intracellular Ca2+ (top) and voltage (bottom) obtained for individual uncoupled compartments (gsyn = 0). Left and right panels show outputs for sigh and eupnea compartments, respectively. B2, Model with two compartments connected through an inhibitory synapse (blue) from eupnea to sigh and an excitatory synapse (red) from sigh to eupnea subpopulations. The difference in symbol thickness represents the difference in synaptic strength. Bottom trace shows the average voltage trace of the coupled model that is concomitantly generating sigh and eupnea bursts. Orange stars indicate sigh events. XII, Hypoglossal nucleus; io, inferior olive; na, nucleus ambiguus.
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Figure 1: Sigh and eupnea activity patterns in vitro and in silico. A, Schematic representation of an in vitro transverse brainstem slice preparation isolating the pre-Bötzinger complex respiratory network (preBötC). Raw (upper trace) and integrated (bottom trace) preBötC activity recordings were obtained with an extracellular macro-electrode positioned at the surface of the slice. B1, Diagrams of sigh (left) and eupnea (right) network models. Except for parameter values for the ER capacity (λ), INaP, and Ih, the sigh and eupnea models are identical. Intracellular Ca2+ (top) and voltage (bottom) obtained for individual uncoupled compartments (gsyn = 0). Left and right panels show outputs for sigh and eupnea compartments, respectively. B2, Model with two compartments connected through an inhibitory synapse (blue) from eupnea to sigh and an excitatory synapse (red) from sigh to eupnea subpopulations. The difference in symbol thickness represents the difference in synaptic strength. Bottom trace shows the average voltage trace of the coupled model that is concomitantly generating sigh and eupnea bursts. Orange stars indicate sigh events. XII, Hypoglossal nucleus; io, inferior olive; na, nucleus ambiguus.

Mentions: Embryonic brainstem transverse slices isolating the preBötC network were obtained using the following procedure: pregnant mice were killed by cervical dislocation on E18.5, the day of the plug being considered to be E0.5. Embryos were excised from their uterine bags, manually stimulated to trigger spontaneous breathing behavior and then kept under a slight heating light until their experimental use. Slice preparations were dissected in cold oxygenated artificial CSF (aCSF) composed of (in mM): 120 NaCl, 8 KCl, 1.26 CaCl2, 1.5 MgCl2, 21 NaHCO3, 0.58 NaH2PO4, 30 glucose, pH 7.4. First, the hindbrain was isolated from the embryo's body by a rostral section made at the level of the rhombencephalon and a caudal section made at the level of the first cervical roots (between C2 and C4). Second, the isolated hindbrain was placed in a low melting point agar block and carefully oriented in order to proceed to serial transverse sectioning from rostral to caudal, using a vibratome (Leica). A 450-µm-thick slice, with its anterior limit set 250-300 µm caudal to the more caudal extension of the facial nucleus, was isolated. Other anatomical landmarks such as the wide opening of the fourth ventricle, the presence of the inferior olive, the nucleus ambiguous, and the hypoglossal nucleus were also used to select the appropriate sectioning axis (as also referred to in newborn mice by Ruangkittisakul et al., 2011; see also Fig. 1A). Such slice preparations encompass the region containing a significant portion of the preBötC network capable of spontaneously generating rhythmic fictive inspiratory activities. Slices were then transferred to the recording chamber, rostral surface up, and continuously alimented with oxygenated aCSF at a temperature of 30 °C. Preparations were allowed to recover from the slicing procedure over a period of 20 min before any recording sessions were started.


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)

Sigh and eupnea activity patterns in vitro and in silico. A, Schematic representation of an in vitro transverse brainstem slice preparation isolating the pre-Bötzinger complex respiratory network (preBötC). Raw (upper trace) and integrated (bottom trace) preBötC activity recordings were obtained with an extracellular macro-electrode positioned at the surface of the slice. B1, Diagrams of sigh (left) and eupnea (right) network models. Except for parameter values for the ER capacity (λ), INaP, and Ih, the sigh and eupnea models are identical. Intracellular Ca2+ (top) and voltage (bottom) obtained for individual uncoupled compartments (gsyn = 0). Left and right panels show outputs for sigh and eupnea compartments, respectively. B2, Model with two compartments connected through an inhibitory synapse (blue) from eupnea to sigh and an excitatory synapse (red) from sigh to eupnea subpopulations. The difference in symbol thickness represents the difference in synaptic strength. Bottom trace shows the average voltage trace of the coupled model that is concomitantly generating sigh and eupnea bursts. Orange stars indicate sigh events. XII, Hypoglossal nucleus; io, inferior olive; na, nucleus ambiguus.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Sigh and eupnea activity patterns in vitro and in silico. A, Schematic representation of an in vitro transverse brainstem slice preparation isolating the pre-Bötzinger complex respiratory network (preBötC). Raw (upper trace) and integrated (bottom trace) preBötC activity recordings were obtained with an extracellular macro-electrode positioned at the surface of the slice. B1, Diagrams of sigh (left) and eupnea (right) network models. Except for parameter values for the ER capacity (λ), INaP, and Ih, the sigh and eupnea models are identical. Intracellular Ca2+ (top) and voltage (bottom) obtained for individual uncoupled compartments (gsyn = 0). Left and right panels show outputs for sigh and eupnea compartments, respectively. B2, Model with two compartments connected through an inhibitory synapse (blue) from eupnea to sigh and an excitatory synapse (red) from sigh to eupnea subpopulations. The difference in symbol thickness represents the difference in synaptic strength. Bottom trace shows the average voltage trace of the coupled model that is concomitantly generating sigh and eupnea bursts. Orange stars indicate sigh events. XII, Hypoglossal nucleus; io, inferior olive; na, nucleus ambiguus.
Mentions: Embryonic brainstem transverse slices isolating the preBötC network were obtained using the following procedure: pregnant mice were killed by cervical dislocation on E18.5, the day of the plug being considered to be E0.5. Embryos were excised from their uterine bags, manually stimulated to trigger spontaneous breathing behavior and then kept under a slight heating light until their experimental use. Slice preparations were dissected in cold oxygenated artificial CSF (aCSF) composed of (in mM): 120 NaCl, 8 KCl, 1.26 CaCl2, 1.5 MgCl2, 21 NaHCO3, 0.58 NaH2PO4, 30 glucose, pH 7.4. First, the hindbrain was isolated from the embryo's body by a rostral section made at the level of the rhombencephalon and a caudal section made at the level of the first cervical roots (between C2 and C4). Second, the isolated hindbrain was placed in a low melting point agar block and carefully oriented in order to proceed to serial transverse sectioning from rostral to caudal, using a vibratome (Leica). A 450-µm-thick slice, with its anterior limit set 250-300 µm caudal to the more caudal extension of the facial nucleus, was isolated. Other anatomical landmarks such as the wide opening of the fourth ventricle, the presence of the inferior olive, the nucleus ambiguous, and the hypoglossal nucleus were also used to select the appropriate sectioning axis (as also referred to in newborn mice by Ruangkittisakul et al., 2011; see also Fig. 1A). Such slice preparations encompass the region containing a significant portion of the preBötC network capable of spontaneously generating rhythmic fictive inspiratory activities. Slices were then transferred to the recording chamber, rostral surface up, and continuously alimented with oxygenated aCSF at a temperature of 30 °C. Preparations were allowed to recover from the slicing procedure over a period of 20 min before any recording sessions were started.

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