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Mechanisms Leading to Rhythm Cessation in the Respiratory PreBötzinger Complex Due to Piecewise Cumulative Neuronal Deletions(1,2,3).

Song H, Hayes JA, Vann NC, Drew LaMar M, Del Negro CA - eNeuro (2015)

Bottom Line: When the recruitment rate drops below 1 neuron/ms the network stops spontaneous rhythmic activity.Neurons that play pre-eminent roles in rhythmogenesis include those that commence spiking during the quiescent phase between respiratory bursts and those with a high number of incoming synapses, which both play key roles in recruitment, i.e., recurrent excitation leading to network bursts.This study provides a theoretical framework for the operating mechanism of mammalian central pattern generator networks and their susceptibility to loss-of-function in the case of disease or neurodegeneration.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Applied Science, The College of William & Mary , Williamsburg, Virginia 23187-8795.

ABSTRACT
The mammalian breathing rhythm putatively originates from Dbx1-derived interneurons in the preBötzinger complex (preBötC) of the ventral medulla. Cumulative deletion of ∼15% of Dbx1 preBötC neurons in an in vitro breathing model stops rhythmic bursts of respiratory-related motor output. Here we assemble in silico models of preBötC networks using random graphs for structure, and ordinary differential equations for dynamics, to examine the mechanisms responsible for the loss of spontaneous respiratory rhythm and motor output measured experimentally in vitro. Model networks subjected to cellular ablations similarly discontinue functionality. However, our analyses indicate that model preBötC networks remain topologically intact even after rhythm cessation, suggesting that dynamics coupled with structural properties of the underlying network are responsible for rhythm cessation. Simulations show that cumulative cellular ablations diminish the number of neurons that can be recruited to spike per unit time. When the recruitment rate drops below 1 neuron/ms the network stops spontaneous rhythmic activity. Neurons that play pre-eminent roles in rhythmogenesis include those that commence spiking during the quiescent phase between respiratory bursts and those with a high number of incoming synapses, which both play key roles in recruitment, i.e., recurrent excitation leading to network bursts. Selectively ablating neurons with many incoming synapses impairs recurrent excitation and stops spontaneous rhythmic activity and motor output with lower ablation tallies compared with random deletions. This study provides a theoretical framework for the operating mechanism of mammalian central pattern generator networks and their susceptibility to loss-of-function in the case of disease or neurodegeneration.

No MeSH data available.


Stimulation of four individual constituent neurons (which remain the network after cumulative ablation stops rhythmicity) evokes a network-wide burst and accelerates the rate of recurrent excitation. For the same network realization and random neuron deletion sequence as in Figures 8 and 9A,B, running time spike histogram (10 spks/ms) versus cycle time. Time calibration applies to both traces. At right, the rate of recurrent excitation (right) is plotted versus cycle time (s), where the cycle time is reinitialized to zero immediately following the final network-wide burst. The dotted line indicates the threshold rate of 1 neuron/ms (Fig. 9). B differs from A only in that four neurons are transiently stimulated 3 simulated minutes after rhythm cessation (see Materials and Methods for details of stimulation).
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Figure 10: Stimulation of four individual constituent neurons (which remain the network after cumulative ablation stops rhythmicity) evokes a network-wide burst and accelerates the rate of recurrent excitation. For the same network realization and random neuron deletion sequence as in Figures 8 and 9A,B, running time spike histogram (10 spks/ms) versus cycle time. Time calibration applies to both traces. At right, the rate of recurrent excitation (right) is plotted versus cycle time (s), where the cycle time is reinitialized to zero immediately following the final network-wide burst. The dotted line indicates the threshold rate of 1 neuron/ms (Fig. 9). B differs from A only in that four neurons are transiently stimulated 3 simulated minutes after rhythm cessation (see Materials and Methods for details of stimulation).

Mentions: The rhythm terminated after 32 ablations in that particular network realization. At 975 s the ablated network was no longer spontaneously active (Fig. 10A), yet simultaneously and transiently stimulating four neurons (the synaptic gating variable was raised to s = 0.6 for 200 ms) evoked a network-wide burst (Fig. 10B), showing that the network was capable of generating an inspiratory burst, but not autonomously and without sustainable rhythmicity.


Mechanisms Leading to Rhythm Cessation in the Respiratory PreBötzinger Complex Due to Piecewise Cumulative Neuronal Deletions(1,2,3).

Song H, Hayes JA, Vann NC, Drew LaMar M, Del Negro CA - eNeuro (2015)

Stimulation of four individual constituent neurons (which remain the network after cumulative ablation stops rhythmicity) evokes a network-wide burst and accelerates the rate of recurrent excitation. For the same network realization and random neuron deletion sequence as in Figures 8 and 9A,B, running time spike histogram (10 spks/ms) versus cycle time. Time calibration applies to both traces. At right, the rate of recurrent excitation (right) is plotted versus cycle time (s), where the cycle time is reinitialized to zero immediately following the final network-wide burst. The dotted line indicates the threshold rate of 1 neuron/ms (Fig. 9). B differs from A only in that four neurons are transiently stimulated 3 simulated minutes after rhythm cessation (see Materials and Methods for details of stimulation).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4596029&req=5

Figure 10: Stimulation of four individual constituent neurons (which remain the network after cumulative ablation stops rhythmicity) evokes a network-wide burst and accelerates the rate of recurrent excitation. For the same network realization and random neuron deletion sequence as in Figures 8 and 9A,B, running time spike histogram (10 spks/ms) versus cycle time. Time calibration applies to both traces. At right, the rate of recurrent excitation (right) is plotted versus cycle time (s), where the cycle time is reinitialized to zero immediately following the final network-wide burst. The dotted line indicates the threshold rate of 1 neuron/ms (Fig. 9). B differs from A only in that four neurons are transiently stimulated 3 simulated minutes after rhythm cessation (see Materials and Methods for details of stimulation).
Mentions: The rhythm terminated after 32 ablations in that particular network realization. At 975 s the ablated network was no longer spontaneously active (Fig. 10A), yet simultaneously and transiently stimulating four neurons (the synaptic gating variable was raised to s = 0.6 for 200 ms) evoked a network-wide burst (Fig. 10B), showing that the network was capable of generating an inspiratory burst, but not autonomously and without sustainable rhythmicity.

Bottom Line: When the recruitment rate drops below 1 neuron/ms the network stops spontaneous rhythmic activity.Neurons that play pre-eminent roles in rhythmogenesis include those that commence spiking during the quiescent phase between respiratory bursts and those with a high number of incoming synapses, which both play key roles in recruitment, i.e., recurrent excitation leading to network bursts.This study provides a theoretical framework for the operating mechanism of mammalian central pattern generator networks and their susceptibility to loss-of-function in the case of disease or neurodegeneration.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Applied Science, The College of William & Mary , Williamsburg, Virginia 23187-8795.

ABSTRACT
The mammalian breathing rhythm putatively originates from Dbx1-derived interneurons in the preBötzinger complex (preBötC) of the ventral medulla. Cumulative deletion of ∼15% of Dbx1 preBötC neurons in an in vitro breathing model stops rhythmic bursts of respiratory-related motor output. Here we assemble in silico models of preBötC networks using random graphs for structure, and ordinary differential equations for dynamics, to examine the mechanisms responsible for the loss of spontaneous respiratory rhythm and motor output measured experimentally in vitro. Model networks subjected to cellular ablations similarly discontinue functionality. However, our analyses indicate that model preBötC networks remain topologically intact even after rhythm cessation, suggesting that dynamics coupled with structural properties of the underlying network are responsible for rhythm cessation. Simulations show that cumulative cellular ablations diminish the number of neurons that can be recruited to spike per unit time. When the recruitment rate drops below 1 neuron/ms the network stops spontaneous rhythmic activity. Neurons that play pre-eminent roles in rhythmogenesis include those that commence spiking during the quiescent phase between respiratory bursts and those with a high number of incoming synapses, which both play key roles in recruitment, i.e., recurrent excitation leading to network bursts. Selectively ablating neurons with many incoming synapses impairs recurrent excitation and stops spontaneous rhythmic activity and motor output with lower ablation tallies compared with random deletions. This study provides a theoretical framework for the operating mechanism of mammalian central pattern generator networks and their susceptibility to loss-of-function in the case of disease or neurodegeneration.

No MeSH data available.