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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.


Networks of Dbx1 preBötC neurons with various EL and gNa-P. Blocks show the mean cycle period according to the colorimetric scale (right) for one 30 s simulation on the same network realization without any neuron deletions of each (EL, gNa-P) pair. Ablation tallies on representative parameter sets are indicated on corresponding blocks. The dotted white line encloses all (EL, gNa-P) pairs that produce a mean cycle period of 3.5–5 s.
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Figure 1: Networks of Dbx1 preBötC neurons with various EL and gNa-P. Blocks show the mean cycle period according to the colorimetric scale (right) for one 30 s simulation on the same network realization without any neuron deletions of each (EL, gNa-P) pair. Ablation tallies on representative parameter sets are indicated on corresponding blocks. The dotted white line encloses all (EL, gNa-P) pairs that produce a mean cycle period of 3.5–5 s.

Mentions: The above tally underestimates the experimental tally by approximately one-half, 85 ± 20. Although we proposed that premotor neurons in the preBötC, which the model lacks, could explain, at least in part, this model-experiment disparity (Wang et al., 2014), we did not previously investigate whether the excitability parameter EL or the conductance gNa-P influenced the ablation tally. To do so here, we first tested how EL and gNa-P influence network behavior. Using the same network realization, i.e., the same underlying G(n,p) structure, we simulated networks with EL spanning from −60.6 to −62.5 mV (EL outside this range is not physiologically realistic) and gNa-P spanning from 1 to 1.5 nS (gNa-P < 1 nS is not physiologically realistic). Simulations ran for 30 s absent neuron deletions to quantify network rhythmicity (Fig. 1; blocks are color-coded for cycle period). Lowering either EL or gNa-P slowed down the rhythm, such that for some (EL, gNa-P) pairs the rhythm stopped (Fig. 1, black squares) and for some the period would exceed 10 s (Fig. 1, grey squares), whereas elevating EL or gNa-P had the opposite effect (it speeds up the rhythm) such that for some (EL, gNa-P) pairs the cycle period was ∼1 s (Fig. 1, red squares). Networks along the diagonal (Fig. 1, within the dotted white line) reflect the set of (EL, gNa-P) pairs whose networks produce experimentally reasonable cycle periods of 3.5–5 s. The ablation tally did not vary systematically along this diagonal (29.1 ± 8.0, mean ± SD, n = 17) when the network was subjected to the same neuron deletion sequence. However, cumulative ablation experiments performed on networks to the right of this diagonal resulted in much faster cycle periods (∼1 s) and notably higher ablation tallies (Fig. 1, orange and red squares with ablation tallies). These results indicate that the ablation tally depends on the initial cycle period such that the initial period could be treated as a proxy for the network robustness. Furthermore, these results indicate that (EL, gNa-P) combinations that yield networks with cycle period in the range 3.5–5 s are equally sensitive to cumulative cellular ablation.


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)

Networks of Dbx1 preBötC neurons with various EL and gNa-P. Blocks show the mean cycle period according to the colorimetric scale (right) for one 30 s simulation on the same network realization without any neuron deletions of each (EL, gNa-P) pair. Ablation tallies on representative parameter sets are indicated on corresponding blocks. The dotted white line encloses all (EL, gNa-P) pairs that produce a mean cycle period of 3.5–5 s.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Networks of Dbx1 preBötC neurons with various EL and gNa-P. Blocks show the mean cycle period according to the colorimetric scale (right) for one 30 s simulation on the same network realization without any neuron deletions of each (EL, gNa-P) pair. Ablation tallies on representative parameter sets are indicated on corresponding blocks. The dotted white line encloses all (EL, gNa-P) pairs that produce a mean cycle period of 3.5–5 s.
Mentions: The above tally underestimates the experimental tally by approximately one-half, 85 ± 20. Although we proposed that premotor neurons in the preBötC, which the model lacks, could explain, at least in part, this model-experiment disparity (Wang et al., 2014), we did not previously investigate whether the excitability parameter EL or the conductance gNa-P influenced the ablation tally. To do so here, we first tested how EL and gNa-P influence network behavior. Using the same network realization, i.e., the same underlying G(n,p) structure, we simulated networks with EL spanning from −60.6 to −62.5 mV (EL outside this range is not physiologically realistic) and gNa-P spanning from 1 to 1.5 nS (gNa-P < 1 nS is not physiologically realistic). Simulations ran for 30 s absent neuron deletions to quantify network rhythmicity (Fig. 1; blocks are color-coded for cycle period). Lowering either EL or gNa-P slowed down the rhythm, such that for some (EL, gNa-P) pairs the rhythm stopped (Fig. 1, black squares) and for some the period would exceed 10 s (Fig. 1, grey squares), whereas elevating EL or gNa-P had the opposite effect (it speeds up the rhythm) such that for some (EL, gNa-P) pairs the cycle period was ∼1 s (Fig. 1, red squares). Networks along the diagonal (Fig. 1, within the dotted white line) reflect the set of (EL, gNa-P) pairs whose networks produce experimentally reasonable cycle periods of 3.5–5 s. The ablation tally did not vary systematically along this diagonal (29.1 ± 8.0, mean ± SD, n = 17) when the network was subjected to the same neuron deletion sequence. However, cumulative ablation experiments performed on networks to the right of this diagonal resulted in much faster cycle periods (∼1 s) and notably higher ablation tallies (Fig. 1, orange and red squares with ablation tallies). These results indicate that the ablation tally depends on the initial cycle period such that the initial period could be treated as a proxy for the network robustness. Furthermore, these results indicate that (EL, gNa-P) combinations that yield networks with cycle period in the range 3.5–5 s are equally sensitive to cumulative cellular ablation.

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.