Limits...
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.


Related in: MedlinePlus

In-degree correlates with normalized ICAN ordering and targeted ablation tallies. A, Linear regression between in-degree (unitless) and normalized ICAN ordering among neurons in the same network. ICAN order was computed based on the maximum number of appearances in the active subnetwork given 15 different thresholds. Blue symbols show the scattered distribution of in-degrees and normalized ICAN ordering. Linear fit is shown by a dotted line. B, Ablation tallies (number of neurons) for three deletion strategies on different network realizations (n = 8). X-symbols mark the tally from eight different simulations where low ICAN-order neurons were selectively ablated. Triangles mark when high ICAN-order neurons were selectively ablated. Circles mark the tally for random neuron deletions (control default strategy).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4596029&req=5

Figure 7: In-degree correlates with normalized ICAN ordering and targeted ablation tallies. A, Linear regression between in-degree (unitless) and normalized ICAN ordering among neurons in the same network. ICAN order was computed based on the maximum number of appearances in the active subnetwork given 15 different thresholds. Blue symbols show the scattered distribution of in-degrees and normalized ICAN ordering. Linear fit is shown by a dotted line. B, Ablation tallies (number of neurons) for three deletion strategies on different network realizations (n = 8). X-symbols mark the tally from eight different simulations where low ICAN-order neurons were selectively ablated. Triangles mark when high ICAN-order neurons were selectively ablated. Circles mark the tally for random neuron deletions (control default strategy).

Mentions: ICAN generates inspiratory bursts in the Rubin–Hayes model. Therefore, it is straightforward to predict that neurons with greater ICAN, which appear more frequently in the active subnetwork, play a more important role in rhythmogenesis. We ordered the neurons according to average ICAN, which was correlated with in-degree, the number of presynaptic partners (Fig. 7A). Large in-degree did not represent a greater overall synaptic conductance because gsyn was scaled according to total number of inputs, i.e., the product of in-degree and gsyn was uniform among neurons (see Materials and Methods). To test whether neurons with larger ICAN were more important for rhythmogenesis, we ablated neurons according to ICAN ordering (instead of randomly). Figure 7B shows eight cumulative-ablation simulations (8 different network realizations, eight random deletion sequences, n = 8) in which targeting neurons high in the ICAN ordering systematically decreased the ablation tally (black triangles, 20±7) required to stop the rhythm compared to random deletions (cyan circles, 32±9). Conversely, targeting neurons low in the ICAN ordering systematically raised the ablation tally (magenta X’s, 46±17) to stop the rhythm. A standard one-way ANOVA showed that there was a statistically significant effect (α = 0.05) of targeting condition on mean ablation tally (F = 9.17, p = 0.0014). Post hoc comparisons using the Tukey HSD test indicated that the mean ablation tally for the higher ICAN ordering was significantly different than the lower ICAN ordering (mean difference = 25.38, SD = 14.95, p = 0.0009). However, the ablation tallies of random deletion sequences did not significantly differ from the higher ICAN ordering (mean difference = 11.75, SD = 14.95, p = 0.14). We interpret these data to indicate that the neurons with higher ICAN tend to play a more important role, and that deleting such neurons damages the overall ability to spontaneously generate network bursts. Conversely, neurons with lower ICAN play a less crucial rhythmogenic role, and their selective ablation causes less deleterious network effects.


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)

In-degree correlates with normalized ICAN ordering and targeted ablation tallies. A, Linear regression between in-degree (unitless) and normalized ICAN ordering among neurons in the same network. ICAN order was computed based on the maximum number of appearances in the active subnetwork given 15 different thresholds. Blue symbols show the scattered distribution of in-degrees and normalized ICAN ordering. Linear fit is shown by a dotted line. B, Ablation tallies (number of neurons) for three deletion strategies on different network realizations (n = 8). X-symbols mark the tally from eight different simulations where low ICAN-order neurons were selectively ablated. Triangles mark when high ICAN-order neurons were selectively ablated. Circles mark the tally for random neuron deletions (control default strategy).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: In-degree correlates with normalized ICAN ordering and targeted ablation tallies. A, Linear regression between in-degree (unitless) and normalized ICAN ordering among neurons in the same network. ICAN order was computed based on the maximum number of appearances in the active subnetwork given 15 different thresholds. Blue symbols show the scattered distribution of in-degrees and normalized ICAN ordering. Linear fit is shown by a dotted line. B, Ablation tallies (number of neurons) for three deletion strategies on different network realizations (n = 8). X-symbols mark the tally from eight different simulations where low ICAN-order neurons were selectively ablated. Triangles mark when high ICAN-order neurons were selectively ablated. Circles mark the tally for random neuron deletions (control default strategy).
Mentions: ICAN generates inspiratory bursts in the Rubin–Hayes model. Therefore, it is straightforward to predict that neurons with greater ICAN, which appear more frequently in the active subnetwork, play a more important role in rhythmogenesis. We ordered the neurons according to average ICAN, which was correlated with in-degree, the number of presynaptic partners (Fig. 7A). Large in-degree did not represent a greater overall synaptic conductance because gsyn was scaled according to total number of inputs, i.e., the product of in-degree and gsyn was uniform among neurons (see Materials and Methods). To test whether neurons with larger ICAN were more important for rhythmogenesis, we ablated neurons according to ICAN ordering (instead of randomly). Figure 7B shows eight cumulative-ablation simulations (8 different network realizations, eight random deletion sequences, n = 8) in which targeting neurons high in the ICAN ordering systematically decreased the ablation tally (black triangles, 20±7) required to stop the rhythm compared to random deletions (cyan circles, 32±9). Conversely, targeting neurons low in the ICAN ordering systematically raised the ablation tally (magenta X’s, 46±17) to stop the rhythm. A standard one-way ANOVA showed that there was a statistically significant effect (α = 0.05) of targeting condition on mean ablation tally (F = 9.17, p = 0.0014). Post hoc comparisons using the Tukey HSD test indicated that the mean ablation tally for the higher ICAN ordering was significantly different than the lower ICAN ordering (mean difference = 25.38, SD = 14.95, p = 0.0009). However, the ablation tallies of random deletion sequences did not significantly differ from the higher ICAN ordering (mean difference = 11.75, SD = 14.95, p = 0.14). We interpret these data to indicate that the neurons with higher ICAN tend to play a more important role, and that deleting such neurons damages the overall ability to spontaneously generate network bursts. Conversely, neurons with lower ICAN play a less crucial rhythmogenic role, and their selective ablation causes less deleterious network effects.

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.


Related in: MedlinePlus