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.


Group data for instantaneous frequency and active subnetwork size. Instantaneous frequency (Hz) and active subnetwork size (number of neurons) at threshold θ7 = –3.5 pA are plotted for cumulative neuron deletion simulations on six different network realizations. Black traces show instantaneous frequency (Hz); red traces show active subnetwork size (number of neurons) for each cycle period, plotted versus the percentage of total cellular ablations (%).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Group data for instantaneous frequency and active subnetwork size. Instantaneous frequency (Hz) and active subnetwork size (number of neurons) at threshold θ7 = –3.5 pA are plotted for cumulative neuron deletion simulations on six different network realizations. Black traces show instantaneous frequency (Hz); red traces show active subnetwork size (number of neurons) for each cycle period, plotted versus the percentage of total cellular ablations (%).

Mentions: It may seem counterintuitive that the network burst output did not change during the ablation sequence (Fig. 3, red traces), whereas the ICAN active subnetwork size decreased stepwise (Figs. 4A, 5, as well as n = 6 simulations shown in Fig. 6). Although the average ICAN declined during the sequence, network burst output remained stable because ICAN has a biphasic influence on the ability to generate action potentials; intra-burst spiking decreases when ICAN is too low or too high. ICAN generally ensures that inspiratory bursts remain more robust and larger in magnitude than is needed to sustain rhythmogenesis (Kam et al., 2013b). However, the ability of ICAN to enhance burst magnitude causes depolarization block of spiking when its magnitude is large, which cuts down on the number of spikes per burst (Rubin et al., 2009; Fig. 3, example cells). Thus, as the average ICAN decreases during the cumulative cell ablation sequence, neurons with low gCAN decrease burst amplitude and generate fewer intra-burst spikes, whereas other neurons with larger gCAN generate more intra-burst spikes because the ability of ICAN to cause depolarization block of spiking is reduced during the course of the ablation sequence. As a result, the network burst output, as quantified by the running time spike histogram, does not decline.


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)

Group data for instantaneous frequency and active subnetwork size. Instantaneous frequency (Hz) and active subnetwork size (number of neurons) at threshold θ7 = –3.5 pA are plotted for cumulative neuron deletion simulations on six different network realizations. Black traces show instantaneous frequency (Hz); red traces show active subnetwork size (number of neurons) for each cycle period, plotted versus the percentage of total cellular ablations (%).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Group data for instantaneous frequency and active subnetwork size. Instantaneous frequency (Hz) and active subnetwork size (number of neurons) at threshold θ7 = –3.5 pA are plotted for cumulative neuron deletion simulations on six different network realizations. Black traces show instantaneous frequency (Hz); red traces show active subnetwork size (number of neurons) for each cycle period, plotted versus the percentage of total cellular ablations (%).
Mentions: It may seem counterintuitive that the network burst output did not change during the ablation sequence (Fig. 3, red traces), whereas the ICAN active subnetwork size decreased stepwise (Figs. 4A, 5, as well as n = 6 simulations shown in Fig. 6). Although the average ICAN declined during the sequence, network burst output remained stable because ICAN has a biphasic influence on the ability to generate action potentials; intra-burst spiking decreases when ICAN is too low or too high. ICAN generally ensures that inspiratory bursts remain more robust and larger in magnitude than is needed to sustain rhythmogenesis (Kam et al., 2013b). However, the ability of ICAN to enhance burst magnitude causes depolarization block of spiking when its magnitude is large, which cuts down on the number of spikes per burst (Rubin et al., 2009; Fig. 3, example cells). Thus, as the average ICAN decreases during the cumulative cell ablation sequence, neurons with low gCAN decrease burst amplitude and generate fewer intra-burst spikes, whereas other neurons with larger gCAN generate more intra-burst spikes because the ability of ICAN to cause depolarization block of spiking is reduced during the course of the ablation sequence. As a result, the network burst output, as quantified by the running time spike histogram, does not decline.

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.