Dynamics of ramping bursts in a respiratory neuron model

Rubin

2022

eLife

Self Cite

Inspiratory breathing rhythms arise from synchronized neuronal activity in a bilaterally distributed brainstem structure known as the preBötzinger complex (preBötC). In in vitro slice preparations containing the preBötC, extracellular potassium must be elevated above physiological levels (to 7 - 9mM) to observe regular rhythmic respiratory motor output in the hypoglossal nerve to which the preBötC projects. Reexamination of how extracellular K+ affects preBötC neuronal activity has revealed that low amplitude oscillations persist at physiological levels. These oscillatory events are sub-threshold from the standpoint of transmission to motor output and are dubbed burstlets. Burstlets arise from synchronized neural activity in a rhythmogenic neuronal subpopulation within the preBötC that in some instances may fail to recruit the larger network events, or bursts, required to generate motor output. The fraction of subthreshold preBötC oscillatory events (burstlet fraction) decreases sigmoidally with increasing extracellular potassium. These observations underlie the burstlet theory of respiratory rhythm generation. Experimental and computational studies have suggested that recruitment of the non-rhythmogenic component of the preBötC population requires intracellular Ca2+ dynamics and activation of a calcium-activated non-selective cationic current. In this computational study, we show how intracellular calcium dynamics driven by synaptically triggered Ca2+ influx as well as Ca2+ release/uptake by the endoplasmic reticulum in conjunction with a calcium-activated non-selective cationic current can reproduce and offer an explanation for many of the key properties associated with the burstlet theory of respiratory rhythm generation. Altogether, our modeling work provides a mechanistic basis that can unify a wide range of experimental findings on rhythm generation and motor output recruitment in the preBötC.

Section: Discussionmentioning

confidence: 93%

“…This buffering effect can also explain why the burstlet fraction remains constant in experimental studies when

is lowered from 5 mM to 3 mM ( Kallurkar et al, 2020 ). Our model also does not incorporate short-term extracellular potassium dynamics that depend on

and may impact the ramping shape of burstlet onset ( Abdulla et al, 2021 ). Importantly, over the range of

values relevant both to experiments and our model, we find clear agreement on the dependence of burstlet fraction on

( Figure 4I ).…”

Section: Discussionmentioning

confidence: 99%

Putting the theory into ‘burstlet theory’ with a biophysical model of burstlets and bursts in the respiratory preBötzinger complex

Rubin

2022

eLife

Self Cite

“…Moreover, some additional currents or dynamical processes (e.g. inhibitory currents from local circuit connections, synaptic depression, burst terminating currents, ionic dynamics; Thoby-Brisson et al, 2000 ; Hayes et al, 2008 ; Jasinski et al, 2013 ; Kottick and Del Negro, 2015 ; Phillips et al, 2018 ; Baertsch et al, 2018 ; Juárez-Vidales et al, 2021 ; Abdulla et al, 2022 ; Revill et al, 2021 ), which are not considered in the model, may play a role in augmenting/shaping inspiratory bursting, contribute to robustness of the rhythm such as the electrogenic transmembrane Na + /K + -ATPase pump ( Jasinski et al, 2013 ), as well as affect preBötC dynamics on longer time scales than those investigated here. For example, the current model does not predict the minutes long decrease in network burst frequency that may occur following optogenetic stimulation in some experiments (see Figure 3 , but also see Figure 7B , where this effect is less strong).…”

Section: Discussionmentioning

confidence: 99%

Predictions and experimental tests of a new biophysical model of the mammalian respiratory oscillator

Koizumi²,

Molkov

et al. 2022

eLife

Self Cite

Previously our computational modeling studies (Phillips et al., 2019) proposed that neuronal persistent sodium current (INaP) and calcium-activated non-selective cation current (ICAN) are key biophysical factors that, respectively, generate inspiratory rhythm and burst pattern in the mammalian preBötzinger complex (preBötC) respiratory oscillator isolated in vitro. Here, we experimentally tested and confirmed three predictions of the model from new simulations concerning the roles of INaP and ICAN: (1) INaP and ICAN blockade have opposite effects on the relationship between network excitability and preBötC rhythmic activity; (2) INaP is essential for preBötC rhythmogenesis; and (3) ICAN is essential for generating the amplitude of rhythmic output but not rhythm generation. These predictions were confirmed via optogenetic manipulations of preBötC network excitability during graded INaP or ICAN blockade by pharmacological manipulations in slices in vitro containing the rhythmically active preBötC from the medulla oblongata of neonatal mice. Our results support and advance the hypothesis that INaP and ICAN mechanistically underlie rhythm and inspiratory burst pattern generation, respectively, in the isolated preBötC.

“…The first is that the duration and slope (i.e., shape) of the burstlet onset are statistically indistinguishable from the ramping pre-inspiratory activity that immediately precedes inspiratory bursts (Kallurkar et al, 2020). We note, however, that this shape of pre-inspiratory activity can arise through intrinsic mechanisms at the individual neuron level (Abdulla et al, 2021). The second observation evoked in support of the percolation idea is that holographic photstimulaton of small subsets (4 − 9) of preBötC neurons can elicit bursts with delays lasting hundreds of milliseconds (Kam et al, 2013b).…”

Section: Holographic Photostimulation Percolation and Rhythm Generationmentioning

confidence: 73%

“…This buffering effect can also explain why the burstlet fraction remains constant in experimental studies when ℎ is lowered from 5 to 3 (Kallurkar et al, 2020). Our model also does not incorporate short-term extracellular potassium dynamics that may impact the ramping shape of burstlet onset (Abdulla et al, 2021).…”

Section: Additional Comparisons To Experimental Resultsmentioning

confidence: 99%

Putting the theory into ‘burstlet theory’: A biophysical model of bursts and burstlets in the respiratory preBötzinger complex

Rubin

2021

Preprint

Self Cite

Inspiratory breathing rhythms arise from synchronized neuronal activity in a bilaterally distributed brainstem structure known as the preBötzinger complex (preBötC). In in vitro slice preparations containing the preBötC, extracellular potassium must be elevated above physiological levels (to 7 − 9 mM) to observe regular rhythmic respiratory motor output in the hypoglossal nerve to which the preBötC projects. Reexamination of how extracellular K+ affects preBötC neuronal activity has revealed that low amplitude oscillations persist at physiological levels. These oscillatory events are sub-threshold from the standpoint of transmission to motor output and are dubbed burstlets. Burstlets arise from synchronized neural activity in a rhythmogenic neuronal subpopulation within the preBötC that in some instances may fail to recruit the larger network events, or bursts, required to generate motor output. The fraction of subthreshold preBötC oscillatory events (burstlet fraction) decreases sigmoidally with increasing extracellular potassium. These observations underlie the burstlet theory of respiratory rhythm generation. Experimental and computational studies have suggested that recruitment of the non-rhythmogenic component of the preBötC population requires intracellular Ca2+ dynamics and activation of a calcium-activated non-selective cationic current. In this computational study, we show how intracellular calcium dynamics driven by synaptically triggered Ca2+ influx as well as Ca2+ release/uptake by the endoplasmic reticulum in conjunction with a calcium-activated non-selective cationic current can explain all of the key observations underlying the burstlet theory of respiratory rhythm generation. Thus, we provide a mechanistic basis to unify the experimental findings on rhythm generation and motor output recruitment in the preBötC.