Search for: All records

Recordings from pre-Bötzinger complex neurons responsible for the inspiratory phase of the respiratory rhythm reveal a ramping burst pattern, starting around the time that the transition from expiration to inspiration begins, in which the spike rate gradually rises until a transition into a high-frequency burst occurs. The spike rate increase along the burst is accompanied by a gradual depolarization of the plateau potential that underlies the spikes. These effects may be functionally important for inducing the onset of inspiration and hence maintaining effective respiration; however, most mathematical models for inspiratory bursting do not capture this activity pattern. Here, we study how the modulation of spike height and afterhyperpolarization via the slow inactivation of an inward current can support various activity patterns including ramping bursts. We use dynamical systems methods designed for multiple timescale systems, such as bifurcation analysis based on timescale decomposition and averaging over fast oscillations, to generate an understanding of and predictions about the specific dynamic effects that lead to ramping bursts. We also analyze how transitions between ramping and other activity patterns may occur with parameter changes, which could be associated with experimental manipulations, environmental conditions, and/or development. 

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 subthreshold 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 Ca 2+ dynamics and activation of a calcium-activated nonselective cationic current. In this computational study, we show how intracellular calcium dynamics driven by synaptically triggered Ca 2+ influx as well as Ca 2+ release/uptake by the endoplasmic reticulum in conjunction with a calcium-activated nonselective 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. 

Previously our computational modeling studies (Phillips et al., 2019) proposed that neuronal persistent sodium current (I NaP ) and calcium-activated non-selective cation current (I CAN ) 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 I NaP and I CAN : (1) I NaP and I CAN blockade have opposite effects on the relationship between network excitability and preBötC rhythmic activity; (2) I NaP is essential for preBötC rhythmogenesis; and (3) I CAN 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 I NaP or I CAN 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 I NaP and I CAN mechanistically underlie rhythm and inspiratory burst pattern generation, respectively, in the isolated preBötC.