Figure 1.
Closed-loop respiratory system.
A. General diagram of interactions between the brainstem respiratory neural network and the lungs. B. Model schematic. See text for detailed description. Abbreviations: Abd. – abdominal; AbN – abdominal nerve; aug-E – augmenting expiratory neuron; BötC – Bötzinger complex; CPG – central pattern generator; cVRG – caudal ventral respiratory group; early-I – early-inspiratory neuron; late-E – late-expiratory neuron; Mns – motoneurons; NTS - nucleus of the tractus solitarius; P-cells – Pump cells; P(e) – excitatory pump cells; P(i) – inhibitory pump cells; pFRG – parafacial respiratory group; PN – phrenic nerve; post-I – post-inspiratory neuron; pre-BötC – pre-Bötzinger complex; pre-I/I – pre-inspiratory/inspiratory neuron; PSRs – pulmonary stretch receptors; ramp-I – ramp-inspiratory neuron; RTN – retrotrapezoid nucleus; rVRG – rostral ventral respiratory group; VRC – ventral respiratory column.
Figure 2.
Model performance in control conditions (A) and after vagotomy (B).
The top 6 traces in A and B represent output activity (normalized firing rate) of the corresponding neurons. The bottom two traces represent the end capillary blood pc (pce) just before the next heart beat and the RTN drive, respectively. Note that vagotomy (removal of mechanical feedback) prolongs inspiration and expiration, increases the amplitude of ramp-I (and hence PN) activity and lung inflation (maximal lung volume and tidal volume), and slows the respiratory oscillations.
Figure 3.
Perturbations of respiratory neural activity pattern by pontine removal and vagal stimulations.
A. Model performance after vagotomy. B. Model performance after vagotomy and subsequent removal of pontine excitatory drive. Note the apneustic breathing pattern characterized by the significant increase in the duration of inspiration and slowing of the respiratory oscillations. C. Simulations of the effects of brief and continuous stimulation of mechanoreceptor afferents. The first stimulus (bottom trace, 7 ml of lung inflation) applied in the middle of the respiratory phase terminated the current inspiration. The second, reduced stimulus (5 ml) applied at the same phase was unable to terminate inspiration. The third stimulus of the same size as the second one (5 ml) applied later in inspiration terminated the inspiratory phase. Finally, continuous linearly increasing stimulation was applied. This stimulation shortened inspiration and prolonged expiration and then produced expiratory “apnea”, when all inspiratory neurons were inhibited by continuously active expiratory neurons.
Figure 4.
Effects of hypercapnia maintained at fcm = 5% in the intact (A) and vagotomized (B) models.
fcm is CO2 content in the mouth. In both cases, hypercapnia evoked increases in RTN drive (bottom traces in A and B). The applied hypercapnia increased the RTN drive to the late-E neuron evoking late-E discharges with the ratio 1∶3 to the ramp-I discharges in the vagus intact model (late-E trace in A) and the ratio 1∶2 in the vagotomized model (late-E trace in B). Each late-E pulse actuates the abdominal pump, reducing the base level of lung volume (see VA traces in A and B).
Figure 5.
Simulation of progressive hypercapnia in the intact model.
The continuous increase of hypercapnia (the grey ramp at the bottom) was induced by increasing CO2 content in the mouth fcm from 0 to 10%. Active expiration starts with the first appearance of late-E discharges (indicated by the left vertical dot-dashed line at fcm = 2.6%) and reaches the regime with a 1∶1 ratio of late-E to ramp-I activations at fcm = 7.2%. As described in the text, each late-E discharge, representing the activity of AbN output, actuates the abdominal pump that reduces the baseline level of lung volume (see in the VA trace).
Figure 6.
Simulation of progressive hypercapnia in the vagotomized model.
The continuous increase of hypercapnia (the grey ramp at the bottom) was induced by increasing CO2 content in the mouth fcm from 0 to 10%. Active expiration starts with the first appearance of late-E discharges (indicated by the left vertical dot-dashed line at fcm = 1.2%) and reaches the regime with the 1∶1 ratio of late-E to ramp-I activations at fcm = 7%. Again, each late-E discharge, representing the activity of AbN output, actuates the abdominal pump that reduces the baseline level of lung volume (see in the VA trace).
Figure 7.
Changes in tidal volume, breathing rate, and ventilation (relative to normocapnia) with the development of hypercapnia in the intact (panel A) and vagotomized (panel B) models.
CO2 content in the mouth fcm was linearly increased from zero to 10%. Changes in three major breathing characteristics (tidal volume, breathing rate, and ventilation) that would occur without active expiration (simulated by setting AbN = 0) are shown by the corresponding dashed lines. The vertical dot-dashed lines bound the development (quantal acceleration) of active expiration.
Figure 8.
Comparison of model simulations with experimental data.
A. Breathing stimulation elicited in conscious adult rat in a flow-through, whole-body plethysmography chamber by photostimulation via channelrodopsin genetically engineered in RTN Phox2b-expressing glutamatergic neurons. The left diagrams were constructed for hyperoxic normocapnia (100% O2), and the right diagrams for hypercapnia (8% CO2, balance O2). Continuous RTN stimulation (23 Hz, 3 ms pulses, 30 s total duration, blue bar at the top) raised tidal volume, VT, and breathing frequency, fR. During hyperoxic hypercapnia (right), RTN photostimulation produced a small increase in VT but no increase in fR. Adapted from Abbott et al. [52], Fig. 1B, with permission. B. The results of our simulations. An additional 30s-duration increase in the blood CO2 level (Δpc = 30 mmHg, blue bar at the top) was applied in the normocapnic case (left) and on the background of simulated hypercapnia (fcm = 8%) (right).
Table 1.
Parameters of neural network.
Table 2.
Parameters of the model.