Reconfiguration of the pontomedullary respiratory network: a computational modeling study with coordinated in vivo experiments.

A large body of data suggests that the pontine respiratory group (PRG) is involved in respiratory phase-switching and the reconfiguration of the brain stem respiratory network. However, connectivity between the PRG and ventral respiratory column (VRC) in computational models has been largely ad hoc. We developed a network model with PRG-VRC connectivity inferred from coordinated in vivo experiments. Neurons were modeled in the "integrate-and-fire" style; some neurons had pacemaker properties derived from the model of Breen et al. We recapitulated earlier modeling results, including reproduction of activity profiles of different respiratory neurons and motor outputs, and their changes under different conditions (vagotomy, pontine lesions, etc.). The model also reproduced characteristic changes in neuronal and motor patterns observed in vivo during fictive cough and during hypoxia in non-rapid eye movement sleep. Our simulations suggested possible mechanisms for respiratory pattern reorganization during these behaviors. The model predicted that network- and pacemaker-generated rhythms could be co-expressed during the transition from gasping to eupnea, producing a combined "burst-ramp" pattern of phrenic discharges. To test this prediction, phrenic activity and multiple single neuron spike trains were monitored in vagotomized, decerebrate, immobilized, thoracotomized, and artificially ventilated cats during hypoxia and recovery. In most experiments, phrenic discharge patterns during recovery from hypoxia were similar to those predicted by the model. We conclude that under certain conditions, e.g., during recovery from severe brain hypoxia, components of a distributed network activity present during eupnea can be co-expressed with gasp patterns generated by a distinct, functionally "simplified" mechanism.

Respiratory pattern generator model using Ca++-induced Ca++ release in neurons shows both pacemaker and reciprocal network properties.

There are two contradictory explanations for central respiratory rhythmogenesis. One suggests that respiratory rhythm emerges from interaction between inspiratory and expiratory neural semicenters that inhibit each other and thereby provide reciprocal rhythmic activity (Brown 1914). The other uses bursting pacemaker activity of individual neurons to produce the rhythm (Feldman and Cleland 1982). Hybrid models have been developed to reconcile these two seemingly conflicting mechanisms (Smith et al. 2000; Rybak et al. 2001). Here we report computer simulations that demonstrate a unified mechanism of the two types of oscillator. In the model, we use the interaction of Ca(++)-dependent K+ channels (Mifflin et al. 1985) with Ca(++)-induced Ca++ release from intracellular stores (McPherson and Campbell 1993), which was recently revealed in neurons (Hernandez-Cruz et al. 1997; Mitra and Slaughter 2002a,b; Scornik et al. 2001). Our computations demonstrate that uncoupled neurons with these intracellular mechanisms show conditional pacemaker properties (Butera et al. 1999) when exposed to steady excitatory inputs. Adding weak inhibitory synapses (based on increased K+ conductivity) between two model neural pools surprisingly synchronizes the activity of both neural pools. As inhibitory synaptic connections between the two pools increase from zero to higher values, the model produces first dissociated pacemaker activity of individual neurons, then periodic synchronous bursts of all neurons (inspiratory and expiratory), and finally reciprocal rhythmic activity of the neural pools.

Suppression of diaphragmatic activity during spontaneous ponto-geniculo-occipital waves in cat.

It has been reported that spontaneous ponto-geniculo-occipital (PGO) waves, which occur during REM sleep in the cat, are associated with a brief inhibition of diaphragmatic activity (Orem, 1980). This report was preliminary and not supported by a detailed analysis. We report here analysis of the relationship between PGO waves and diaphragmatic activity based on 3073 PGO waves recorded simultaneously with diaphragmatic activity. The results show that there is indeed an inhibition of diaphragmatic activity during PGO waves. This inhibition has an amplitude up to 20% of background, and a duration (approximately 80 ms) approximately coinciding with the temporal duration of the PGO wave. In addition, we analyzed the relationships among the activity of medullary respiratory neurons, PGO waves, and diaphragmatic activity. Two neurons were observed whose relationships to diaphragmatic activity and PGO waves were consistent with the idea that they mediated the PGO-associated inhibition of diaphragmatic activity. However, the number of PGO waves involved in the analysis of the interaction between medullary respiratory neuronal activity and diaphragmatic activity was small and, although suggestive, was not conclusive.

Intercostal muscle activity of the cat in the curled, semiprone sleeping posture.

We examined the effect of different sleeping postures on intercostal muscle activity in the cat. Cats assume a variety of sleeping positions, but the semiprone, curled position with one side bearing most of the weight was the posture studied in these experiments. In this posture the cat's head rests upon the forepaws and may be slightly tilted. A lateral and ventral curvature of the spine and a lateral flexion of the neck form a curl with an upward-concave side and a downward-convex side. We examined the differences in intercostal activity on the concave and convex sides in this semiprone curled position in seven adult cats. Activity was studied at 14 sites (7 showing inspiratory and 7 showing expiratory activity). Inspiratory intercostal muscle activity was in all cases greater on the concave-upward side; similarly, expiratory intercostal muscle activity was, with the exception of activity at one site, greater on the concave-upward side than on the convex downward side. This effect was evident in rapid eye-movement (REM) as well as nonrapid-eye-movement (NREM) sleep.