Spatial organization and state-dependent mechanisms for respiratory rhythm and pattern generation

Abstract

The brainstem respiratory network can operate in multiple functional states engaging different statedependent neural mechanisms. These mechanisms were studied in the in situ perfused rat brainstemspinal cord preparation using sequential brainstem transections and administration of riluzole, a pharmacological blocker of persistent sodium current (I NaP ). Dramatic transformations in the rhythmogenic mechanisms and respiratory motor pattern were observed after removal of the pons and subsequent medullary transactions down to the rostral end of pre-Bötzinger complex (pre-BötC). A computational model of the brainstem respiratory network was developed to reproduce and explain these experimental findings. The model incorporates several interacting neuronal compartments, including the ventral respiratory group (VRG), pre-BötC, Bötzinger complex (BötC), and pons. Simulations mimicking the removal of circuit components following transections closely reproduce the respiratory motor output patterns recorded from the intact and sequentially reduced brainstem preparations. The model suggests that both the operating rhythmogenic mechanism (i.e., networkbased or pacemaker-driven) and the respiratory pattern generated (e.g., three-phase, two-phase, or one-phase) depend on the state of the pre-BötC (expression of I NaP -dependent intrinsic rhythmogenic mechanisms) and the BötC (providing expiratory inhibition in the network). At the same time, tonic drives from pons and multiple medullary chemoreceptive sites appear to control the state of these compartments and hence the operating rhythmogenic mechanism and motor pattern. Our results suggest that the brainstem respiratory network has a spatial (rostral-to-caudal) organization extending from the rostral pons to the VRG, in which each functional compartment is controlled by more rostral compartments. The model predicts a continuum of respiratory network states relying on different contributions of intrinsic cellular properties versus synaptic interactions for the generation and control of the respiratory rhythm and pattern.

Patterns of inspiratory phase-dependent activity in the in vitro respiratory network

“…Characterization of the typical firing behavior of single neurons with respect to the respiratory cycle has been central to models of respiratory rhythm generation (Molkov et al 2010;Rubin et al 2009;Rybak et al 2007;Smith et al 2007). Categorization of this behavior into different types has provided the substrate for understanding rhythmogenesis as arising from antagonistic pools of neurons with characteristic firing patterns.…”

“…In the respiratory and locomotor networks, catalogs of 5-20 different firing patterns and their hypothesized connections have been incorporated into increasingly complex models of rhythm generation with the idea that they can potentially explain how these networks generate rhythmicity (Molkov et al 2010;Ogilvie et al 1992;Rubin et al 2009;Rybak et al 1997aRybak et al , 1997bRybak et al , 1997cRybak et al , 2007Rybak et al , 2008Sherwood et al 2011;Smith et al 2007). Yet, despite the reliance of current models on the concept of different physiological categories, the quantitative basis for these categories has not been rigorously established, nor have the criteria that specify inclusion into one or another cell class been described in detail.…”

Reconfiguration of respiratory-related population activity in a rostrally tilted transversal slice preparation following blockade of inhibitory neurotransmission in neonatal rats

“…Configuration and reconfiguration of the in vitro network activity in the tilted transversal slice Recent studies showed that the integrity of the pontomedullary respiratory network is required to generate the eupnoeic three-phasic motor pattern (inspiration, postinspiration, late expiration) of breathing [15,23,24]. Neverthe-less, specific compartments, which particularly include the pre-BötC, maintain their rhythmic activity in vitro [26], and such rhythmic slice preparations were extensively used to study cellular mechanisms of the primary respiratory-like rhythm generation.…”

“…Thus, excitatory drive to the RTN/pFRG would fit to a chemoreceptor-induced increase of the inspiratory rate. Finally, recently published data from the perfused brainstem preparation of juvenile rats suggest that the interaction between the neuronal population of the RTN/pFRG and pre-BötC relate to the inspiratory ramp pattern generator [3,15,23,24,54,55]. This is also supported by the presence of excitatory drive from the preinspiratory-like to the inspiratory-like neuron populations of the pre-BötC, because the excitatory coupling of preinspiratory neurones to augmenting inspiratory neurones is indeed a hallmark for the initiation of the inspiratory ramp in hypothetical models of respiratory rhythm generation [3,23,24,[54][55][56].…”

“…Nevertheless, synaptic inhibition is required from birth on to generate a physiological threephase motor pattern [22]. The generation of this threephase motor pattern of breathing (inspiration, postinspiration and late expiration) requires the functional and structural integrity of a pontomedullary respiratory network [3,4,14,15,23,24]. Nevertheless, the network can be separated anatomically and functionally into compartments.…”