Spatial and Functional Architecture of the Mammalian Brain Stem Respiratory Network: A Hierarchy of Three Oscillatory Mechanisms

Abstract

Smith JC, Abdala AP, Koizumi H, Rybak IA, Paton JF. Spatial and functional architecture of the mammalian brain stem respiratory network: a hierarchy of three oscillatory mechanisms. J Neurophysiol 98: 3370 -3387, 2007. First published October 3, 2007; doi:10.1152/jn.00985.2007. Mammalian central pattern generators (CPGs) producing rhythmic movements exhibit extremely robust and flexible behavior. Network architectures that enable these features are not well understood. Here we studied organization of the brain stem respiratory CPG. By sequential rostral to caudal transections through the pontine-medullary respiratory network within an in situ perfused rat brain stem-spinal cord preparation, we showed that network dynamics reorganized and new rhythmogenic mechanisms emerged. The normal three-phase respiratory rhythm transformed to a two-phase and then to a one-phase rhythm as the network was reduced. Expression of the three-phase rhythm required the presence of the pons, generation of the two-phase rhythm depended on the integrity of Bötzinger and pre-Bötzinger complexes and interactions between them, and the one-phase rhythm was generated within the pre-Bötzinger complex. Transformation from the three-phase to a two-phase pattern also occurred in intact preparations when chloridemediated synaptic inhibition was reduced. In contrast to the threephase and two-phase rhythms, the one-phase rhythm was abolished by blockade of persistent sodium current (I NaP ). A model of the respiratory network was developed to reproduce and explain these observations. The model incorporated interacting populations of respiratory neurons within spatially organized brain stem compartments. Our simulations reproduced the respiratory patterns recorded from intact and sequentially reduced preparations. Our results suggest that the three-phase and two-phase rhythms involve inhibitory network interactions, whereas the one-phase rhythm depends on I NaP . We conclude that the respiratory network has rhythmogenic capabilities at multiple levels of network organization, allowing expression of motor patterns specific for various physiological and pathophysiological respiratory behaviors. I N T R O D U C T I O NThe structural and functional organizations of various central pattern generators (CPGs) producing rhythmic movements have been studied for decades in an attempt to understand the neural basis of motor behavior. In contrast to CPGs in several invertebrates and lower vertebrates (Grillner 2006;Marder and Calabrese 1996;Selverston and Ayers 2006), the spatial and functional architectures of CPG circuits in the mammalian CNS, such as those generating breathing movements, have not been well defined. Breathing in mammals is a dynamically mutable motor behavior that not only performs a vital homeostatic function but is also integrated with many other physiological functions including suckling, swallowing, sniffing, chewing, and vocalization. With such functional diversity, respiratory CPG circuits must have a robust, yet highly flexible organ...

Central and peripheral chemoreceptors evoke distinct responses in simultaneously recorded neurons of the raphé-pontomedullary respiratory network

“…Correlations between neuronal spike trains indicate paucisynaptic interactions among neurons responsive to stimulation of either or both types of chemoreceptors; a functional projection to at least one other neuron could be inferred for approximately 50 per cent of the cells in each brain region. Detected correlational linkages suggest multiple feedback loops between different categories of neurons in the VRC and cells in the PRG and brainstem midline, supporting recent models of respiratory network architecture (Smith et al 2007;Rybak et al 2008;Nuding et al 2009). …”

Phase response properties of half-center oscillators

“…(iv) Our HCO model consists of two neurons coupled by mutual inhibition. However, many biological CPGs contain more than two populations of neurons (Grillner 2003;Kiehn 2006;Kristan et al 2005;Varkonyi et al 2008;Smith et al 2007). A different analysis may be required to study the phase response properties of these CPGs.…”

“…HCOs consist of two neurons (or neuronal populations) connected by reciprocal inhibition (Brown 1914;Mulloney and Smarandache 2010). This half-center organization is integral to many CPG circuits (e.g., Calabrese 1995;Satterlie 1985;Mulloney and Hall 2007;Smith et al 2007). The reciprocal inhibition and some form of slow adaptation leads to antiphase oscillations in which the units alternate between an active state and a suppressed (inhibited) state.…”

Central Neurogenic Hyperventilation in Anti-NMDA Receptor Encephalitis

“…Furthermore, a sustained normal (or perhaps increased) level of activation of non-NMDA glutamatergic receptors on pump cells of the nucleus tractus solitarius, which normally relay the inhibitory slowly adapting receptors input to the ventral respiratory column (VRC) and the pons, may contribute to the development of hypoventilation (10). In these cases, arousal might increase the breathing rate if the respiratory rhythm generators composed of the preBötzinger complex (PBötC) and the parafacial respiratory group (pRG) are operant (11). The PBötC neurokinin-1 receptor positive pre-inspiratory pacemaker cells express the type 2 vesicular glutamate transporter (VGlut2), indicating that these neurons play a role in glutamatergic transmission and might provide an excitatory stimulus to the remainder of the VRC, thus resulting in CNH (10).…”