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

The brainstem respiratory network can operate in multiple functional states engaging different state-dependent neural mechanisms. These mechanisms were studied in the in situ perfused rat brainstem-spinal cord preparation using sequential brainstem transections and administration of riluzole, a pharmacological blocker of persistent sodium current (INaP). 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., network-based 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 INaP-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.

[1]  Julian F. R. Paton,et al.  Defining eupnea , 2003, Respiratory Physiology & Neurobiology.

[2]  J. Paton,et al.  Characterizations of eupnea, apneusis and gasping in a perfused rat preparation. , 2000, Respiration physiology.

[3]  J. C. Smith,et al.  Pre-Bötzinger complex: a brainstem region that may generate respiratory rhythm in mammals. , 1991, Science.

[4]  J. Lipski,et al.  Extensive monosynaptic inhibition of ventral respiratory group neurons by augmenting neurons in the Bötzinger complex in the cat , 2006, Experimental Brain Research.

[5]  F. Plum.  Handbook of Physiology. , 1960 .

[6]  J C Smith,et al.  Respiratory rhythm generation in neonatal and adult mammals: the hybrid pacemaker-network model. , 2000, Respiration physiology.

[7]  D. Bayliss,et al.  Retrotrapezoid nucleus: a litmus test for the identification of central chemoreceptors. , 2005, Experimental physiology.

[8]  J. C. Smith,et al.  Models of respiratory rhythm generation in the pre-Bötzinger complex. II. Populations Of coupled pacemaker neurons. , 1999, Journal of neurophysiology.

[9]  Julian F R Paton,et al.  Respiratory rhythm generation during gasping depends on persistent sodium current , 2006, Nature Neuroscience.

[10]  T Lumsden,et al.  Observations on the respiratory centres in the cat , 1923, The Journal of physiology.

[11]  I. Leusen,et al.  Central Neurone Environment , 1983 .

[12]  N. Mellen,et al.  Opioid-Induced Quantal Slowing Reveals Dual Networks for Respiratory Rhythm Generation , 2003, Neuron.

[13]  I. A. Rybak,et al.  Modeling the ponto-medullary respiratory network , 2004, Respiratory Physiology & Neurobiology.

[14]  J C Smith,et al.  Isolation of the kernel for respiratory rhythm generation in a novel preparation: the pre-Bötzinger complex "island". , 2001, Journal of neurophysiology.

[15]  Ilya A. Rybak,et al.  Intrinsic bursting activity in the pre-Bötzinger Complex: Role of persistent sodium and potassium currents , 2003, Biological Cybernetics.

[16]  Allan I. Pack,et al.  Regulation of breathing , 1994 .

[17]  Ilya A Rybak,et al.  Endogenous rhythm generation in the pre‐Bötzinger complex and ionic currents: modelling and in vitro studies , 2003, The European journal of neuroscience.

[18]  T. Lumsden.  Observations on the respiratory centres , 1923, The Journal of physiology.

[19]  J. Duffin.  A commentary on eupnoea and gasping , 2003, Respiratory Physiology & Neurobiology.

[20]  Ilya A Rybak,et al.  Potential switch from eupnea to fictive gasping after blockade of glycine transmission and potassium channels. , 2002, American journal of physiology. Regulatory, integrative and comparative physiology.

[21]  D. Richter.  Neural Regulation of Respiration: Rhythmogenesis and Afferent Control , 1996 .

[22]  Uwe Windhorst,et al.  Comprehensive Human Physiology , 1996, Springer Berlin Heidelberg.

[23]  Julian F. R. Paton,et al.  A working heart-brainstem preparation of the mouse , 1996, Journal of Neuroscience Methods.

[24]  J. Feldman,et al.  PreBötzinger complex and pacemaker neurons: hypothesized site and kernel for respiratory rhythm generation. , 1998, Annual review of physiology.

[25]  Fiona E. N. LeBeau,et al.  Microcircuits in action – from CPGs to neocortex , 2005, Trends in Neurosciences.

[26]  D. Bayliss,et al.  Respiratory control by ventral surface chemoreceptor neurons in rats , 2004, Nature Neuroscience.

[27]  Jeffrey C. Smith,et al.  Neuronal pacemaker for breathing visualized in vitro , 1999, Nature.

[28]  H. Herbert,et al.  The Kölliker‐Fuse nucleus gates the postinspiratory phase of the respiratory cycle to control inspiratory off‐switch and upper airway resistance in rat , 2006, The European journal of neuroscience.

[29]  A. Goodchild,et al.  Firing patterns of pre-Bötzinger and Bötzinger neurons during hypocapnia in the adult rat , 2001, Brain Research.

[30]  M. I. Cohen,et al.  Neurogenesis of respiratory rhythm in the mammal. , 1979, Physiological reviews.

[31]  J. Ramirez,et al.  Defining eupnea. Commentaries , 2003 .

[32]  G. Richerson,et al.  Re: Retrotrapezoid nucleus: a litmus test for the identification of central chemoreceptors , 2005 .

[33]  K. Ezure,et al.  Synaptic connections between medullary respiratory neurons and considerations on the genesis of respiratory rhythm , 1990, Progress in Neurobiology.

[34]  John H. Peever,et al.  Bötzinger-complex, bulbospinal expiratory neurones monosynaptically inhibit ventral-group respiratory neurones in the decerebrate rat , 1999, Experimental Brain Research.

[35]  W. M. St John,et al.  Neurogenesis of patterns of automatic ventilatory activity. , 1998 .

[36]  I. Rybak,et al.  Potential switch from eupnea to fictive gasping following blockade of glycine transmission and potassium channels , 2002 .

[37]  J. C. Smith,et al.  Models of respiratory rhythm generation in the pre-Bötzinger complex. I. Bursting pacemaker neurons. , 1999, Journal of neurophysiology.

[38]  I A Rybak,et al.  Modeling neural mechanisms for genesis of respiratory rhythm and pattern. III. Comparison of model performances during afferent nerve stimulation. , 1997, Journal of neurophysiology.

[39]  I. Rybak,et al.  Modeling neural mechanisms for genesis of respiratory rhythm and pattern. II. Network models of the central respiratory pattern generator. , 1997, Journal of neurophysiology.

[40]  Donald R McCrimmon,et al.  Sodium currents in neurons from the rostroventrolateral medulla of the rat. , 2003, Journal of neurophysiology.

[41]  D. Richter,et al.  Calcium oscillations in rhythmically active respiratory neurones in the brainstem of the mouse , 1999, The Journal of physiology.

[42]  J. Feldman,et al.  Looking for inspiration: new perspectives on respiratory rhythm , 2006, Nature Reviews Neuroscience.

[43]  Ilya A. Rybak,et al.  Generation of the respiratory rhythm: state-dependency and switching , 2002, Neurocomputing.

[44]  Ronald J. MacGregor,et al.  Neural and brain modeling , 1987 .

[45]  The 3-2-1 state respiratory rhythm generator hypothesis revealed by microsectioning, reduced extracellular chloride and alterations in arterial gas tensions in the in situ rat , 2007 .

[46]  J C Smith,et al.  Abdominal expiratory activity in the rat brainstem–spinal cord in situ: patterns, origins and implications for respiratory rhythm generation , 2009, The Journal of physiology.

[47]  J. C. Smith,et al.  Neural control of respiratory pattern in mammals: an overview , 1995 .

[48]  D. Richter,et al.  A Three Phase Theory About the Basic Respiratory Pattern Generator , 1983 .

[49]  E. Nattie,et al.  CO2, brainstem chemoreceptors and breathing , 1999, Progress in Neurobiology.

[50]  J. Ramirez,et al.  Calcium Currents of Rhythmic Neurons Recorded in the Isolated Respiratory Network of Neonatal Mice , 1998, The Journal of Neuroscience.

[51]  George F. Alheid,et al.  Pontine influences on breathing: an overview , 2004, Respiratory Physiology & Neurobiology.

[52]  J C Smith,et al.  Spatial and functional architecture of the mammalian brain stem respiratory network: a hierarchy of three oscillatory mechanisms. , 2007, Journal of neurophysiology.

[53]  Ilya A. Rybak,et al.  Modeling neural mechanisms for genesis of respiratory rhythm and pattern. I. Models of respiratory neurons. , 1997, Journal of neurophysiology.