The logic behind neural control of breathing pattern

The respiratory rhythm generator is spectacular in its ability to support a wide range of activities and adapt to changing environmental conditions, yet its operating mechanisms remain elusive. We show how selective control of inspiration and expiration times can be achieved in a new representation of the neural system (called a Boolean network). The new framework enables us to predict the behavior of neural networks based on properties of neurons, not their values. Hence, it reveals the logic behind the neural mechanisms that control the breathing pattern. Our network mimics many features seen in the respiratory network such as the transition from a 3-phase to 2-phase to 1-phase rhythm, providing novel insights and new testable predictions.

[1]  B Liss,et al.  A role for neuronal K(ATP) channels in metabolic control of the seizure gate. , 2001, Trends in pharmacological sciences.

[2]  Ruli Zhang,et al.  Voltage-Dependent Rhythmogenic Property of Respiratory Pre-Bötzinger Complex Glutamatergic, Dbx1-Derived, and Somatostatin-Expressing Neuron Populations Revealed by Graded Optogenetic Inhibition123 , 2016, eNeuro.

[3]  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.

[4]  Denis Thieffry,et al.  Logical Modeling and Dynamical Analysis of Cellular Networks , 2016, Front. Genet..

[5]  Kendall F Morris,et al.  Carotid Bodies and the Integrated Cardiorespiratory Response to Hypoxia. , 2018, Physiology.

[6]  Robert J. Butera,et al.  Two types of independent bursting mechanisms in inspiratory neurons: an integrative model , 2011, Journal of Computational Neuroscience.

[7]  D. Galletly,et al.  Influence of breathing frequency on the pattern of respiratory sinus arrhythmia and blood pressure: old questions revisited. , 2010, American journal of physiology. Heart and circulatory physiology.

[8]  Michelle L. Wynn,et al.  Logic-based models in systems biology: a predictive and parameter-free network analysis method. , 2012, Integrative biology : quantitative biosciences from nano to macro.

[9]  Ilya A. Rybak,et al.  A Closed-Loop Model of the Respiratory System: Focus on Hypercapnia and Active Expiration , 2014, PloS one.

[10]  H. Othmer,et al.  The topology of the regulatory interactions predicts the expression pattern of the segment polarity genes in Drosophila melanogaster. , 2003, Journal of theoretical biology.

[11]  Bruce G Lindsey,et al.  Computational models and emergent properties of respiratory neural networks. , 2012, Comprehensive Physiology.

[12]  L. Glass,et al.  The logical analysis of continuous, non-linear biochemical control networks. , 1973, Journal of theoretical biology.

[13]  D. Bayliss,et al.  Interdependent feedback regulation of breathing by the carotid bodies and the retrotrapezoid nucleus , 2017, The Journal of physiology.

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

[15]  Soo Borson,et al.  Respiratory sinus arrhythmia is associated with efficiency of pulmonary gas exchange in healthy humans. , 2003, American journal of physiology. Heart and circulatory physiology.

[16]  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.

[17]  Ilya A. Rybak,et al.  Organization of the core respiratory network: Insights from optogenetic and modeling studies , 2018, PLoS Comput. Biol..

[18]  M. Elstad,et al.  Respiratory variations in pulmonary and systemic blood flow in healthy humans , 2012, Acta physiologica.

[19]  Alona Ben-Tal,et al.  Central regulation of heart rate and the appearance of respiratory sinus arrhythmia: new insights from mathematical modeling. , 2014, Mathematical biosciences.

[20]  J. Ramirez,et al.  Advances in cellular and integrative control of oxygen homeostasis within the central nervous system , 2018, The Journal of physiology.

[21]  Jeffrey C. Smith,et al.  Respiratory rhythm generation in vivo. , 2014, Physiology.

[22]  Joseph A Fisher,et al.  Direct effect of Pa(CO2) on respiratory sinus arrhythmia in conscious humans. , 2002, American journal of physiology. Heart and circulatory physiology.

[23]  Demetrios Kazakos,et al.  Relations between the dynamics of network systems and their subnetworks , 2017 .

[24]  Gary C Sieck,et al.  Breathing: Motor Control of Diaphragm Muscle. , 2018, Physiology.

[25]  Jerry Silver,et al.  Phasic inhibition as a mechanism for generation of rapid respiratory rhythms , 2017, Proceedings of the National Academy of Sciences.

[26]  J. Ramirez,et al.  The interdependence of excitation and inhibition for the control of dynamic breathing rhythms , 2018, Nature Communications.

[27]  Alona Ben-Tal,et al.  A model for control of breathing in mammals: coupling neural dynamics to peripheral gas exchange and transport. , 2008, Journal of theoretical biology.

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

[29]  R. Stornetta,et al.  Phox2b-Expressing Neurons of the Parafacial Region Regulate Breathing Rate, Inspiration, and Expiration in Conscious Rats , 2011, The Journal of Neuroscience.

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

[31]  Katrin Suder,et al.  One-dimensional, nonlinear determinism characterizes heart rate pattern during paced respiration. , 1998, American journal of physiology. Heart and circulatory physiology.

[32]  J. Feldman,et al.  Breathing matters , 2018, Nature Reviews Neuroscience.

[33]  I. Rybak,et al.  Brainstem respiratory networks: building blocks and microcircuits , 2013, Trends in Neurosciences.

[34]  J. Rubin,et al.  Computational models of the neural control of breathing , 2017, Wiley interdisciplinary reviews. Systems biology and medicine.

[35]  Nathan A Baertsch,et al.  The Dynamic Basis of Respiratory Rhythm Generation: One Breath at a Time. , 2018, Annual review of neuroscience.

[36]  Joseph T. Costello,et al.  The human ventilatory response to stress: rate or depth? , 2017, The Journal of physiology.

[37]  S. Kauffman Homeostasis and Differentiation in Random Genetic Control Networks , 1969, Nature.

[38]  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.

[39]  G. Ermentrout,et al.  Multiple rhythmic states in a model of the respiratory central pattern generator. , 2009, Journal of neurophysiology.

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

[41]  Anna Devor,et al.  The great gate: Control of sensory information flow to the cerebellum , 2008, The Cerebellum.