Generation of the respiratory motor pattern is performed in the lower brainstem and involves complex cross-level interactions of cellular, network, and systems-level mechanisms. Because of these complex interactions, the system can operate in different functional states and engage different rhythmogenic mechanisms in each state. We hypothesize that the rhythmogenic mechanism operating in the respiratory network (i.e., network-based, pacemaker-driven or hybrid) is defined by the state of the pre-Botzinger complex, which in turn operates under control of other medullary and pontine circuits. We also suggest that the pons controls the state of the pre-Botzinger complex (and hence the rhythmogenic mechanism) directly and/or through other medullary circuits, such as the Botzinger complex. The overall goal of this multidisciplinary collaborative project is to investigate and understand these complex interactions and the state-dependency of respiratory rhythm generation by using experimental studies combined with computational modeling. The experimental studies will be performed by Dr. Smith (NINDS, NIH) and Dr. Paton (University of Bristol). The applied experimental methods will include (1) reduction of the operating respiratory network by sequential and highly precise transections applied to the pons and medulla and (2) using specific blockers of intrinsic neuronal properties (e.g., persistent sodium and other ionic channels) and network interactions (e.g., inhibitory synaptic transmission) applied to intact and reduced preparations. The computational model of the ponto-medullary respiratory network will be further developed by the group of Dr. Rybak (Drexel University) in close interactive collaboration with Drs. Smith and Paton using data accumulated in their laboratories. In turn, complementary experimental studies in these laboratories will be driven by modeling predictions. The resultant comprehensive computational model will be developed, tested and elaborated to reproduce the experimentally observed state-dependent changes in the firing patterns of respiratory neurons and in the discharge patterns of output motor nerves (phrenic, hypoglossal, central vagal and abdominal) under different experimental conditions. The proposed collaborative study will provide important insights into the complex neural mechanisms for control of breathing Ultimately, the model that will be developed in this project may be used for simulation of multiple respiratory disorders and diseases (e.g., sleep apnea, brainstem/spinal cord injury, CCHS), and for developing and investigations new methods for their treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS057815-05
Application #
7898548
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (50))
Program Officer
Liu, Yuan
Project Start
2006-08-02
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2010
Total Cost
$281,177
Indirect Cost
Name
Drexel University
Department
None
Type
Schools of Engineering
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Shevtsova, Natalia A; Büsselberg, Dietrich; Molkov, Yaroslav I et al. (2014) Effects of glycinergic inhibition failure on respiratory rhythm and pattern generation. Prog Brain Res 209:25-38
Molkov, Yaroslav I; Zoccal, Daniel B; Baekey, David M et al. (2014) Physiological and pathophysiological interactions between the respiratory central pattern generator and the sympathetic nervous system. Prog Brain Res 212:1-23
Rybak, Ilya A; Molkov, Yaroslav I; Jasinski, Patrick E et al. (2014) Rhythmic bursting in the pre-Bötzinger complex: mechanisms and models. Prog Brain Res 209:1-23
Smith, Jeffrey C; Abdala, Ana P L; Borgmann, Anke et al. (2013) Brainstem respiratory networks: building blocks and microcircuits. Trends Neurosci 36:152-62
Jasinski, Patrick E; Molkov, Yaroslav I; Shevtsova, Natalia A et al. (2013) Sodium and calcium mechanisms of rhythmic bursting in excitatory neural networks of the pre-Bötzinger complex: a computational modelling study. Eur J Neurosci 37:212-30
Molkov, Yaroslav I; Bacak, Bartholomew J; Dick, Thomas E et al. (2013) Control of breathing by interacting pontine and pulmonary feedback loops. Front Neural Circuits 7:16
Brocard, Frederic; Shevtsova, Natalia A; Bouhadfane, Mouloud et al. (2013) Activity-dependent changes in extracellular Ca2+ and K+ reveal pacemakers in the spinal locomotor-related network. Neuron 77:1047-54
Koizumi, Hidehiko; Koshiya, Naohiro; Chia, Justine X et al. (2013) Structural-functional properties of identified excitatory and inhibitory interneurons within pre-Botzinger complex respiratory microcircuits. J Neurosci 33:2994-3009
Lindsey, Bruce G; Rybak, Ilya A; Smith, Jeffrey C (2012) Computational models and emergent properties of respiratory neural networks. Compr Physiol 2:1619-70
Shevtsova, Natalia A; Manzke, Till; Molkov, Yaroslav I et al. (2011) Computational modelling of 5-HT receptor-mediated reorganization of the brainstem respiratory network. Eur J Neurosci 34:1276-91

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