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Gang Song, Ph.D., Research Scientist Harvard-MIT Division of Health Sciences and Technology

Neuroscience of Breathing –Don’t take my breath away: Pace-maker mechanisms of respiratory rhythmogenesis. Gang Song, Ph.D., Research Scientist Harvard-MIT Division of Health Sciences and Technology Massachusetts Institute of Technology. normal. vagotomy. Apneusis. 1. 2. 50 sec. 3.

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Gang Song, Ph.D., Research Scientist Harvard-MIT Division of Health Sciences and Technology

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  1. Neuroscience of Breathing –Don’t take my breath away: Pace-maker mechanisms of respiratory rhythmogenesis Gang Song, Ph.D., Research Scientist Harvard-MIT Division of Health Sciences and Technology Massachusetts Institute of Technology

  2. normal vagotomy Apneusis 1 2 50 sec 3 Gasping Changes of breathing pattern after sequential brainstem sectioning. (Adapted from Thomas Lumsden, 1923, J. Physiol.)

  3. Example of a parasagittal section (neutral red stain) of the brain stem after rostral to caudal serial transections (250- to 350-{micro}m-thick slices indicated by arrows) made with a piezo-driven microvibratome (custom built) from an arterially perfused brain stem-spinal cord preparation of a 4-wk-old rat Smith, J. C. et al. J Neurophysiol 98: 3370-3387 2007; doi:10.1152/jn.00985.2007

  4. Brainstem transection performed on neonatal rat brainstem identified pre-Bötzinger complex as the respiratory pace-maker (Smith et. al. Science, 1991)

  5. Del Negro et al., J Neurosci, 2005

  6. Pre-Bot pace-making neurons express NK1 receptors.

  7. Parafacial group of pace-making neurons was reported 4 years before the pre-Bot group. No anatomical marker was identified until now. Onimaru and Homma, Brain Res, 1987

  8. Parafacial pace-making neurons fire first Onimaru and Homma, J Neurosci, 2003

  9. Airflow Inspir. Expir. Airflow Inspir. Expir. Janczewski and Feldman, J Physiol, 2006

  10. Adult rat, anesthesia, bilateral vagotomy, hypoxia …

  11. A tale of two pacemakers • pre-Bötzinger complex (preBötC) • Smith et al. (1991) • Monophasic: inspiratory bursts • Two sub-types of pacemakers: • NaP current (del Negro et al., 2002) • CAN current (Thoby-Brisson & Ramirez, 2001) • Parafacial respiratory group (pFRG) • Onimaru & Homma (1987, 2003) • Rostral to preBötC; overlaps retrotrapezoid nucleus • Biphasic: Pre-I and post-I bursts • Possibly NaP current (Onimaru et al., 1997)

  12. Embarrassment of Riches • Two-rhythms hypothesis • preBötC: inspiratory rhythm generator (IRG) • pFRG: expiratory rhythm generator (ERG) • Q: How do the two harmonize with one another? • Master rhythm hypothesis • pFRG paces preBötC • pFRG: ERG-cum-IRG Q: pFRG lesions didn’t abolish respiratory rhythm: why?

  13. Pacemakers Handshake Hypothesis • Handshake • pFRG → preBötC excitation • preBötC →pFRG reverse inhibition/hyperpolarization • pFRG post-hyperpolarization rebound • post-I inspiratory off-switch

  14. Model Formulation • NaP conditional pacemaker models base on Hodgkin-Huxley formalism (Butera et al., 1999) • Each pacemaker represents the lumped effect of the pFRG or preBötC rhythmogenic network • preBötC pacemaker less excitable than pFRG (hence lower burst frequency)

  15. Simulates Phase Resetting of pFRG bursts Model simulation of experimental data from Onimaru et al., Brain Res. (1988)

  16. Simulate Phase Resetting of preBötC bursts Model simulation of experimental data from Onimaru et al., Brain Res. (1988)

  17. No Yes Stimulated cycle Post-stim. cycle preBötC veto of handshake Model simulation of experimental data from Onimaru et al., Brain Res. (1988)

  18. Simulates fractional Quantal Breathing (preBötC under depression) Skipped cycle shorter than full cycles – no rebound excitation Model simulation of experimental data from Mellon et al., Neuron (2003)

  19. Conclusions • Model supports two-rhythms hypothesis and master rhythm hypothesis • ERG-IRG neither totally autonomous nor totally master-slave, but collaborative in partnership • Both can oscillate, but it takes two to tango • preBötC is prime mover but pFRG is “better half”: • it strengthens preBötC by synchronizing it • It backs up preBötC when it fails or falls short • Fail-safe redundancy avoids “putting all eggs in one basket” • Handshake mechanism may be evolutionarily conserved

  20. Thank you for your attention!

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