gang song, ph.d., research scientist harvard-mit division of health sciences and technology
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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. - PowerPoint PPT PresentationTRANSCRIPT
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Gang Song, Ph.D., Research ScientistHarvard-MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology
Neuroscience of Breathing –Don’t take my breath away: Pace-maker mechanisms of respiratory
rhythmogenesis
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normal
vagotomy
Apneusis
50 sec
Gasping
Changes of breathing pattern after sequential brainstem sectioning. (Adapted from Thomas Lumsden, 1923, J. Physiol.)
1
2
3
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Smith, J. C. et al. J Neurophysiol 98: 3370-3387 2007;doi:10.1152/jn.00985.2007
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
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Brainstem transection
performed on neonatal
rat brainstem identified
pre-Bötzinger complex
as the respiratory
pace-maker (Smith et.
al. Science, 1991)
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Del Negro et al., J Neurosci, 2005
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Pre-Bot pace-making neurons express NK1 receptors.
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Onimaru and Homma, Brain Res, 1987
Parafacial group of pace-making neuronswas reported 4 years before the pre-Bot group.
No anatomical marker was identified until now.
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Onimaru and Homma, J Neurosci, 2003
Parafacial pace-making neurons fire first
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Janczewski and Feldman, J Physiol, 2006
Airflow
Inspir.
Expir.
Airflow
Inspir.
Expir.
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Adult rat, anesthesia, bilateral vagotomy, hypoxia …
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A tale of two pacemakersA tale of two pacemakers
pre-Bötzinger complex (preBötC) pre-Bötzinger complex (preBötC) Smith et al. (1991)Smith et al. (1991) Monophasic: inspiratory burstsMonophasic: inspiratory bursts Two sub-types of pacemakers: Two sub-types of pacemakers:
NaP current (del Negro et al., 2002)NaP current (del Negro et al., 2002) CAN current (Thoby-Brisson & Ramirez, 2001)CAN current (Thoby-Brisson & Ramirez, 2001)
Parafacial respiratory group (pFRG)Parafacial respiratory group (pFRG) Onimaru & Homma (1987, 2003)Onimaru & Homma (1987, 2003) Rostral to preBötCRostral to preBötC;; overlaps retrotrapezoid nucleus overlaps retrotrapezoid nucleus Biphasic: Pre-I and post-I burstsBiphasic: Pre-I and post-I bursts Possibly NaP current (Onimaru et al., 1997)Possibly NaP current (Onimaru et al., 1997)
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Embarrassment of RichesEmbarrassment of Riches
Two-rhythms hypothesis Two-rhythms hypothesis preBötC: inspiratory rhythm generator (IRG)preBötC: inspiratory rhythm generator (IRG) pFRG: expiratory rhythm generator (ERG)pFRG: expiratory rhythm generator (ERG) Q: How do the two Q: How do the two harmonizeharmonize with one another? with one another?
Master rhythm hypothesisMaster rhythm hypothesis pFRG paces preBötC pFRG paces preBötC pFRG: ERG-cum-IRGpFRG: ERG-cum-IRG
Q: pFRG lesions didn’t abolish respiratory Q: pFRG lesions didn’t abolish respiratory rhythm: why?rhythm: why?
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Handshake • pFRG → preBötC excitation
• preBötC → pFRG reverse inhibition/hyperpolarization
• pFRG post-hyperpolarization rebound
• post-I inspiratory off-switch
Pacemakers Handshake HypothesisPacemakers Handshake Hypothesis
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Model FormulationModel Formulation
NaP conditional pacemaker models base on NaP conditional pacemaker models base on Hodgkin-Huxley formalism (Butera et al., 1999)Hodgkin-Huxley formalism (Butera et al., 1999)
Each pacemaker represents the lumped effect of the Each pacemaker represents the lumped effect of the pFRG or preBötC rhythmogenic networkpFRG or preBötC rhythmogenic network
preBötC pacemaker less excitable than pFRG preBötC pacemaker less excitable than pFRG (hence lower burst frequency)(hence lower burst frequency)
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Simulates Phase Resetting of pFRG burstsSimulates Phase Resetting of pFRG bursts
Model simulation of experimental data from Onimaru et al., Brain Res. (1988)
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Simulate Phase Resetting of preBötC burstsSimulate Phase Resetting of preBötC bursts
Model simulation of experimental data from Onimaru et al., Brain Res. (1988)
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preBötC veto of handshakepreBötC veto of handshake
No Yes
Stimulated cycle
Post-stim. cycle
Model simulation of experimental data from Onimaru et al., Brain Res. (1988)
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Simulates fractional Quantal Breathing (preBötC under depression)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)
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ConclusionsConclusions Model supports two-rhythms hypothesis Model supports two-rhythms hypothesis andand master rhythm master rhythm
hypothesishypothesis
ERG-IRG neither totally autonomous nor totally master-slave, ERG-IRG neither totally autonomous nor totally master-slave, but collaborative in partnershipbut collaborative in partnership
Both can oscillate, but it takes two to tangoBoth can oscillate, but it takes two to tango
preBötC is prime mover but preBötC is prime mover but pFRG is “better half”: pFRG is “better half”:
it strengthens it strengthens preBötC by synchronizing itpreBötC by synchronizing it
It backs up preBötC when it fails or falls shortIt backs up preBötC when it fails or falls short
Fail-safe redundancy avoids “putting all eggs in one basket”Fail-safe redundancy avoids “putting all eggs in one basket”
Handshake mechanism may be evolutionarily conservedHandshake mechanism may be evolutionarily conserved
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Thank you for your attention!