Transcript Evolving Our Understanding of the Neural Control of Breathing Jeff

Evolving Our Understanding of
the Neural Control of Breathing
Jeff Mendenhall
College of William and Mary
Department of Applied Sciences, Room #314
Outline
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Why Investigate Breathing
Review
Standard Model
Shortcomings of the Standard Model
The Next Step
Dealing with the Problem of Detailed Models
Where to from here
Outline
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Why Investigate Breathing
Review
Standard Model
Shortcomings of the Standard Model
The Next Step
Dealing with the Problem of Detailed Models
Where to from here
Our Motivation
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Necessity of Breathing
SIDS
ALS
Rett Syndrome
Sleep Apnea
Outline
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Why Investigate Breathing
Review
Standard Model
Shortcomings of the Standard Model
The Next Step
Dealing with the Problem of Detailed Models
Where to from here
Basics
• Neural Control of Breathing Takes Place in the
PreBötzinger Complex (PBC)1
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
•3 Neuron Phenotypes 2
- Differentiated by size and presence or absence of
various currents (ionic fluxes carried by different
channels)
Available Data
• Electrical recordings of single
neurons and network output
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
• Electrical and Calcium
Imaging Data from Large
Regions of the Network
QuickTime™ and a
Animation decompressor
are needed to see this picture.
Outline
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Why Investigate Breathing
Review
Standard Model
Shortcomings of the Standard Model
The Next Step
Dealing with the Problem of Detailed Models
Where to from here
Standard Model
• Assumptions: Effectively Isospatial
Currents Present:
INaP, INaF, IK, IL, Itonic-e, Isyn
• Predictions: “Pacemaker” neurons and
INaP Essential for Network-Level Bursts
Outline
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Why Investigate Breathing
Review
Standard Model
Shortcomings of the Standard Model
The Next Step
Dealing with the Problem of Detailed Models
Where to from here
Problems with the
Standard Model I
• Assumptions: Effectively Isospatial
• Currents Present: INaP, INaF, IK(DR), IL, Itonic-e
+ ICAN, Ih, IA, INMDA, IGABA
Problems with the
Standard Model II
• Predictions: “Pacemaker” neurons
and INaP are Essential for Network
Functioning
-Pace, Mackay, Feldman, and Del Negro, in review process at
the J. Physiology, 2007. 3
-Del Negro, Morgado-Valle. Mackay, and Feldman, J.
Neuroscience, 25(2): 446-53.4
-Del Negro, Morgado-Valle, and Feldman, Neuron 34: 82130, 2002.5
Outline
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Why Investigate Breathing
Review
Standard Model
Shortcomings of the Standard Model
The Next Step
Dealing with the Problem of Detailed Models
Where to from here
The Next Step I
Dendritic Compartment
Somatic Compartment
gC
ECAN
g CAN
ESyn-Ex
g AMPA
ESyn-Ex
g NMDA
INaK
ENa
g NaF
INaK
ENa
g NaP
EK
gK
gK
EK
g K(Ca)
EK,Na,Ca
g L (K,Na,Ca)
EK,Na,Ca
g L(K,Na,Ca)
ECa
g Ca
ECa
g Ca
EK
gA
EAv. Neigh bor
g elec
ESyn-Ex
g tonic
CDend rite
ICa-ATP
EH
• Use Realistic
gNaP Conductance
• Add Other Currents
EK
ICa-ATP
• Correct Isospatial
Assumption
gH
CSom a
• Adjust parameters
for different phenotypes
of neurons
The Next Step II
• Add mGluR-IP3-Ca2+-ICAN pathway
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
• Add calcium microdomains
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Outline
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Why Investigate Breathing
Review
Standard Model
Shortcomings of the Standard Model
The Next Step
Dealing with the Problem of Detailed Models
Where to from here
The Problem:
Too Many Poorly Constrained Parameters
Dendritic Compartment
Somatic Compartment
gC
ECAN
g CAN
ESyn-Ex
g AMPA
ESyn-Ex
g NMDA
INaK
ENa
g NaF
INaK
ENa
g NaP
EK
gK
EK
gK
EK
g K(Ca)
EK,Na,Ca
g L (K,Na,Ca)
EK,Na,Ca
g L(K,Na,Ca)
ECa
g Ca
ECa
g Ca
ICa-ATP
EK
gA
EAv. Neigh bor
g elec
ESyn-Ex
g tonic
CDend rite
ICa-ATP
EH
gH
CSom a
What We Want
Parameter Space
Parameter Y
X
X
Parameter X
Methods: Evolving Solutions
Advantages of Evolutionary
Algorithm
• Efficiently Handles Large Parameter
Spaces
• Yields Many Good Regions
• Approximates Their Boundaries
Preliminary Results
• Test problem: fit a given curve to a sum
of gaussians
• Parameters: 60 (20 gaussians)
• Fitnesses: 401 (# data points)
Some Evolved Solutions
Generated Curve
Outline
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Why Investigate Breathing
Review
Standard Model
Shortcomings of the Standard Model
The Next Step
Dealing with the Problem of Detailed Models
Where to from here
Future Directions
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Improve Evolutionary Algorithm
Add mGluR IP3 Ca2+ Pathway
Test Networks
Make / Test Predictions
References
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Smith, J.C., Ellenberger, H.H., Ballanyi, K., Richter, D.W. & Feldman, J.L.
“Pre-Bötzinger complex: a brainstem region that may generate respiratory
rhythm in mammals.” Science 254, 726-9 (1991).
Rekling, J.C., Champagnat, J. & Denavit-Saubie, M. (1996)
“Electroresponsive properties and membrane potential trajectories of three
types of inspiratory neurons in the newborn mouse brain stem in vitro.” J
Neurophysiol 75, 795-810.
Ryland W. Pace, Devin D. Mackay, Jack L. Feldman, and Christopher A. Del
Negro (2007). “Cellular And Synaptic Mechanisms That Generate Inspiratory
Drive Potentials In Pre-Bötzinger Neurons In Vitro.” in review at J. Physiology.
Del Negro, C. A., C. Morgado-Valle, et al. (2005). "Sodium and Calcium
Current-Mediated Pacemaker Neurons and Respiratory Rhythm Generation."
J. Neurosci. 25(2): 446-453.
Del Negro, C. A., N. Koshiya, et al. (2002). "Persistent sodium current,
membrane properties and bursting behavior of pre-botzinger complex
inspiratory neurons in vitro." J Neurophysiol 88(5): 2242-50.