1. Evolving Our Understanding of the Neural Control of Breathing Jeff Mendenhall College of William and Mary Department of Applied Sciences, Room #314

2. Outline 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

3. Outline 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

4. Our Motivation Necessity of Breathing SIDS ALS Rett Syndrome Sleep Apnea

5. Outline 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

6. Basics Neural Control of Breathing Takes Place in the PreBötzinger Complex (PBC) 1 3 Neuron Phenotypes 2 - Differentiated by size and presence or absence of various currents (ionic fluxes carried by different channels)

7. Available Data Electrical recordings of single neurons and network output Electrical and Calcium Imaging Data from Large Regions of the Network

8. Outline 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

9. Standard Model Assumptions: Effectively Isospatial Currents Present: I NaP, I NaF, I K, I L, I tonic-e, I syn Predictions: “Pacemaker” neurons and I NaP Essential for Network-Level Bursts

10. Outline 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

11. Problems with the Standard Model I Assumptions: Effectively Isospatial Currents Present: I NaP, I NaF, I K(DR), I L, I tonic-e + I CAN, I h, I A, I NMDA, I GABA

12. Problems with the Standard Model II Predictions: “Pacemaker” neurons and I NaP 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: 821- 30, 2002. 5

13. Outline 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

14. The Next Step I Correct Isospatial Assumption Use Realistic gNaP Conductance Adjust parameters for different phenotypes of neurons Dendritic Compartment Somatic Compartment Add Other Currents

15. The Next Step II Add mGluR-IP 3 -Ca 2+ -I CAN pathway Add calcium microdomains

16. Outline 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

17. The Problem: Too Many Poorly Constrained Parameters Dendritic Compartment Somatic Compartment

18. What We Want Parameter Y Parameter X X X Parameter Space

19. Methods: Evolving Solutions

20. Advantages of Evolutionary Algorithm Efficiently Handles Large Parameter Spaces Yields Many Good Regions Approximates Their Boundaries

21. Preliminary Results Test problem: fit a given curve to a sum of gaussians Parameters: 60 (20 gaussians) Fitnesses: 401 (# data points)

22. Generated Curve Some Evolved Solutions

23. Outline 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

24. Future Directions Improve Evolutionary Algorithm Add mGluR IP 3 Ca 2+ Pathway Test Networks Make / Test Predictions

25. References 1.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). 2.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. 3. 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. 4. 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. 5. 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.