Advances in Experimental Medicine and Biology

Volume 669

Editorial Board:

NATHAN BACK, State University of New York at BuffaloIRUN R. COHEN, The Weizmann Institute of ScienceABEL LAJTHA, N.S. Kline Institute for Psychiatric ResearchJOHN D. LAMBRIS, University of PennsylvaniaRODOLFO PAOLETTI,

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University of Milan

Ikuo Homma · Hiroshi Onimaru ·Yoshinosuke FukuchiEditors

New Frontiers in RespiratoryControl

XIth Annual Oxford Conference on Modelingand Control of Breathing

123

ISBN 978-1-4419-5691-0 e-ISBN 978-1-4419-5692-7DOI 10.1007/978-1-4419-5692-7Springer New York Dordrecht Heidelberg London

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EditorsIkuo HommaDepartment of PhysiologyShowa University School of Medicine1-5-8 Hatanodai, Shinagawa-kuTokyo 142-8555, Japanihomma@med.showa-u.ac.jp

Yoshinosuke FukuchiDepartment of Respiratory MedicineJuntendo University School of Medicine2-1-1 Hongo, Bunkyo-kuTokyo 113-8421, Japanyfukuchi@tea.ocn.ne.jp

Hiroshi OnimaruDepartment of PhysiologyShowa University School of Medicine1-5-8 Hatanodai, Shinagawa-kuTokyo 142-8555, Japanoni@med.showa-u.ac.jp

Preface Breathing is performed by the rhythmic contraction of respiratory muscles. It main-tains homeostasis of the organism by taking in the oxygen necessary to live and work and by controlling the level of CO2 within the organism. At first glance, breathing seems simple; however, it is produced by a complex system in the brain with various afferents and efferents. The control of breathing is of the utmost importance in sus-taining life, and although more than 150 years have passed since research on breath-ing control was first begun, many unsolved mysteries still remain. Breathing is like watching the tides at a beach that are created by the vast, complex open sea.

The first Oxford Conference on Modeling and Control of Breathing was held 30 years ago in September of 1978 at the University Laboratory of Physiology in Oxford, England. During this first conference, the participants engaged in a hot dis-cussion on the problem of whether breathing rhythm was produced by pacemaker cells or a neural network. This was before the discovery of the Bötinger complex in the medulla, and at the time, central chemoreceptive areas were still the focus of research. This conference was an especially unforgettable moment in the dawning of the new age of respiratory research. It has since been held every 3 years in various countries around the globe and is widely appreciated as the best respiratory meeting in the world.

We were very much honored to organize the XIth Oxford Conference in Nara, the ancient capital of Japan, and it was timely that the city was just beginning the celebration of its founding as the capital 1300 years ago. Nara is famous for its an-cient temples, ruins, and forests, which collectively form the Historic Monuments of Ancient Nara, a UNESCO World Heritage Site. The conference was held at the Noh Theater in Nara Park and included 43 oral and 71 poster presentations focussing mainly on the control of breathing. More than 140 participants from 15 countries attended, and we believe that the participants could feel the tradition of old Japan and at the same time discover new frontiers in respiratory control in Nara. At the busi-ness meeting of the Oxford Conference, the international committee decided that the next Oxford Conference will be held

We are very grateful to all the participants who attend the Conference and to the local program committees. The Editors especially offer their heartfelt thanks to Lena Akai, Michiko Iwase, and the members of Department of Physiology, Showa University School of Medicine, for editorial assistance in the production of this book. Publication of this book was supported by Private University High Technology Research Center Project.

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in Groningen, Holland.

The Editors

Conference Co-Chairs: Ikuo Homma (Tokyo, Japan) Yoshinosuke Fukuchi (Tokyo, Japan)

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Conference Proceedings

ix

Dr. Gila Benchetrit Laboratoire de Physiologie

Respiratoire Expérimentale Université Joseph Fourier Université de Grenoble (PRETA-TIMC, UMR CNRS 5525) 38700 La Tronche, France

Dr. Jean Champanat Neurobiologie Génétique et

Intégrative Institut de Neurobiolo-gie Alfred Fessard, bât.

33, C.N.R.S. C.N.R.S. - U.P.R. 2216 91198, Gif-sur-Yvette, France Dr. Ikuo Homma Department of Physiology Showa University School

of Medicine 1-5-8 Hatanodai, Shinagawa-ku Tokyo 142-8555, Japan Dr. Richard L. Hughson Cardiorespiratory and Vascular

Dynamics Laboratory, University of Waterloo

Waterloo, Ontario, Canada Dr. Homayoun Kazemi Pulmonary and Critical Care Unit Harvard Medical School Bulfinch 148 Massachusetts General Hospital Boston, MA, 02114, USA

Dr. Chi-Sang Poon Harvard-MIT, Division of Health

Science & Technology, Massachusetts Institute of Technology 77 Massachusetts Avenuse- Bldg. E25-501 Cambridge, MA

02139, USA Dr. Marc J. Poulin Department of Physiology & Biophysics Faculty of Medicine, University

of Calgary 3330 Hospital Drive NW Calgary, Alberta T2N 4N1, Canada Dr. Peter Sheid Institute für Physiologie Ruhr-Universität Bochum D-44780 Bochum, Germany Dr. John W. Severinghaus Department of Anesthesiology, University of California Medical

School San Francisco, California 91143-0542, USA Dr. Peter A. Robbins University Laboratory

of Physiology University of Oxford, Parks Road Oxford Ox1 3PT, United Kingdom

The XIth Oxford Conference: International Organizing Committee

x The XIth Oxford Conference Dr. Susan A Ward Human Bio-Energetics Research

Centre Crickhowell Powys, NP8 1AT, United Kingdom Dr. Brian J. Whipp Human Bio-Energetics Research

Centre Crickhowell Powys, NP8 1AT, United Kingdom

Dr. Richard Wilson Department of Physiology &

Biophysics Faculty of Medicine, University

of Calgary 3330 Hospital Drive NW Calgary, Alberta T2N 4N1, Canada

President Dr. Ikuo Homma Showa University School

of Medicine 1-5-8 Hatanodai, Shinagawa-ku, Tokyo142-8555, Japan

Dr. Yoshinosuke Fukuchi Juntendo University School

of Medicine 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan

Committee Dr. Akiko Arata Division of Physiome Department

of Physiology, Hyogo College of Medicine

1-1 Mukogawa, Nishinomiya Hyogo 663-8501, Japan

Dr. Makito Iizuka Center for Medical Sciences,

Ibaraki Prefectural University of Health Sciences

4669-2 Ami Ibaraki 300-0394, Japan

Dr. Naofumi Kimura Department of Pharmacology (II),

Jikei University School of Medicine

3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan

Dr. Hajime Kurosawa Department of Internal Medicine

and Rehabilitation Science, Tohoku University School of Medicine

1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan

Dr. Tomoyuki Kuwaki Department of Physiology, Kagoshi-

ma University, Graduate School of Medical & Dental Sciences

8-35-1 Sakuragaoka, Kagoshima-city Kagoshima, 890-8520, Japan

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Dr. Hiroshi Kimura Second Department of Internal

Medicine, Nara Medical University School of

Medicine 840 Shijo-cho, Kashihara, Nara

634-8522, Japan

The XIth Oxford Conference: Local Organizing Committee

The XIth Oxford Conference xii

Dr. Shun-ichi Kuwana Department of Physiology, Faculty

of Health Sciences, Uekusa Gakuen University

0639-3 Ogura-cho, Wakaba-ku, Chiba 264-0007, Japan

Dr. Yasumasa Okada Department of Medicine, Keio University Tsukigase

Rehabilitation Center 380-2 Tsukigase, Izu City 410-3215 Japan Dr. Yoshitaka Oku Division of Physiome, Department

of Physiology, Hyogo College of Medicine

1-1 Mukogawa, Nishinomiya Hyogo 663-8501, Japan Dr. Hiroshi Onimaru Department of Physiology, Showa University School of

Medicine 1-5-8 Hatanodai, Shinagawa-ku

Tokyo 142-8555, Japan

Dr. Eiji Takahashi Department of Physiology, Yamagata University School

of Medicine Yamagata 990-9585, Japan Conference Assistants Ms. Yuki Kuwayama Showa University School

of Medicine 1-5-8 Hatanodai, Shinagawa-ku

Tokyo 142-8555, Japan Ms. Emi Kato Convention Academia Inc. 3-35-3 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Conference Overview Title: The 11th Oxford Conference on Modeling and Control of Breathing Theme: New Frontiers in Respiratory Control Date: July 23 (Thursday) - 26 (Sunday), 2009 Venue: Nara Prefectural New Public Hall, Nara City, JAPAN Presidents: Ikuo Homma, M.D., Ph.D. Showa University, School of Medicine, Tokyo Yoshinosuke Fukuchi M.D., Ph.D. Juntendo University, School of Medicine, Tokyo Web-site: http://www.oxford-conference.com Secretariat: Head Office: Showa University, School of Medicine, Tokyo, Japan Administration Office: c/o Convention Academia Inc.

TEL. +81 (0)3 5808 5261 FAX. +81 (0)3 3815 2028 E-MAIL: 11oxfordconfarence@coac.co.jp Acknowledgements The Organizing Committee would like to thank the following parties for their generous contribution towards the success of the 11th Oxford Conference (2009). This Conference has been supported by: – The Commemorative Organization for the Japan World Exposition (‘70) – The Federation of Pharmaceutical Manufacturer’s Associations of JAPAN – Nara Prefecture – Nara City – Association for Commemorative Events of the 1300th Anniversary of Nara

Heijokyo Capital – Nara Medical Association – Nara Medical University – Showa University Special Thanks to: – Abbott Japan Co., Ltd. – Otsuka Pharmaceutical Co., Ltd. – Teijin Pharma Ltd. Corporate Sponsors – Brainvision Inc. – CHEST M.I., Inc. – FUJI RESPIRONICS Co., Ltd. – FUKUDA DENSHI

– MINATO MEDICAL SCIENCE Co., Ltd.

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Past Oxford Conferences Ist Oxford Conference University Laboratory of Physiology, Oxford, United Kingdom (September l978) Publication: Modelling of a Biological Control System: The Regulation of Breathing. E.R. Carson, D.J. C. Cunningham, R. Herczynski, D.J. Murray-Smith and E.S. Peterson, eds., Oxford: Institute of Measurement and Control, 1978 IInd Oxford Conference University of California Conference Centre at Lake Arrowhead California, USA (13-16 September, 1982) Publication: Modelling and the Control of Breathing. B.J. Whipp and D.M. Wiberg, eds., Elsevier Press, New York, 1983. IIIrd Oxford Conference Medieval Abbey of Solignac, Solignac, France (September l985) Publication: Concepts and Formalizations in the Control of Breathing. G. Benchetrit, P. Baconnier and J. Demongeot, eds., Manchester University Press, 1987. IVth Oxford Conference Shadow Cliff Life Centre at Grand Lake, Grand Lake, Colorado, USA (September 1988) Publication: Respiratory Control: A Modeling Perspective, G.D. Swanson, F.S. Grodins, and R.L. Hughson, eds., Plenum Press, New York, 1989. Vth Oxford Conference Fuji Institute, Fuji, Japan (199l) Publication: Control of Breathing and its Modelling Perspective, Y. Honda, Y. Miyamoto, K. Konno and J. Widdicombe, eds., Plenum Press, New York, 1992.

xvii

Pass Oxford Conference xviii

Publication: Advances in Modeling and Control of Ventilation (Advances in Expe-rimental Medicine and Biology series, Vol. 450). R.L. Hughson, DA. Cunningham, and J. Duffin, eds., Plenum Press, New York, 1998. VIIIth Oxford Conference North Falmouth, Cape Cod, Massachusetts, USA (1 1-l5 October, 2000) Publication: Frontiers in Modeling and Control of Breathing: Integration at Mole-cular, Cellular, and Systems Levels (Advances in Experimental Medicine and Biolo-gy series, Vol. 499). C.-S. Poon and H. Kazemi, eds., Kluwer Academic/Plenum Publishers, New York, 2001. IXth Oxford Conference Paris, France (September, 2003) Publication: Post-Genomic Perspectives in Modeling and Control of Breathing (Advances in Experimental Medicine and Biology series, Vol. 551). J. Champagnat, M. Denavit-Saubie', G. Fortin, A.S. Foutz. M. Thoby-Brisson, eds., Kluwer Academic/Plenum Publishers, New York, 2004. Xth Oxford Conference Chateau Lake Louise, Lake Louise, Alberta, Canada (l9-24 September, 2006)

VIth Oxford Conference Royal Holloway College, Egham, Surrey, United Kingdom (September, l994) Publication: Modeling and Control of Ventilation (Advances in Experimental Medi-cine and Biology series, Vol. 393). S.J.G. Semple, L. Ahms, and B.J. Whipp, eds., Plenum Press, New York, 1995. VIIth Oxford Conference Grandview Inn, Huntsville, Ontario, Canada (September, 1997)

Publication: Integration in Respiratory Control, From Genes to Systems (Advances in Experimental Medicine and Biology series, Vol. 605) M.J.Poulin, R.J.A Wilson, eds., Springer, New York, 2008. XIth Oxford Conference Nara Prefectural New Public Hall, Nara City, JAPAN (23-26 July, 2009) Publication: New Frontiers in Respiratory Control (Advances in Experimental Med-icine and Biology Series), I. Homma, H. Onimaru, and Y. Fukuchi, eds., Springer, New York, 2010.

xix

Contents

Part I Comparative Aspects ………………………………………………… 1 1 Evidence for a Distributed Respiratory Rhythm

Generating Network in the Goldfish (Carassius auratus) ………………. 3 Maryana Duchcherer, Andrew Kottick, and R.J.A. Wilson

2 Fictive Lung Ventilation in the Isolated Brainstem

Preparation of the Aquatic Frog, Xenopus Laevis ……………………… 9 Naofumi Kimura

Part II Development …………………………………………………........... 13 3 Loss of Pre-Inspiratory Neuron Synchroneity in Mice

with DSCAM Deficiency ………………………………………………… 15 Kenji Amano, Morimitsu Fujii, Satoru Arata, Masaharu Ogawa,

Kazuhiro Yamakawa, and Akiko Arata

4 Central Respiratory Failure in a Mouse Model Depends on the Gentic Background of the Host ………………………………….. 21

Satoru Arata, Kenji Amano, Kazuhiro Yamakawa, and Akiko Arata

5 Adrenaline Modulates on the Respiratory Network Development …… 25 Morimitsu Fujii and Akiko Arata

6 Ontogeny of Homeostasis in Mouse Hypoglossal Nucleus ………… 29 Akihito Okabe, Akiko Arata, Yoshitaka Oku, Chitoshi Takayama, and Atsuo Fukuda 7 Anatomical Changes of Phrenic Motoneurons During Development ………………………………………………………33 Yasumasa Okada, Shigefumi Yokota, Yoshio Shinozaki, Fumikazu

Miwakeichi, Yoshitaka Oku, and Yukihiko Yasui

Cl-

Contents xx 8 Postnatal Changes in Morphology and Dendritic Organization of

Neurones Located in the Area of the Kölliker-Fuse Nucleus of Rat ….. 37 Julia Reuter, Miriam Kron, and Mathias Dutschmann

Part III Modeling ……………………………………………………………43 9 Geometrical Analysis of Bursting Pacemaker Neurons

Generated by Computational Models: Comparison to In Vitro pre-Bötzinger Complex Bursting Neurons ………………………………45

Juan M. Cordovez, Christopher G. Wilson, and Irene C. Solomon 10 Origami Model for Breathing Alveoli ……………………………………49 Hiroko Kitaoka, Carlos A. M. Hoyos, and Ryuji Takaki 11 Biologically Variable Respiration as a Stochastic Process

in Ventilation – a Stochastic Model Study ………………........................ 53 Kyongyob Min, Keita Hosoi, Masayuki Degami, and Yoshinori

Kinoshita 12 Future Perspectives - Proposal for Oxford Physiome Project …..…...... 57 Yoshitaka Oku 13 Homeostatic Competition: Evidence of a Serotonin-Gated

Spinopara Brachial Pathway for Respiratory and Thermoregulatory Interaction ………………………………………61

Chi-Sang Poon 14 A Simplified Model for Explaining Negative Feedback

to Beginners in Life Sciences ……………………………………………. 67 Masato Shibuya, Yoshitaka Oku, and Ikuo Homma 15 Paradoxical Potentiation of Exercise Hyperpnea in Congestive

Heart Failure Contradicts Sherrington Chemoreflex Model and Supports a Respiratory Optimization Model ………………69

Chung Tin, Karlman Wasserman, Neil S. Cherniack, and Chi-Sang Poon

Part IV Respiratory rhythm generation …………………………………..73 16 Indirect Opioid Actions on Inspiratory pre-Bötzinger

Complex Neurons in Newborn Rat Brainstem Slices ………………….75 Klaus Ballanyi, Bogdan Panaitescu, and Araya Ruangkittisakul

Contents xxi 17 Multiphoton/Confocal Ca2+-Imaging of Inspiratory

pre-Bötzinger Complex Neurons at the Rostral or Caudal Surface of Newborn Rat Brainstem Slices …………………. 81

Nicoleta Bobocea, Araya Ruangkittisakul, and Klaus Ballanyi 18 Phox2b Expressing Neurons in the Most Rostral Medulla of Newborn Rats ……………………………………………….. 87 Hiroshi Onimaru, Keiko Ikeda, and Kiyoshi Kawakami 19 Depression by Ca2+ and Stimulation by K+ of Fictive Inspiratory

Rhythm in Newborn Rat Brainstem Slices ………………………………91 Bogdan Panaitescu, Araya Ruangkittisakul, and Klaus Ballanyi 20 Glycinergic Interneurons in the Respiratory Network

of the Rhythmic Slice Preparation …………………………………........ 97 Stefan M. Winter, Jens Fresemann, Christian Schnell, Yoshitaka Oku, Johannes Hirrlinger, and Swen Hülsmann

Part V Neuromodulation …………………………………………………. 101 21 Cholinergic Sensitivity of the Developing Bullfrog (Rana catesbeiana) Does Not Explain Vulnerability

to Chronic Nicotine Exposure …………………………………………. 103 Cord M. Brundage, Carla A. Nelson, and Barbara E. Taylor 22 Modulation of Respiratory Activity by Hypocretin-1 (Orexin A)

In Situ and In Vitro ……………………………………………………. 109 Andrea Corcoran, George Richerson, and Michael Harris 23 Effect of JM-1232(-), a New Sedative on Central Respiratory

Activity in Newborn Rats ………………………………………………. 115 Junya Kuribayashi, Shun-ichi Kuwana, Yuki Hosokawa, Eiki Hatori, and

Junzo Takeda 24 PACAP Modulates the Respiratory Rhythm Generated

in the Brainstem Slice Preparation ……………………………………. 119 Fernando Peña

25 Caffeine Reversal of Opioid-Evoked and Endogenous

Inspiratory Depression in Perinatal Rat En Bloc Medullas and Slices …………………………………………………………………123

Araya Ruangkittisakul, Bogdan Panaitescu, Junya Kuribayashi, and Klaus Ballanyi

Contents xxii

26 Acute Morphine Effects on Respiratory Activity in Mice with Target Deletion of the Tachykinin 1 Gene (Tac1-/-) ……………. 129 Yuri Shvarev, Jonas Berner, Andras Bilkei-Gorzo, Hugo Lagercrantz, and Ronny Wickström

Part VI Respiratory rhythm and motor pattern generation ……………133 27 Active Inspiratory-Expiratory Phase Switching Mechanism Exists in the Neonatal Nucleus Parabrachialis ……………………….. 135 Akiko Arata, Ikuko Tanaka, Morimitsu Fujii, and Kazuhisa Ezure 28 Influence of 5-HT2A Receptor Blockade on Phrenic Nerve Discharge at Three Levels of Extracellular K+ in Arterially-Perfused Adult Rat …………………………………….... 139 Tejus A. Bale and Irene C. Solomon 29 The Generation of Post-Inspiratory Activity in Laryngeal Motoneurons: A Review ……………………………………………...... 143 Tara G. Bautista, Peter G.R. Burke, Qi-Jian Sun, Robert G. Berkowitz, and Paul M. Pilowsky 30 Plasticity of Respiratory Rhythm-Generating Mechanism in Adult Goats …………………………………………………………….. 151 Hubert V. Forster, Katie L. Krause, Tom Kiner, Suzanne E. Neumueller, Josh M. Bonis, Baogang Qian, and Lawrence G. Pan 31 Abdominal Respiratory Motor Pattern in the Rat …………………… 157

Makito Iizuka 32 What Does the Multi-peaked Respiratory Output Pattern Tell Us About the Respiratory Pattern Generating Neuronal Network? …………………………………………………….. 163 Makio Ishiguro, Shigeharu Kawai, Yasumasa Okada, Yoshitaka Oku, Fumi kazu Miwakeichi, Yoshiyasu Tamura, and Amit Lal 33 The Diaphragm: a Hidden but Essential Organ for the Mammal and the Human ………………………………………. 167 Hiroko Kitaoka and Koji Chihara

34 Upper Airway and Abdominal Motor Output During Sneezing: Is the In Vivo Decerebrate Rat an Adequate Model? …………………173 Kenichi Ono, Tabitha Y. Shen, Hyun Hye Chun, and Irene C. Solomon

Con tents xxiii 35 Laudanosine has No Effects on Respiratory Activity but Induces Non-Respiratory Excitement Activity in Isolated Brainstem-Spinal Cord Preparation of Neonatal Rats ………………. 177 Shigeki Sakuraba, Yuki Hosokawa, Yuki Kaku, Junzo Takeda, and Shun-ichi Kuwana 36 Influence of Extracellular [K+]o on Inspiratory Network Complexity of Phrenic and Hypoglossal Nerve Discharge in Arterially-Perfused Adult Rat …………………………………....... 181 Tabitha Y. Shen, Kenichi Ono, and Irene C. Solomon 37 Bilateral Lesions of Pontine Kölliker-Fuse Nuclei Provoke Apnea instead of Apneusis in Anesthetized Adult Rats ……………… 185 Gang Song, Chung Tin, and Chi-Sang Poon 38 Vesicular Glutamate Transporter 2-immunoreactive Synapses onto Phrenic Motoneurons in the Neonatal Rat ……………………… 189 Shigefumi Yokota, Yoshio Shinozaki, Yoshitaka Oku, Yasumasa Okada, and Yukihiko Yasui Part VII Hypoxic sensing …………………………………………………. 193 39 Hypoxic Responses of Arterial Chemoreceptors in Rabbits are Primarily Mediated by Leak K Channels ………………………… 195 40 Halothane and Sevoflurane Exert Different Degrees of Inhibition on Carotid Body Glomus cell Intracellular Ca2+ Response to Hypoxia …………………………………………….... 201 Jaideep J. Pandit and Keith J Buckler 41 Differential effects of Halothane and Isoflurane on Carotid Body Glomus Cell Intracellular Ca2+ and Background K+ Channel Responses to Hypoxia ………………………………………… 205 Jaideep J. Pandit, Victoria Winter, Rebecca Bayliss, and Keith J. Buckler 42 ‘Hypoxic Ventilatory Decline’ in the Intracellular Ca2+ Response to Sustained Isocapnic Hypoxia in Carotid Body Glomus Cells …….. 209 Jaideep J Pandit, Josie Collyer, and Keith J Buckler

43 Intracellular Diffusion of Oxygen and Hypoxic Sensing: Role of Mitochondrial Respiration…………………………………… 213 Eiji Takahashi and Michihiko Sato

N. Kobayashi and Y. Yamamoto

...

Contents xxiv

Part VIII Integrative aspect of control of breathing ……………………..219 44 Measuring the Hypoxic Ventilatory Response …………………………221

A. Battisti, J.A. Fisher, and J.Duffin 45 Multiple Pathways to Long-Lasting Phrenic Motor Facilitation …..... 225 Erica A. Dale-Nagle, Michael S. Hoffman, Peter M. MacFarlane,

46 Phase Relations Between Rhythmical Movements and Breathing in Wind Instrument Players ……………………………………………. 231 D. Ebert, E. Georgas, D. Rosenthal, C. Wibowo, T. Massing, T. Barth, and H. Hefter 47 Circadian Changes in Respiratory Responses to Acute Hypoxia and Histamine H1 Receptors in Mice ………………………………...... 235 Michiko Iwase, Yasuyoshi Ohshima, Masahiko Izumizaki, and Ikuo Homma 48 Chemical Control of Airway and Ventilatory Responses Mediated Via Dorsomedial Medullary 5-HT2 Receptors……………………....... 239 Mitsuko Kanamaru and Ikuo Homma 49 Hypothalamic Modulation of Breathing ………………………………. 243 Tomoyuki Kuwaki 50 Rapid Increase to Double Breathing Rate Appears During REM Sleep in Synchrony with REM-A Higher CNS Control of Breathing? - ……………………………………………………………249 Shinichi Sato, Takashi Kanbayashi, Hideaki Kondo, Namiko Matsubuchi, Kyoichi Ono, and Tetsuo Shimizu 51 The Diaphragmatic Activities During Trunk Movements……………. 253 Minako Uga, Masatoshi Niwa, Naoyuki Ochiai, and Sei-Ichi Sasaki Part IX Sleep apnea ………………………………………………………. 257 52 GABAergic and Glycinergic Control of Upper Airway Motoneurons in Rapid Eye Movement Sleep ………………………….. 259 Patricia L. Brooks and John H. Peever 53 Antioxidant Treatment Does Not Prevent Chronic Hypoxia-Induced Respiratory Muscle Impairment in Developing Rats …………………263 Jayne Carberry, Aidan Bradford, and Ken D. O Halloran

and Gordon S. Mitchell

’

Con tents xxxxv 54 Respiratory Plasticity in the Behaving Rat Following Chronic Intermittent Hypoxia …………………………………………. 267 Deirdre Edge, J. Richard Skelly, Aidan Bradford, and Ken D. O Halloran 55 Cardiorespiratory Alterations Induced by Intermittent Hypoxia in a Rat Model of Sleep Apnea…………………………………………. 271 Rodrigo Iturriaga, Esteban A. Moya, and Rodrigo Del Rio 56 Model-Based Studies of Autonomic and Metabolic Dysfunction in Sleep Apnea ………………………………………………………….. 275 Michael C.K. Khoo 57 Noradrenergic Control of Trigeminal Motoneurons in Sleep: Relevance to Sleep Apnea ……………………………………………… 281 Peter B. Schwarz and John H. Peever 58 Intermittent Hypoxia Impairs Pharyngeal Dilator Muscle Function in Male But Not Female Rats ………………………………………….. 285 J. Richard Skelly, Aidan Bradford, and Ken D. O'Halloran 59 Sleep Loss Reduces Respiratory Motor Plasticity ……………………. 289 Arash Tadjalli and John Peever

60 Role of Neurotrophic Signaling Pathways in Regulating Respiratory Motor Plasticity ……………………………… 293 Arash Tadjalli and John Peever 61 Repeated Obstructive Apneas Induce Long-term Facilitation

of Genio lossus Muscle Tone……………………………………………. 297 Arash Tadjalli, James Duffin, and John Peever 62 Mouse Models of Apnea: Strain Differences in Apnea Expression and its Pharmacologic and Genetic Modification …………………….. 303 Motoo Yamauchi, Hiroshi Kimura, and Kingman P. Strohl

Part X Muscle and exercise ……………………………………………..... 309 63 Influence of Cycling History on the Ventilatory Response to Cycle- Ergometry in Humans: A Role for Respiratory Memory? ………….. 311 Andrew J. Cathcart, Brian J. Whipp, Anthony P. Turner, John Wilson, and Susan A. Ward

’

Contents xxvi

64 Low pH Enhances Response of Thin Muscle Afferents to Mechanical Stimuli ……………………………………………………315 Norio Hotta, Toru Taguchi, and Kazue Mizumura 65 Effects of Deconditioning on the Initial Ventilatory and Circulatory Responses at the Onset of Exercise in Man ………………………….... 319 K. Ishida, K. Katayama, H. Akima, S. Iwase, K. Sato, N. Hotta, and M. Miyamura 66 Kinetics of the Ventilatory and Metabolic Responses to Moderate- In tensity Exercise in Humans following Prior Exercise-Induced Metabolic Acidaemia ……………………………………………………. 323 Susan A. Ward and Brian J. Whipp

Part XI Higher brain function and dyspnea ……………………………. 327 67 Characteristics of Respiratory Pattern and Anxiety in Rhythmic Gymnasts …………………………………………………. 329 68 Effects of Hypocapnia on Spontaneous Burst Activity in the Piriform- Amygdala Complex of Newborn Rat Brain Preparation In Vitro ……333 69 Breathing and Noh :Emotional Breathing ……………………………. 337 Ikuo Homma 70 Patterns of Brain Activity in Response to Respiratory Stimulation in Patients with Idiopathic Hyperventilation (IHV) …………………. 341 71 Respiratory Response toward Olfactory Stimuli might be an Index for Odor-Induced Emotion and Recognition ………………….. 347 72 Periaqueductal Gray Control of Breathing ………………………….... 353 Hari H. Subramanian and Gert Holstege Author Index ………………………………………………………………... 359 Subject Index ………………………………………………………….......... 367

Lena Akai, Sakuko Ishizaki, Masao Matsuoka, and Ikuo Homma

T. Fujii, H. Onimaru, M. Suganuma, and I. Homma

S. Jack, G.J. Kemp, W.E. Bimson, P.M.A. Calverley, and D.R. Corfield

Yuri Masaoka and Ikuo Homma

Part IComparative Aspects

1 Evidence for a Distributed Respiratory Rhythm Generating Network in the Goldfish (Carassius auratus)

1 Department of Physiology and Biophysics, University of Calgary, Calgary, Canada, mduchche@ucalgary.ca

2 Department of Physiology and Biophysics, University of Calgary, Calgary, Canada, akottick@ucalgary.ca

3 Department of Physiology and Biophysics, University of Calgary, Calgary, Canada, wilsonr@ucalgary.ca

Abstract Central pattern generators located in the brainstem regulate ventilatory behaviors in verte-brates. The development of the isolated brainstem preparation has allowed these neural networks to be characterized in a number of aquatic species. The aim of this study was to explore the architec-ture of the respiratory rhythm-generating site in the goldfish (Carassius auratus) and to determine the utility of a newly developed isolated brainstem preparation, the Sheep Dip. Here we provide evidence for a distributed organization of respiratory rhythm generating neurons along the rostro-caudal axis of the goldfish brainstem and outline the advantages of the Sheep Dip as a tool used to survey neural networks.

1 Introduction

Water-breathing fish use a buccal force pump to produce unidirectional flow of water over the gills. Central pattern generators in the brainstem regulate this activity and have been characterized in a number of lower vertebrates (Kawasaki 1979; Wilson et al. 2000). The evolutionary transition from water ventilation to air breathing likely required a func-tional reorganization of some primitive respiratory CPG (Milsom 2008). In order to fully understand the mechanisms by which ventilatory drive is generated and maintained in modern air-breathers, it may be important to characterize the neural networks that govern water ventilation in our fish ancestors.

Adrian and Buytendijk (1931) pioneered the field of the isolated fish brainstem prep-aration using the goldfish (Cyprinus carassius). They were able to demonstrate the exis-tence of a neural network capable of producing rhythmic output in the absence of any peripheral feedback. Using similar preparations, respiratory rhythm generators have been investigated in a number of aquatic species including the water-breathing lamprey ( 1977), and the facultative air-breathing gar (Wilson et al. 2000).

In early stages of development the respiratory network appears to be diffuse, with each maturing rhombomere containing its own respiratory rhythm generating circuit (Fortin et al.1995). In some fish species such diffuse organization is thought to per-

3I. Homma et al. (eds.), New Frontiers in Respiratory Control, Advances in Experimental Medicine and Biology 669, DOI 10.1007/978-1-4419-5692-7_1, © Springer Science+Business Media, LLC 2010

Maryana Duchcherer1, Andrew Kottick2, and R.J.A. Wilson3

Rovainen

sist into adulthood, contrasting the tightly nucleated networks often observed in amphibians and mammals (Rekling and Feldman 1998; Vasilakos et al. 2006).

It is hypothesized that the fish central nervous system contains a local rhythm ge-nerating area that drives gill ventilation. The aim of this study was to investigate the architecture of the respiratory rhythm generator in the goldfish using a novel, verti-cally mounted, isolated brainstem preparation known as the Sheep Dip.

2 Methods

This study was carried out on goldfish (C. auratus). Experimental procedures were ap-proved by the Animal Care Committee at the University of Calgary. Prior to experimen-tation, each animal was anesthetized in 1% MS-222 solution until unresponsive to touch. Once fully anesthetized, the fish were mounted horizontally on a Sylgard™ platform and superfused with fish artificial cerebrospinal fluid (aCSF) cooled to 2–5˚C, aerated with 98% O2/2% CO2, and containing (in mM): 120 NaCl, 3.5 KCl, 1.3 MgCl, 11 D-Glucose, 13 NaHCO3, 1.25 NaH2PO4, and 2 CaCl. The brainstem was dis-sected from the level of the rostral tectum to the caudal spinal cord, isolated and trans-ferred to the Sheep Dip apparatus (Fig. 1) where it was mounted vertically on a fixed stage and fully immersed in chamber containing aCSF.

Fig. 1 The Sheep Dip isolated brainstem preparation

4 M. Duchcherer et al.

Evidence for a Distributed Respiratory Rhythm Generating Network in the Goldfish

Rhythmic bursts of activity, assumed to be respiratory, were recorded from cranial nerve VII rootlet using an extracellular glass microelectrode. The signal was amplified using a differential AC amplifier (A-M Systems, Inc.). Data was acquired using the Digi-data 1322A 16-bit data acquisition system (Axon Instruments/Molecular Devices) at a sampling rate of 5 KHz. Axoscope 10.1 software (Axon Instruments/Molecular Devices) was used to visualize and analyze the collected data.

After an initial stabilization period (30–60 min) the chamber containing aCSF was lowered: adequate superfused of the preparation was maintained entirely by a drip system. The aCSF in the chamber was replaced with aCSF containing high magnesium (40 mM) and low calcium (0mM) intended to block synaptic activity. At the beginning of each experiment the entire preparation was briefly exposed to the high magnesium aCSF to ensure it was able to block rhythmic output. Following a second stabilization period under the aCSF drip, the chamber containing high mag-nesium was raised in 500 µM increments at 10 min intervals in a caudal to rostral direction beginning at the most caudal cranial nerve root. Upon complete cessation of rhythmic output, a 2% neutral red solution was added to the chamber for several minutes.

3 Results

Initially, when the level of high magnesium solution was below the most caudal cranial nerve root, CN VII produced a rhythmic motor output with a mean frequency of 44.1 +/− 7.5 min-1 (n = 6). The pattern was characterized by rhythmic high frequency bursts which in some preparations were occasionally interrupted by bursts of slightly larger amplitude. Each experiment began with complete submersion of the preparation in the high magnesium solution to ensure that it was able to block rhythmic output. In every experiment block of motor output was achieved within 10 seconds and the preparation recovered when returned to control conditions.

Starting at the caudal most CN root, the chamber was raised in 500 µM intervals every 10 min submersing more and more of the preparation (Fig. 2A). In all six preparations there was a progressive detrimental effect on respiratory frequency leading to burst cessation (Fig. 2B). The number of submersion steps necessary to block output completely varied from 6–8 steps (3–4mm). The first trial received an additional washout period after the sheep dip was complete. During this washout, the frequency of respiratory motor output returned to control levels.

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