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Brainstem Mechanisms Underlying Ingestion and Rejection

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Brainstem Mechanisms Underlying Ingestion and Rejection BRAINSTEM MECHANISMS UNDERLYING INGESTION AND REJECTION DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of the Ohio State University By Zhixiong Chen, M.S., M.D. ***** The Ohio State University 2002 Dissertation Committee: Approved by Professor Joseph B. Travers, Adviser Professor Robert Stephens ________________________ Adviser Professor Scott M. Herness Oral Biology Graduate Program Professor Susan P. Travers ABSTRACT Feeding behavior is controlled by brain structures distributed in the cerebral cortex, limbic system and brainstem. In the brainstem, a central pattern generator (CPG) for mastication has been localized to the midline medullary reticular formation based on cortically induced rhythmic jaw movements (fictive mastication), or to the reticular formation (RF) between the trigeminal and facial motor nuclei based on chemically elicited rhythmic trigeminal discharge in a tissue slice preparation. Other studies, however, suggest a role for the lateral medullary RF in orchestrating ingestive oromotor activity. Direct behavioral evidence supporting the location of these CPGs, however, is lacking. Thus, the first study tested the hypothesis that the lateral medullary RF is essential for organizing oromotor patterns of ingestion and rejection. In the behaving rat, licking was induced by either intra-oral (IO) infusions of sucrose or saline, or sucrose presented in a bottle. Gaping (rejection) responses were elicited by IO delivery of quinine hydrochloride. All responses were measured electromyographically from the anterior digastric (jaw-opener) and geniohyoid (tongue-protruder) muscles. Inactivation of the lateral medullary RF with the GABAA agonist muscimol suppressed both licking and gaping. Infusions into other RF regions were ineffective, indicating an essential role for the lateral medullary RF. Because both excitatory and inhibitory amino acids (EAA, IAA) are involved in fictive mastication, we further examined whether they are also important for ingestive responses elicited by natural stimuli. In a second series of ii experiments, EAA and IAA antagonists were infused into the lateral medullary RF. It was found that (1) the lateral medullary RF is driven by glutamatergic inputs, mediated by both non-NMDA and NMDA receptors, (2) it is under tonic inhibition from GABAergic and glycinergic inputs, (3) this substrate is also involved in the suppression of eupnea that is mediated by non-NMDA receptors. These findings provide behavioral evidence to support the hypothesis that the lateral medullary RF is a multifunctional substrate that controls the oromotor nuclei to generate licking and gaping, and the oromotor components of gasping. iii This work is dedicated to my mother, father, wife and daughter, for their love and unwavering support through the years iv ACKNOWLEDGMENTS I wish to thank my mentor, Dr. Joseph B. Travers, for his constant support, guidance, enthusiastic encouragement, which made this thesis possible, and for his patience in correcting both my stylistic and scientific errors. I would also like to thank Dr. Susan P. Travers for her guidance and help during the course of conducting this project, especially for teaching me how to identify the tiny rostral nucleus of the solitary tract via electrophysiological recording in the anesthetized rat. The other members of my candidacy examination and thesis committee, Dr. Robert Stephens, Dr. Scott Herness, and Dr. Richard Rogers have also given me valuable suggestions and criticism. These have helped in general perspective, experimental design, data analysis, and method development. Special thanks are due Mr. Ken Herman for excellent technical assistance and to Dr. Hecheng Hu for introducing me to Drs Travers’ laboratory. I am grateful to Dr. Keith Alley for his valuable suggestions, guidance and help and to Dr. Hiroshi Kato for encouraging me to study in the United States. Last, but certainly not least, I would like to express my deep appreciation to my wife, Shengying, and my daughter, Jingjing, for their love and support, which has made my research life in a foreign country more joyful. v VITA 1985 …………………………M.D. Medicine, Zhejiang Medical University 1985 – 1987 …………………Assistant Professor, Department of Physiology, Zhejiang Jinhua Medical School, P. R. China 1990 …………………………M.S. Physiology, Zhejiang Medical University 1990 – 1994 …………………Assistant Professor, Department of Physiology, Zhejiang Medical University, P. R. China 1994 – 1995 …………………Visiting Scholar, Yamagata University School of Medicine, Japan 1995 – 1997 ………………… Associate Professor, Co-Chair, Department of Physiology, Zhejiang Medical University, P. R. China 1997 – Present ……………… Graduate Teaching and vi Research Associate, The Ohio State University PUBLICATIONS Research Publication 1. Chen Z.X. Travers S.P. and Travers J.B., Microinfusion of D-CPP into the brainstem reticular formation suppresses ingestion and rejection in the awake rat. Appetite 37: 131-132, 2001. 2. Chen Z.X. Travers S.P. and Travers J.B., Muscimol infusions in the brain stem reticular formation reversibly block ingestion in the awake rat. Am J Physiol Regulatory Integrative Comp Physiol 280: R1085- R1094, 2001 3. Chen Z.X. Travers S.P. and Travers J.B., Inhibition of licking and the oral phase of rejection by microinjections of lidocaine into the medullary reticular formation. Appetite 33: 259, 1999. 4. Zhixiong Chen, Ken-ichi Ito, Satoshi Fujii, Hiroyoshi Miyakawa and Hiroshi Kato. Study on synaptic plasticity in hippocampal CA1 region. Papers on Science and Technology of China 1: 915-916, 1998. 5. Gemin Chen, Minjie Jiang and Zhixiong Chen. Study on long-term depression of synaptic transmission. Progress in Physiological Sciences 283: 259-261, 1997. 6. Satoshi Fujii, Yoichiro Kuroda, Masami Miura, Hidekazu Furuse, Hiroshi Sasaki, Kenya Kaneko, Ken-ichi Ito, Zhixiong Chen, Hiroshi Kato. The long-term suppressive effect of prior activation of synaptic inputs by low-frequency stimulation on induction of long-term potentiation in CA1 neurons of guinea pig hippocampal slices. Exp Brain Res 111: 305-312, 1996. 7. Zhixiong Chen, Ken-Ichi Ito, Satoshi Fujii, Hiroshi Miyakawa and Hiroshi Kato. Effects of low frequency stimulation with different parameters on synaptic plasticity in hippocampus. In Jun Zhu, Ping Wu and Kunsong Chen Eds. Research and Application of Life Science. Zhejiang University Press. 1996: 663 vii 8. Zhixiong Chen, Ken-Ichi Ito, Satoshi Fujii, Masami Miura, Hidekazu Furuse Kenya Kaneko, Hiroshi Sasaki and Hiroshi Kato. Opposite roles of two types of dopamine receptors in long-term depression in CA1 neurons of rat hippocampus. The Japanese Journal of Physiology 46, Supplement: S153, 1996. 9. Ken-Ichi Ito, Satoshi Fujii, Zhixiong Chen, Hiroyoshi Miyakawa, Hiroshi Sasaki, Kenya Kaneko, Hiroshi Kato. LTD and depotentiation in hippocampus. Brain Processes and Memory, K. Ishikawa, J.L. McGaugh and H. Sakata, editors, pp 249-257, 1996. 10. Zhixiong Chen, Ken-Ichi Ito, Satoshi Fujii, Masami Miura, Hidekazu Furuse, Hiroshi Sasaki, Kenya Kaneko, Hiroshi Kato and Hiroyoshi Miyakawa. Roles of dopamine receptors in long-term depression: enhancement via D1 receptors and inhibition via D2 receptors. Recept & Chann 4: 1-8, 1996. 11. Zhixiong Chen and Hiroshi Kato. Dopamine D1 receptors and hippocampal long-term depression of synaptic transmission induced by low frequency stimulation. Proceedings of the Second Academic Conference of Young Scientists, 1995: 646-49 12. Zhixiong Chen, Satoshi Fujii, Ken-Ichi Ito, Hiroshi Kato, Kenya Kaneko and Hiroyoshi Miyakawa. Activation of dopamine D1 receptors enhances long-term depression of synaptic transmission induced by low frequency stimulation in rat hippocampal CA1 neurons. Neurosci Lett 188: 195-198, 1995. 13. Satoshi Fujii, Ken-Ichi Ito, Zhixiong Chen, Hiroshi Kato and Yoichiro Kuroda. The mechanism of ATP-induced long-term potentiation in guinea-pig hippocampal CA1 neurons. The Japanese Journal of Physiology 45, Supplement: S146, 1995. 14. Zhixiong Chen and Hiroshi Kato. Properties of long-term depression of synaptic transmission induced by low frequency stimulation in the hippocampal CA1 region. Chin J Neurosci Suppl: 139, 1995. 15. Ken-Ichi Ito, Masami Miura, Hidekazu Furuse, Zhixiong Chen, Hiroshi Kato, Daisuke Yasutomi, Takafumi Inoue, Katsuhiko Mikoshiba, Tetsutoshi Kimura, Shunpei Sakakibara, Hiroyoshi Miyakawa. Voltage- gated Ca2+ channel blockers, -AgaIVA and Ni2+, suppress the induction of - burst induced long-term potentiation in guinea-pig hippocampal CA1 neurons. Neurosci Lett 183: 112-115, 1995. viii 16. Satoshi Fujii, Ken-ichi Ito, Zhixiong Chen, Hiroshi Kato and Yoichiro Kuroda. Ecto-protein kinase contributes to the maintenance of hippocampal long-term potentiation. Neurosci Res Suppl 19: S38, 1994. 17. Ken-Ichi Ito, Masami Miura, Hidekazu Furuse, Zhixiong Chen, Satoshi Fujii and Hiroshi Kato. Contribution of inhibitory inputs on [Ca2+]in of CA1 pyramidal neurons in hippocampus. Neurosci Res Suppl 19: S33, 1994. 18. Rongbao Zhang, Xinwei Zhang, Zhixiong Chen. Enkephalin involvement in the inhibitory effect of somatic afferent inputs on the brain stem cardiovascular sympathetic center in rabbits. Neurosci Lett Suppl 44: S19, 1993. 19. Zhixiong Chen and Rongbao Zhang. Effect of electric stimulation of some major nuclei in rostral ventrolateral medulla on cardiovascular activities. J Zhejiang Medical University 213: 97-100, 1992. 20. Zhixiong Chen and Rongbao Zhang. Role of rostral ventrolateral
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