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Study of the Whole Celiac Ganglion and of Artery-Projecting and Vein-Projecting Pathways in the Celiac Ganglion

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Study of the Whole Celiac Ganglion and of Artery-Projecting and Vein-Projecting Pathways in the Celiac Ganglion STUDY OF THE WHOLE CELIAC GANGLION AND OF ARTERY-PROJECTING AND VEIN-PROJECTING PATHWAYS IN THE CELIAC GANGLION By Amit Harendra Shah A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Neuroscience—Doctor of Philosophy 2014 ABSTRACT STUDY OF THE WHOLE CELIAC GANGLION AND OF ARTERY-PROJECTING AND VEIN-PROJECTING PATHWAYS IN THE CELIAC GANGLION By Amit Harendra Shah The rat celiac ganglion (CG) contains ~10,000 sympathetic postganglionic neurons that innervate abdominal organs and the corresponding splanchnic vascular bed that supplies these organs. Splanchnic circulation holds approximately one-third of total blood volume and is a major source of blood redistribution to other vascular beds. In hypertension, blood from the high- capacitance splanchnic circulation may get redistributed to the low-capacitance central compartment, increasing arterial pressure. Surgical removal of the whole CG attenuates the development of hypertension, which suggests that the sympathetic innervation of the splanchnic circulation functions to regulate systemic arterial pressure. However, the pattern of hypertension- related increase in sympathetic activity of the ganglionic neurons that innervate the splanchnic vasculature is not known. Furthermore, the distribution of postganglionic sympathetic axons to the mesenteric vasculature is not fully understood. The studies reported in this dissertation address these two deficits in our knowledge by 1) comparing the levels of activation of CG neurons in normotensive rats to levels in hypertensive rats; 2) examining the extent and distribution of CG neuron innervation of mesenteric arteries and veins. Collectively, these studies suggest that there is not widespread increased activation of CG neurons in hypertension; in fact, neurons show a reduced sensitivity to activation by nicotine. Also, 72% of neurons that innervate mesenteric arteries and veins distribute their axons to widely separated vessels. This suggests that activation of relatively small number of ganglionic neurons can constrict the entire mesenteric circulation. In Chapters two and three of this dissertation, factors in the whole CG that are influenced by hypertension are studied. In Chapter two, 5-HT was measured in the whole CG as it can activate sympathetic postganglionic neurons. It was found to be synthesized in a substrate- independent manner in the CG. While 5-HT levels were not different between normotensive and hypertensive CGs, lower gene expression was measured for TPH2 and for 5-HT3A in hypertensive compared to normotensive CGs. In Chapter three, higher c-fos expression was observed at 6 Hz than 2 Hz preganglionic nerve stimulation indicating that c-fos expression is a good marker of neuronal activation. Basal levels of neuronal activation were similar between normotensive and hypertensive CGs but following preganglionic nerve stimulation and nicotine treatment, a smaller increase in c-fos expression was observed in hypertensive than normotensive sympathetic ganglia. Thus, these findings together question whether sympathetic activity is higher in the whole ganglion and instead, whether specific pathways in the CG may be overactive in hypertension. Artery-projecting and vein-projecting sympathetic pathways were studied in Chapters four and five using a novel, in vivo preparation where tracers were applied to small segments of adjacent mesenteric arteries and veins. Two PRVs were initially used but control experiments indicated that they competed for productive replication in a given neuron and instead, PRV was used with CTb. A majority of labeled CG neurons (60%) projected to both arteries and veins while the remainder projected to either arteries or veins. Moreover, a majority of labeled neurons (72%) projected widely to either arteries or veins that supplied different segments of the small intestine while the remainder of neurons had narrower projection fields. Hence, arteries and veins can be both separately and jointly regulated and also, different subsets of neurons may project to widely separated blood vessels or to more narrowly spaced targets. Copyright by AMIT HARENDRA SHAH 2014 ACKNOWLEDGEMENTS This endeavor was only possible through a great deal of support from my advisor, Dr. Kreulen, collaborators, family, and friends. I would like to thank Dr. Kreulen for introducing me to the study of autonomic ganglia, which after microscopically researching for several years has led to a better understanding of the broader fields of Neuroscience and Physiology. Also, thank you for encouraging me to find the questions that I found interesting and for guiding me in my pursuit of answers. The individual support, technical guidance, and helpful ideas of all my committee members, Drs. Keith Lookingland, Cynthia Jordan, and Gregory Fink, are also deeply appreciated. I was very privileged to work alongside such excellent colleagues: thank you Dr. Timothy Houchin, Dr. Casey Henley, Bradley Hammond, Dr. Lynnette Gerhold, AnnaLiese Durling, and Amy Porter for your support. In addition, Dr. Timothy Houchin provided invaluable help with anatomy and nerve stimulation of sympathetic ganglia, Dr. Lynnette Gerhold kindly reviewed dissertation chapters, and Bradley Hammond did all cell counts of c-fos immunoreactivity. Work with viral tracers was conducted in collaboration with Drs. Alan Sved, Patrick Card, and Georgina Cano at University of Pittsburgh. My parents, Meena and Harendra Shah, inspire me to challenge myself and to persist through these challenges and I am grateful to them for that. Last, but not least, I would like to thank my dear companion, Aisha, for her continual faith, love, and encouragement that motivate me to move forward and to do better in so many aspects in my life. v TABLE OF CONTENTS LIST OF TABLES .......................................................................................................................... x LIST OF FIGURES ....................................................................................................................... xi KEY TO ABBREVIATIONS ...................................................................................................... xiv CHAPTER ONE: GENERAL INTRODUCTION ......................................................................... 1 SYMPATHETIC NERVOUS SYSTEM .................................................................................... 4 SYMPATHETIC GANGLIA ...................................................................................................... 6 Sympathetic Postganglionic Neurons ...................................................................................... 8 SIF Cells ................................................................................................................................ 10 Satellite Cells ......................................................................................................................... 10 Convergence and Divergence of Preganglionic and Postganglionic Input ........................... 11 Intraganglionic Organization ................................................................................................. 11 SYMPATHETIC GANLGIA: GENERALIZED RELAYS OR SPECIALIZED INTEGRATORS? ..................................................................................................................... 12 Integration of Signals in Sympathetic Ganglia ...................................................................... 13 Distinct Pathways through Sympathetic Ganglia .................................................................. 13 Distinct Pathways through Sympathetic Ganglia to Arteries or Veins ................................. 15 SYMPATHETIC NERVE ACTIVITY IN HYPERTENSION ................................................ 17 ARTERIAL PRESSURE REGULATION ................................................................................ 18 REDISTRIBUTION OF BLOOD ............................................................................................. 19 NEURAL TRACERS ................................................................................................................ 22 Fluorescent Tracers ................................................................................................................ 22 Non-Fluorescent Tracers ....................................................................................................... 22 Viral Tracers .......................................................................................................................... 24 Wild-Type PRV ..................................................................................................................... 25 PRV as a Neural Tracer ......................................................................................................... 27 Wild-Type HSV ..................................................................................................................... 29 HSV as a Neural Tracer ......................................................................................................... 30 Use of Viral With Non-Viral Tracers .................................................................................... 31 RESEARCH AIM ..................................................................................................................... 32 SPECIFIC AIMS AND HYPOTHESES ................................................................................... 32 CHAPTER TWO: ROLE OF SEROTONIN IN SYMPATHETIC
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