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By Ruthenium Red Does Not Suppress Hypothalamic Neuronal Thermosensitivity Blockade of the Transient Receptor Potential Vanilloid (TRPV) by Ruthenium Red Does Not Suppress Hypothalamic Neuronal Thermosensitivity THESIS Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Nicholas Thompson Unger Graduate Program in Biophysics The Ohio State University 2012 Master's Examination Committee: Dr. Jack A. Boulant, Advisor Dr. Maqsood A. Chotani Copyright by Nicholas Thompson Unger 2012 Abstract The thermoregulatory preoptic-anterior hypothalamus (POAH) contains both temperature sensitive and insensitive neurons. The cellular mechanisms underlying POAH neuronal thermosensitivity have not been firmly established. While controversial, recent studies suggest that POAH neuronal thermosensitivity is caused by the vanilloid- sensitive transient receptor potential (TRPV) family of TRP receptors. This hypothesis was tested by determining the effect of ruthenium red, a known TRPV channel inhibitor, on POAH neuron populations showing differing degrees of temperature sensitivity. Whole-cell patch microelectrodes recorded the intracellular activity of POAH neurons in rat hypothalamic tissue slices perfused with control artificial cerebral spinal fluid (aCSF) and experimental media containing either 1, 10 or 100 μM ruthenium red. Each neuron was characterized by its spontaneous firing rate at 36°C and its firing rate thermosensitivity (impulses/sec/°C) during changes in tissue temperature. Ruthenium red did not reduce the firing rate thermosensitivity nor the membrane potential thermosensitivity of POAH neurons. In fact, some POAH neurons increased their thermosensitivities during ruthenium red application. This supports our previous studies indicating that TRP channels are not responsible for thermally induced changes in the resting membrane potentials and firing rates of rostral hypothalamic neurons. ii Dedication This document is dedicated to my lovely and patient wife. She has always supported me throughout my academic endeavors. iii Acknowledgments I would like to thank the many people for their help in this project. The most important person to help me was Lorry Kaple. She was both a patient and wise teacher in the subtleties of electrophysiological techniques. Yongjie Miao has been instrumental in helping me both formulate and understand the various statistical methods chosen to represent my data. I would like to sincerely thank Dr. Maqsood Chotani for his encouragement for me to finish my thesis work and for his support throughout my endeavor. Also, Dr. Selvi Jeyaraj was instrumental in helping me revise my thesis, elevating it to a more professional level. I would like to personally acknowledge Dr. Pamela Lucchesi for her dedication to the various students under her charge. She was a key orchestrator in my return to graduate school. Lastly, I would like to thank Dr. Jack Boulant, for allowing me the pleasure of working in his lab, teaching and training me in the various intricacies of neurophysiology. iv Vita May 2002 .......................................................Evangel Christian Academy High School 2006................................................................B.A. Biology, Capital University 2006 to 2008 .................................................Graduate Research Associate, Department of Physiology and Cell Biology, The Ohio State University 2009 to 2010 .................................................Research Assistant, Center for Cardiovascular and Pulmonary Research, Nationwide Children’s Hospital 2011 to Present ..............................................Graduate Research Associate, Department of Physiology and Cell Biology, The Ohio State University v Publications Unger NT, Kaple ML, Bishop GA, Boulant JA. 2007. Role of hyperpolarization-activated currents in hypothalamic neuronal thermosensitivity. FASEB Journal. Vol. 6, no. 21: A1313. (IF: 6.721) Unger NT, Kaple ML, Boulant JA. 2008. TRPV blockade by ruthenium red does not suppress thermosensitivity in hypothalamic neurons. FASEB Journal, no. 22. (IF: 6.721) Jeyaraj SC, Unger NT, Chotani MA. Rap1 GTPases: an emerging role in the cardiovasculature. Life Sci. 2011 Apr 11;88(15-16):645-52. Epub 2011 Feb 2. Review. Fields of Study Major Field: Biophysics vi Table of Contents 1. Abstract ................................................................................................................... ii 2. Dedication .............................................................................................................. iii 3. Acknowledgments.................................................................................................. iv 4. Vita .......................................................................................................................... v 5. Publications ............................................................................................................ vi 6. Fields of Study ....................................................................................................... vi 7. Table of Contents .................................................................................................. vii 8. List of Tables ....................................................................................................... viii 9. List of Figures ........................................................................................................ ix 10. Chapter 1: Introduction .......................................................................................... 1 11. Chapter 2: Methods ................................................................................................. 4 12. Chapter 3: Results ................................................................................................... 9 13. Chapter 4: Discussion ........................................................................................... 37 14. References ............................................................................................................. 41 vii List of Tables 1. Characteristics of the Neuronal Population ............................................................ 9 2. Effect of Ruthenium Red on Firing Rate Thermosensitivity ................................ 23 3. Effect of Ruthenium Red on Firing Rate .............................................................. 24 4. Effect of Ruthenium Red on Resting Membrane Thermosensitivity.................... 30 viii List of Figures 1. Examples of Three Different Types of POAH Neurons ......................................... 8 2. Increased Firing Thermosensitivity in Response to Varying Concentrations of Ruthenium Red ..................................................................................................... 11 3. 10 μM Ruthenium Red Increases Firing Rate Thermosensitivity in a Warm Sensitive Neuron ................................................................................................... 14 4. 100 μM Ruthenium Red Increases Firing Rate Thermosensitivity in a Warm Sensitive Neuron ................................................................................................... 16 5. 1 μM Ruthenium Red Increases Firing Rate Thermosensitivity in an Moderate Slope Temperature Insensitive Neuron ................................................................. 19 6. 10 μM Ruthenium Red Increases Firing Rate Thermosensitivity in an Moderate Slope Temperature Insensitive Neuron ................................................................. 21 7. Changes in Thermosensitivity Before and During Application of Ruthenium Red in Warm Sensitive Neurons .................................................................................. 25 8. Changes in Thermosensitivity Before and During Application of Ruthenium Red in Moderate Slope Insensitive Neurons ................................................................ 26 ix 9. Changes in Thermosensitivity Before and During Application of Ruthenium Red in Low Slope Insensitive Neurons ........................................................................ 27 10. Changes in Thermosensitivity Before and During Application of Ruthenium Red in Total Population of Neurons ............................................................................. 28 11. Differences in Firing Rate Thermosensitivity Responses to Ruthenium Red ...... 33 12. Differences in Resting Membrane Thermosensitivity Responses to Ruthenium Red ........................................................................................................................ 35 x Chapter 1: Introduction The preoptic-anterior hypothalamus (POAH) senses change in core temperature and evokes physiological and behavioral responses that regulate body temperature (17, 36). Early thermode studies in cats and dogs demonstrated that selective warming of the POAH led to a suppression of ongoing shivering and caused an increase in heat loss responses (18). Conversely, selective cooling caused heat production responses such as shivering and non-shivering thermogenesis (18-20, 23). While most spontaneously firing POAH neurons are considered to be temperature insensitive, about 20% are classified as warm sensitive (54-56). Warm sensitive neurons increase their firing rates during hypothalamic warming and decrease their firing rates during hypothalamic cooling (2, 37). In addition, there are morphological differences between POAH temperature insensitive neurons and warm sensitive neurons. The dendrites of temperature insensitive neurons
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