University of North Dakota UND Scholarly Commons Theses and Dissertations Theses, Dissertations, and Senior Projects January 2014 Role Of The α1A-Adrenergic Receptor In Synaptic Plasticity, Cognition & Neurogenesis Brianna Lynn Goldenstein Follow this and additional works at: https://commons.und.edu/theses Recommended Citation Goldenstein, Brianna Lynn, "Role Of The α1A-Adrenergic Receptor In Synaptic Plasticity, Cognition & Neurogenesis" (2014). Theses and Dissertations. 1537. https://commons.und.edu/theses/1537 This Dissertation is brought to you for free and open access by the Theses, Dissertations, and Senior Projects at UND Scholarly Commons. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of UND Scholarly Commons. For more information, please contact [email protected]. ROLE OF THE α1A-ADRENERGIC RECEPTOR IN SYNAPTIC PLASTICITY, COGNITION & NEUROGENESIS by Brianna Lynn Goldenstein Bachelor of Science, University of North Dakota, 2007 A Dissertation Submitted to the Graduate Faculty of the University of North Dakota In partial fulfillment of the requirements for the degree of Doctor of Philosophy Grand Forks, North Dakota May 2014 Copyright 2014 Brianna Goldenstein ii Title Role of the α1A-Adrenergic Receptor in Synaptic Plasticity, Cognition, & Neurogenesis Department Pharmacology, Physiology & Therapeutics Degree Doctor of Philosophy In presenting this dissertation in partial fulfillment of the requirements for a graduate degree from the University of North Dakota, I agree that the library of this University shall make it freely available for inspection. I further agree that permission for extensive copying for scholarly purposes may be granted by the professor who supervised my dissertation work or, in his absence, by the Chairperson of the department or the dean of the Graduate School. It is understood that any copying or publication or other use of this dissertation or part thereof for financial gain shall not be allowed without my written permission. It is also understood that due recognition shall be given to me and to the University of North Dakota in any scholarly use which may be made of any material in my Dissertation. Brianna Lynn Goldenstein April 17th, 2014 iv TABLE OF CONTENTS LIST OF FIGURES ............................................................................................. viii LIST OF TABLES ................................................................................................. xi ACKNOWLEDGEMENTS .................................................................................... xii ABSTRACT ........................................................................................................ xiv CHAPTER I. ADRENERGIC RECEPTORS .............................................................. 1 1.1 Discovery, history, and classification ............................................... 1 1.2 Structure and second messenger pathway ..................................... 6 1.3 Pharmacological characterization ................................................. 10 1.4 Localization and physiological function ......................................... 12 II. LEARNING, MEMORY & THE α1-ADRENERGIC RECEPTOR ......... 16 2.1 Learning and memory ................................................................... 16 2.2 History of α1-adrenergic receptors, learning & memory ................. 18 2.3 Synaptic plasticity and the α1-adrenergic receptor ........................ 20 2.4 Learning & memory testing paradigms .......................................... 25 III. HIPPOCAMPAL NEUROGENESIS, LEARNING, MEMORY, & THE α1-ADRENERGIC RECEPTOR ............................................... 29 3.1 Adult neurogenesis ....................................................................... 29 3.2 Detecting and modifying adult neurogenesis ................................ 33 v 3.3 Learning, memory and adult neurogenesis ................................... 39 3.4 Adult neurogenesis and the α1-adrenergic receptor ...................... 41 IV. NEUROGENESIS, METABOLISM AND EXERCISE .......................... 44 4.1 The role of adrenergic receptors in metabolism ............................ 44 4.2 Neurogenesis and metabolism ...................................................... 45 4.3 Norepinephrine, adrenergic receptors and exercise ...................... 47 4.4 Exercise-induced neurogenesis .................................................... 48 V. LONG TERM α1A-ADRENERGIC RECEPTOR STIMULATION ENHANCES COGNITIVE FUNCTION AND SYNAPTIC PLASTICITY ........................................................... 51 5.1 Introduction ................................................................................... 51 5.2 Methods ........................................................................................ 51 5.3 Results .......................................................................................... 58 VI. ACTIVATING THE α1A-ADRENERGIC RECEPTOR RESCUES THE NEGATIVE EFFECTS THAT INHIBITING NEUROGENESIS HAS ON LEARNING AND MEMORY IN MICE .................................. 67 6.1 Introduction ................................................................................... 67 6.2 Methods ........................................................................................ 68 6.3 Results .......................................................................................... 84 VII. CYTOSINE ARABINOSIDE DISRUPTS HYPOTHALAMIC NEUROGENESIS AND INDUCES OBESITY IN MICE ...................... 92 7.1 Introduction ................................................................................... 92 7.2 Methods ........................................................................................ 92 vi 7.3 Results .......................................................................................... 95 VIII. ROLE OF THE α1A-ADRENERGIC RECEPTOR IN EXERCISE- INDUCED NEUROGENESIS ........................................................... 100 8.1 Introduction ................................................................................. 100 8.2 Methods ...................................................................................... 100 8.3 Results ........................................................................................ 104 IX. DISCUSSION ................................................................................... 109 9.1 Neurogenesis, the α1A-AR, synaptic plasticity and cognition ................................................................ 109 9.2 Hypothalamic neurogenesis and metabolism .............................. 119 9.3 Exercise-induced neurogenesis and the α1A-adrenergic receptor ............................................................... 124 APPENDIX .............................................................................................................................. 130 REFERENCES ....................................................................................................................... 133 vii LIST OF FIGURES Figure Page 1. Diagram of the historical categorization of adrenergic receptors ...................... 2 2. Complete categorization of the adrenergic receptors and their subtypes ......... 3 3. The adrenergic receptor family and corresponding G-proteins ......................... 6 4. Adrenergic receptor binding epinephrine .......................................................... 7 5. Second-messenger pathway for α1-AR activation ............................................ 9 6. Full and partial agonists for the α1-AR after external calcium removal .............................................................................................. 12 7. Types of memory ............................................................................................ 17 8. Induction of long-term potentiation ................................................................. 23 9. The progressive discovery of neurogenic regions in the brain ........................ 31 10. The five stages of neurogenesis .................................................................. 32 11. The stages of neurogenesis with coinciding markers ................................... 34 12. Expression of DCX, NeuN and BrdU in the adult female rat dentate gyrus of the hippocampus ........................................................................................ 35 13. Diagram of the hypothalamus ....................................................................... 46 14. The satiety and reward circuits of the hypothalamus .................................... 47 15. Barnes maze apparatus ............................................................................... 54 16. Stimulating LTP in the CA1 region of the hippocampus ............................... 57 17. Chronic α1A-AR stimulation improves cognitive performance in the Barnes maze ..................................................................................... 59 viii 18. Hippocampal synaptic plasticity is enhanced with chronic α1AAR activation ....................................................................... 62 19. Chronic treatment with an α1A-AR selective agonist improves cognitive function ............................................................ 64 20. Cognitive performance in the Barnes maze is reduced in mice lacking the α1A-ARs ........................................................................ 66 21. Increasing concentrations of anti-mitotic agent Ara-C induces neuronal toxicity at 3-4% .....................................................