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Alpha1a Adrenergic Receptor Influences on Adult Neurogenesis, Cell Fate, Mood, Learning, Memory, Lifespan, and Cancer Incidence Katie Collette

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Alpha1a Adrenergic Receptor Influences on Adult Neurogenesis, Cell Fate, Mood, Learning, Memory, Lifespan, and Cancer Incidence Katie Collette University of North Dakota UND Scholarly Commons Theses and Dissertations Theses, Dissertations, and Senior Projects January 2015 Alpha1a Adrenergic Receptor Influences On Adult Neurogenesis, Cell Fate, Mood, Learning, Memory, Lifespan, And Cancer Incidence Katie Collette Follow this and additional works at: https://commons.und.edu/theses Recommended Citation Collette, Katie, "Alpha1a Adrenergic Receptor Influences On Adult Neurogenesis, Cell Fate, Mood, Learning, Memory, Lifespan, And Cancer Incidence" (2015). Theses and Dissertations. 1757. https://commons.und.edu/theses/1757 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]. ALPHA1A ADRENERGIC RECEPTOR INFLUENCES ON ADULT NEUROGENESIS, CELL FATE, MOOD, LEARNING, MEMORY, LIFESPAN, AND CANCER INCIDENCE by Katie M. Collette Bachelor of Science, University of North Dakota, 2010 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 2015 Copyright 2015 Katie Collette ii This thesis, submitted by Katie M. Collette in partial fulfillment of the requirements for the Degree of Doctor of Philosophy from the University of North Dakota, has been read by the Faculty Advisory Committee under whom the work has been done and is hereby approved. __________________________________ Chairperson, Van Doze __________________________________ Holly Brown-Borg __________________________________ Diane Darland __________________________________ James Haselton __________________________________ Joyce Ohm This dissertation meets the standards for appearance, conforms to the style and format requirements of the Graduate School of the University of North Dakota, and is hereby approved. Dean of the Graduate School, Wayne Swisher __________________________________ Date iii PERMISSION Title Alpha1A Adrenergic Receptor Influences on Adult Neurogenesis, Cell Fate, Mood, Learning, Memory, Lifespan, and Cancer Incidence Department Pharmacology, Physiology, and 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 maybe 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. Signature Katie Collette Date April 21, 2015 iv TABLE OF CONTENTS LIST OF FIGURES ....................................................................................................................... xii LIST OF TABLES ........................................................................................................................ xiv ACKNOWLEDGEMENTS ............................................................................................................ xv ABSTRACT ............................................................................................................................... xvii CHAPTER I. INTRODUCTION The Noradrenergic System ................................................................... 1 Characterization of the Adrenergic Receptors ..................................... 3 Pharmacological ........................................................................ 3 Genetic ...................................................................................... 6 α1 Adrenergic Receptor Structure and Signaling .................................. 7 Structure ................................................................................... 7 Activation .................................................................................. 8 Signaling .................................................................................... 9 Signal Amplification ................................................................ 11 Deactivation ............................................................................ 11 α1 Adrenergic Receptor Localization in the Brain ............................... 12 Regional Expression ................................................................ 12 Cellular Expression .................................................................. 14 v Cell types with α1AR subtype expression ................... 14 Methods to Study α1 Adrenergic Receptor Function ......................... 16 Pharmacology ......................................................................... 16 Transgenic ............................................................................... 17 Knock-out models ....................................................... 17 Activation models ....................................................... 19 II. ALPHA1A OR ALPHA1B ADRENERGIC RECEPTOR KNOCKOUT DOES NOT IMPAIR NOVEL OBJECT RECOGNITION, SPATIAL LEARNING AND MEMORY, OR PATTERN SEPARATION .................................................................................... 21 Abstract ............................................................................................... 21 Introduction ........................................................................................ 22 Methods .............................................................................................. 24 Animals .................................................................................... 24 Seizure Incidence .................................................................... 25 General Health and Neurological Assessments ...................... 25 Behavioral Testing ................................................................... 26 Novel object recognition ............................................. 27 T-maze ......................................................................... 28 Morris water maze ...................................................... 28 Statistical analysis ................................................................... 30 Results ................................................................................................. 31 General Health and Neurological Assessments ...................... 31 Novel Object Recognition ....................................................... 31 vi T-maze ..................................................................................... 33 Morris Water Maze ................................................................. 33 Learning, Days 1-3 ....................................................... 33 Reversal learning, Days 4-5 ......................................... 35 Search strategies ......................................................... 35 Discussion............................................................................................ 41 III. ALPHA1B ADRENERGIC RECEPTOR KNOCKOUT DECREASES DEPRESSION-LIKE BEHAVIOR WHILE KNOCKOUT OF EITHER THE ALPHA1AAR OR ALPHA1BAR DO NOT RELIABLY AFFECT ANXIETY ...................................................................... 44 Abstract ............................................................................................... 44 Introduction ........................................................................................ 45 Methods .............................................................................................. 48 Animals .................................................................................... 48 Seizure Incidence .................................................................... 48 Behavioral Testing ................................................................... 49 Open field test ............................................................ 49 Zero maze .................................................................... 50 Light dark exploration ................................................. 51 Marble burying test .................................................... 51 Tail suspension test ..................................................... 51 Statistical Analysis ................................................................... 52 Results ................................................................................................. 52 Seizure Incidence .................................................................... 52 vii α1AAR-KO mice have an increased incidence of seizures ....................................................................... 52 Open Field ............................................................................... 53 α1A or α1BAR knockout did not affect basal locomotion in Group 1 mice ........................................................... 53 In Group 1, knockout of either subtype did not affect anxiety in the open field; α1AAR-KO mice had higher levels of anxiety in the elevated zero maze after accounting for seizure activity; but α1BAR-KO did not affect anxiety .............................................................
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