The impact of workplace bullying and repeated social defeat on health and behavioral outcomes: A biopsychosocial perspective Dhaksshaginy Rajalingam Thesis for the degree of Philosophiae Doctor (PhD) University of Bergen, Norway 2020 The impact of workplace bullying and repeated social defeat on health and behavioral outcomes: A biopsychosocial perspective Dhaksshaginy Rajalingam ThesisAvhandling for the for degree graden of philosophiaePhilosophiae doctorDoctor (ph.d (PhD). ) atved the Universitetet University of i BergenBergen Date of defense:2017 09.12.2020 Dato for disputas: 1111 © Copyright Dhaksshaginy Rajalingam The material in this publication is covered by the provisions of the Copyright Act. Year: 2020 Title: The impact of workplace bullying and repeated social defeat on health and behavioral outcomes: A biopsychosocial perspective Name: Dhaksshaginy Rajalingam Print: Skipnes Kommunikasjon / University of Bergen Table of contents TABLE OF CONTENTS ............................................................................................................................................. IV SCIENTIFIC ENVIRONMENT ................................................................................................................................... II ACKNOWLEDGMENTS............................................................................................................................................ III ABBREVIATIONS ...................................................................................................................................................... V ABSTRACT ................................................................................................................................................................VII LIST OF PUBLICATIONS ......................................................................................................................................... IX 1. INTRODUCTION ............................................................................................................................................... 1 1.1. THE OBJECTIVE OF THIS THESIS ..................................................................................................................... 2 1.2. WORKPLACE BULLYING – A BRIEF BACKGROUND .......................................................................................... 6 1.3. DEFINING WORKPLACE BULLYING ................................................................................................................. 8 1.4. MEASURING WORKPLACE BULLYING ........................................................................................................... 10 1.5. WORKPLACE BULLYING AND HEALTH OUTCOMES ....................................................................................... 12 1.6. ALLOSTATIC LOAD ...................................................................................................................................... 15 1.7. THE CONCEPT OF STRESS ............................................................................................................................. 17 1.8. THE STRESS RESPONSE................................................................................................................................. 19 1.9. THE INNATE IMMUNITY ............................................................................................................................... 23 1.10. THE BI-DIRECTIONAL NEUROIMMUNE COMMUNICATION ......................................................................... 25 1.11. STRESS AND MENTAL HEALTH ................................................................................................................. 27 1.11.1. INSOMNIA .............................................................................................................................................................................. 30 1.11.2. ANXIETY ................................................................................................................................................................................ 32 1.12. GENETIC FACTORS .................................................................................................................................. 34 2. AIMS OF THE THESIS .................................................................................................................................... 37 3. METHODS ........................................................................................................................................................ 40 3.1. HUMAN COHORT.......................................................................................................................................... 40 3.1.1. CONTROL VARIABLES ........................................................................................................................................................ 41 3.1.2. EXPOSURE TO BULLYING BEHAVIORS........................................................................................................................... 41 3.1.3. INSOMNIA .............................................................................................................................................................................. 41 3.1.4. SYMPTOMS OF ANXIETY ................................................................................................................................................... 42 3.1.5. GENOTYPING ........................................................................................................................................................................ 42 3.2. ANIMAL STUDIES ......................................................................................................................................... 42 3.2.1. RESIDENT-INTRUDER PARADIGM.................................................................................................................................... 43 3.2.2. SOCIAL INTERACTION TEST (SIT) .................................................................................................................................... 44 3.2.3. BLOOD SAMPLING AND TISSUE HARVESTING ............................................................................................................. 45 3.2.4. ENRICHMENT OF SPLENIC MYELOID CELLS ................................................................................................................. 46 3.3. CELL CULTURE EXPERIMENTS ..................................................................................................................... 46 3.4. STATISTICAL ANALYSES .............................................................................................................................. 47 3.4.1. HUMAN DATA ....................................................................................................................................................................... 47 3.4.2. ANIMAL DATA AND IN VITRO CELL CULTURE EXPERIMENTS................................................................................. 47 4. RESULTS .......................................................................................................................................................... 49 4.1. PAPER I........................................................................................................................................................ 49 4.2. PAPER II ...................................................................................................................................................... 50 4.3. PAPER III ..................................................................................................................................................... 50 5. DISCUSSION .................................................................................................................................................... 53 5.1. DISCUSSION OF RESULTS ............................................................................................................................. 53 5.1.1. INSOMNIA AND MIR-146A GENOTYPE (PAPER I) .......................................................................................................... 53 5.1.2. RESIDENT INTRUDER PARADIGM (PAPER II) ............................................................................................................... 56 5.1.3. Β2 – ADRENERGIC RECEPTOR GENOTYPE (PAPER III) ................................................................................................ 61 5.1.4. SUMMARY OF THE DISCUSSION OF RESULTS............................................................................................................... 62 5.2. METHODOLOGICAL CONSIDERATIONS AND DISCUSSION .............................................................................. 64 5.2.1. SAMPLING, GENERALIZABILITY AND INTERNAL VALIDITY – HUMAN COHORT ................................................ 64 5.2.2. THE RESIDENT INTRUDER PARADIGM ........................................................................................................................... 66 5.2.3. SOCIAL INTERACTION TEST .............................................................................................................................................. 67 5.2.4. ANESTHESIA ......................................................................................................................................................................... 68 5.3. ETHICAL CONSIDERATIONS .........................................................................................................................