Behavioral and dominance rank effects on the hypothalamic-pituitary-adrenal axis and immune system in adult female rhesus macaques Open Access
Kohn, Jordan (2016)
Abstract
In many mammals, including humans, social groups are organized into dominance hierarchies in which an individual's position in the hierarchy determines stress exposure and has important implications for health and mortality risk. Alterations in the hypothalamic-pituitary-adrenal (HPA) axis and the immune system are frequently observed in chronically stressed individuals and have been implicated in the pathophysiology of a number of psychiatric and somatic illnesses, including depression and cardiovascular disease. Importantly, an individual's behavior can modify the effects of chronic stress on physiology, thus serving as a protective or vulnerability factor in the development of stress-associated illness. However, establishing causal links between the social environment and physiological outcomes is challenging in studies with human populations. In this dissertation, we suggest that dominance rank and social behavior interact to affect HPA axis regulation in adult female rhesus macaques, and that rank alters the immune system's response to stress challenge. Through a series of longitudinal experiments, we demonstrate that glucocorticoid sensitivity and negative feedback are diminished by low dominance rank, and that animals with certain behavioral phenotypes may be more sensitive to these effects. Furthermore, we show that low rank is associated with decreased immune cell sensitivity to glucocorticoids and downregulation of genes involved in immune cell adhesion. This dissertation provides evidence that social dominance rank has causal but plastic effects on neuroendocrine and immune system parameters and provides insight into the biological mechanisms by which chronic stress is associated with psychiatric and somatic diseases.
Table of Contents
CHAPTERS PAGE
1. INTRODUCTION 1
1.1. Chronic psychosocial stress is associated with psychiatric and somatic illness 4
1.2. Neuroendocrine regulation of the stress response 7
1.3. Effects of chronic stress on glucocorticoid signaling 11
1.4. Immunological responses to acute and chronic stress 12
1.5. Chronic social stress models in nonhuman primates 15
1.5.1. Dominance rank 17
1.5.2. Social instability 18
1.5.3. Dominance rank affects neuroendocrine and immune parameters 19
1.5.4. Social instability affects neuroendocrine and immune parameters 21
1.6. Study rationale and objectives 23
2. DOMINANCE RANK CAUSALLY AFFECTS PERSONALITY AND GLUCOCORTICOID REGULATION IN FEMALE RHESUS MACAQUES 26
2.1. Abstract 27
2.2. Introduction 27
2.3. Methods 31
2.3.1. Study subjects 31
2.3.2. Behavioral characterization 32
2.3.3. Dominance rank assignment 33
2.3.4. Behavioral analysis 34
2.3.5. Sampling and assay procedures 35
2.3.6. Diurnal cortisol and responsiveness to dexamethasone 37
2.3.7. Statistical analysis of cortisol measures 38
2.4. Results 40
2.4.1. Behavioral characterization 40
2.4.1.1. Predictors of behavioral tendencies 40
2.4.1.2. Causal effects of social context on behavioral tendencies 41
2.4.1.3. Stability of behavioral tendencies across social contexts 42
2.4.2. Effects of rank and behavioral tendency on glucocorticoid regulation 42
2.4.2.1. Diurnal cortisol 42
2.4.2.2. Glucocorticoid negative feedback (DST) 43
2.4.2.3. Sensitivity to acute glucocorticoid challenge (DCT) 43
2.4.3. Causal effects of dominance rank on glucocorticoid regulation 44
2.5. Discussion 44
2.5.1. Behavioral characterization 44
2.5.2. Effects of rank and behavioral tendencies on glucocorticoid regulation 46
2.6. Limitations 48
3. LOW DOMINANCE RANK DESENSITIZES PERIPHERAL BLOOD LEUKOCYTES TO REDISTRIBUTION BY GLUCOCORTICOIDS AND DOWNREGULATES ADHESION MOLECULE EXPRESSION IN FEMALE RHESUS MACAQUES 65
3.1. Abstract 66
3.2. Introduction 66
3.3. Methods 71
3.3.1. Study subjects and dominance rank assignment 71
3.3.2. Social separation stressor and dexamethasone challenge 72
3.3.3. Cortisol assay and flow cytometry 74
3.3.4. Gene expression in FACS-isolated leukocyte subsets 75
3.3.5. Statistical analysis 77
3.4. Results 82
3.4.1. Rank associations with basal leukocyte counts 82
3.4.2. Leukocyte and cortisol responses to social separation 82
3.4.3. Rank effects on cortisol and leukocyte responses to separation 83
3.4.4. Causal effects of rank and GC sensitivity on leukocyte response to Dex 84
3.4.5. Rank effects on CAM gene expression 85
3.4.6. Effects of CAM gene expression on changes in blood composition 86
3.4.7. Associations between leukocyte redistribution by Dex and behavioral tendency 87
3.5. Discussion 87
3.5.1. Dominance rank and basal leukocyte numbers 87
3.5.2. Dominance rank effects on cortisol responses and leukocyte redistribution 88
3.5.3. Dominance rank effects on CAM gene expression 89
3.5.4. Effects of glucocorticoid sensitivity and CAM gene expression on redistribution 90
3.5.5. Associations between leukocyte redistribution and behavioral tendency 92
3.5.6. Limitations and future directions 93
4. SUMMARY AND CONCLUSIONS 114
4.1. Summary of results 115
4.2. Integration of findings and concluding remarks 116
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