Psychosocial stress induces distinct physiological and behavioral phenotypes in female rhesus monkeys 公开

Abstract

Exposure to chronic stressors is a causal and sustaining factor in a number of adverse health outcomes, an observation supported by an extensive literature from epidemiological analyses in humans. Dysfunction of the limbic-hypothalamic pituitary- adrenal (LHPA) axis is characteristic of psychopathologies and other stress-induced disease states that are highly co-morbid, including cardiovascular disease, immune dysfunction, reproductive compromise, emotional feeding and obesity. We propose in this dissertation that psychosocial stress exposure in the form of social subordination results in stress-induced alterations in behavior and physiology in female rhesus monkeys. In a series of experiments, we show that social subordination in female rhesus monkeys dysregulates LHPA activity, decreases sensitivity to the socioemotional effects of estradiol, alters feeding behavior in complex dietary environments, and disrupts reproductive function. This dissertation work provides evidence that social subordination results in two distinct phenotypes that can be studied to assess the etiology of stress- induced disruptions in behavior and physiology due to psychosocial stress exposure specifically in females.

Table of Contents

TABLE OF CONTENTS
1. ADVERSE HEALTH CONSEQUENCES DUE TO EXPOSURE TO CHRONIC STRESSORS IN HUMANS: IMPORTANCE OF DEVELOPING A TRANSLATIONAL ANIMAL MODEL... 1

1.1 Abstract... 2

1.2 Stress in modern society and its ramifications on human health...3
1.3 Neuroendocrine regulation of stress reactivity...5
1.4 Genetics influence individual susceptibility of stress-induced disorders...9
1.5 Animal models of chronic exposure to stressors...14
1.6 Social subordination in female rhesus monkeys...23
1.7 Overall goal and rationale...24
1.8 General material and methods...25

2. SOCIAL SUBORDINATION IMPAIRS HYPOTHALAMIC-PITUITARY-ADRENAL FUNCTION IN FEMALE RHESUS MONKEYS...32

2.1 Abstract...33
2.2 Introduction...34
2.3 Materials and methods...37
2.4 Results...38
2.5 Discussion...42

3. SOCIAL SUBORDINATION ALTERS SOCIOEMOTIONAL EFFECTS OF ESTRADIOL IN FEMALE RHESUS MONKEYS...59

3.1 Abstract...60
3.2 Introduction...61
3.3 Materials and methods...64
3.4 Results...66
3.5 Discussion...70

4. SOCIAL SUBORDINATION INTERACTS WITH DIET HISTORY TO PROMOTE EMOTIONAL FEEDING IN FEMALE RHESUS MONKEYS...82

4.1 Abstract...83
4.2 Introduction...85
4.3 Materials and methods...87
4.4 Results...90
4.5 Discussion...95

5. SOCIAL SUBORDINATION RESULTS IN THE IMPAIRMENT OF REPRODUCTIVE FUNCTION IN FEMALE RHESUS MONKEYS...111

5.1 Abstract...112
5.2 Introduction...114

5.2.1 Regulation of reproductive axis in females...114
5.2.2 Interaction between HPG and LHPA axes...119
5.2.3 Metabolic signals modulate reproductive function...121
5.2.4 SLC6A4 polymorphism and increased vulnerability to stress-induced adverse health outcomes...123
5.2.5 Overall rationale...124

5.3 The effects of social subordination and the polymorphism in the gene encoding 5HTT on estradiol inhibition of luteinizing hormone...125

5.3.1 Introduction...125
5.3.2 Materials and methods...126
5.3.3 Results...128
5.3.4 Discussion...133

5.4 Effects of social subordination and 5HTT genotype on estradiol positive feedback of luteinizing hormone...139

5.4.1 Introduction...139
5.4.2 Materials and methods...140
5.4.3 Results...142
5.4.4 Discussion...143

5.5 Does increase caloric intake diminish E2 negative feedback in subordinate females?...144

5.5.1 Introduction...144
5.5.2 Materials and methods...145
5.5.3 Results...147
5.5.4 Discussion...148

5.6 Conclusions...150

6. TWO DISTICNT PHENOTYPES EMERGE FROM SOCIAL SUBORDINATION IN FEMALE RHESUS MONKEYS...162

6.1 Summary...163
6.2 Materials and methods...166
6.3 Results...170
6.4 Discussion...174

6.4.1 Behavioral domain...174
6.4.2 Metabolic domain...175
6.4.3 Neuroendocrine domain...177
6.4.4 Limitations...179
6.4.5 Possible mechanism underlying stress-induced changes in behavior and physiology...182
6.4.6 Future directions...186

6.5 Conclusion...188

7. PHYSIOLOGICAL EFFECTS OF RESTORATION OF OVARIAN CYCLICITY DUE TO COGNITIVE BEHAVIORAL THERAPY IN WOMEN WITH FUNCTIONAL HYPOTHALAMIC AMMENORHEA...199

7.1 Abstract...200
7.2 Stress-induced reproductive compromise...202

7.2.1 Pathogenesis of stress-induced anovulation/ functional hypothalamic amenorrhea (FHA)...205
7.2.2 Treatment of FHA with cognitive behavioral therapy...209
7.2.3 Overall rationale...210

7.3 Materials and methods...211
7.4 Results...213
7.5 Discussion...214

8. REFERENCES...223

About this Dissertation

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• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Psychology, Psychobiology Biology, Neuroscience Biology, Animal Physiology
关键词	rhesus monkeys psychosocial stress physiology females behavior
Committee Chair / Thesis Advisor	Wilson, Mark, Emory University
Committee Members	Wallen, Kim, Emory University Sanchez, Mar, Emory University Kinkead, Becky, Emory University Ressler, Kerry, Emory University

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