Psychosocial stress modifies the effects of estradiol on female rhesus monkey brain and behavior Öffentlichkeit

Abstract

Exposure to stressors can be a precipitating factor in the development of psychopathology. Women are more likely to develop stress-related disorders than men; however, the mechanisms of this increased susceptibility are not understood. One hypothesis for this gender bias in disease prevalence is that exposure to chronic stress alters the beneficial effects of the ovarian hormone estradiol (E2) on behavior, thus increasing incidence of behavioral disorders. Few studies have examined the effects of chronic stressor exposure on E2's actions in the female brain. To determine whether stress alters E2's effect on both behavior and brain structure and function, I used the well-defined and highly translational female rhesus monkey model of social subordination to examine the consequences of chronic stress on the action of E2 on brain and behavior. I tested the hypothesis that E2 would dose-dependently increase socio-sexual behavior in dominant but not subordinate females. In vivo neuroimaging techniques including structural magnetic resonance imaging (MRI) and resting-state functional MRI were used to identify changes in structure and functional connectivity (FC) of cortico-limbic brain region in ovariectomized females both with and without short term E2 replacement. Evidence from these studies suggests that social subordination attenuates E2's activational effects on sociosexual behavior, which are not overcome with higher dose of E2. The neuroimaging data demonstrate dichotomous effects of E2 on brain structure, such that cingulate gray matter volumes decreased in subordinate and increased in dominant females. Additionally, subordinate females showed decreased negative FC between the amygdala and ventral pallidum and increased positive FC between the anterior cingulate cortex and the supplemental motor area, posterior cingulate cortex, and the superior temporal sulcus. Furthermore, FC between the amygdala and the medial prefrontal cortex increased between in subordinate females and decreased during the E2 condition, although no interaction effects were found. Together, these data represent the first studies identifying the effects of chronic stress, imposed by social subordination, and E2 on the adult female primate brain and behavior. The experiments serve to fill critical gaps in our knowledge of how adaptation to psychosocial stress can increase susceptibility to behavioral disorders in women.

Table of Contents

Table of Contents
1. INTRODUCTION...1

1.1 Stress and gonadal hormone receptors in the brain...3

1.1.1 Estrogen receptors...4
1.1.2 Glucocorticoid receptors...7
1.1.3 Corticotropin releasing factor receptor...9
1.1.4 Summary...11

1.2 Estradiol and stress effects on neuroendocrine regulation...12

1.2.1 Estradiol modifies the hypothalamic-pituitary-gonadal axis...13
1.2.2 Stress signals modify the hypothalamic-pituitary-adrenal axis...16
1.2.3 Summary...21

1.3 Animal models of stress...21

1.3.1 Rodent models of stress...22
1.3.2 Macaque models of stress...26
1.3.3 Summary...29

1.4 Chronic stress modifies estradiol's activational effects on behavior...30

1.4.1 Reproductive behavior...31
1.4.2 Non-reproductive behavior...37
1.4.3 Summary...47

1.5 Estradiol effects on brain structure and function: Interaction with stress...49

1.5.1 Hippocampus...50
1.5.2 Prefrontal Cortex...53
1.5.3 Amygdala...55
1.5.4 Summary...57

1.6 Estradiol effects on brain functional connectivity: Interactions with stress...58
1.7 Aims...61

2. SOCIAL STATUS MODIFIES ESTRADIOL ACTIVATION OF SOCIOSEXUAL BEHAVIOR IN FEMALE RHESUS MONKEYS...63

2.1 Abstract...64
2.2 Introduction...65
2.3 Methods...68

2.3.1 Subjects...68
2.3.2 Social Subordination Stress...69
2.3.3 Experimental Design...71
2.3.4 Behavioral Outcome Measures...72
2.3.5 Hormonal Assay...73
2.3.6 Statistical Assessment...73

2.4 Results...74

2.4.1 Hormonal Assay...74
2.4.2 Sexual and Social Behavior...75
2.4.3 Agonistic Behavior...78
2.4.4 Sociosexual versus Aggressive Behavior...79
2.4.5 Anxiety-Like Behavior...81

2.5 Discussion...81

3. SOCIAL SUBORDINATION ALTERS ESTRADIOL-INDUCED CHANGES IN CORTICO-LIMBIC BRAIN VOLUMES IN ADULT FEMALE RHESUS MONKEYS...97

3.1 Abstract...98
3.2 Introduction...99
3.3 Methods...104

3.3.1 Subjects...104
3.3.2 Social Subordination...105
3.3.3 Estradiol Treatment...106
3.3.4 Neuroimaging Protocol...107
3.3.5 Statistical Analysis...109

3.4 Results...110

3.4.1 Total Brain Volume...110
3.4.2 Prefrontal Cortex...110
3.4.3 Frontal Cortex...111
3.4.4 Cingulate Cortex...113
3.4.5 Hippocampus...114
3.4.6 Amygdala...115

3.5 Discussion...115

4. EFFECTS OF SOCIAL SUBORDINATION AND ESTRADIOL ON RESTING-STATE PREFRONTAL AND AMYGDALA FUNCTIONAL CONNECTIVITY IN ADULT FEMALE RHESUS MONKEYS...128

4.1 Abstract...129
4.2 Introduction...130
4.3 Methods...135

4.3.1 Subjects...135
4.3.2 Estradiol Treatment...137
4.3.3 Behavioral Data...137
4.3.4 fMRI Data Acquisition and Analysis...139
4.3.5 Functional Connectivity Analysis...141

4.4 Results...143

4.4.1 Behavioral Data...143
4.4.2 ROI Functional Connectivity Analysis...143
4.4.3 Voxel-wise Functional Connectivity Analysis...144

4.5 Discussion...146

5. SUMMARY AND CONCLUSION...167

5.1 Summary of results...168

5.1.1 Chapter two...168
5.1.2 Chapter three...168
5.1.3 Chapter four...169

5.2 Integration of findings...170
5.3 Conclusions and future directions...173

List of Tables and Figures
CHAPTER 2

Table 2.1...89
Table 2.2...90
Table 2.3...91
Figure 2.1...92
Figure 2.2...93
Figure 2.3...94
Figure 2.4...95
Figure 2.5...96

CHAPTER 3

Table 3.1...123
Table 3.2...125
Figure 3.1...126

CHAPTER 4

Table 4.1...159
Table 4.2...160
Table 4.3...161
Figure 4.1...163
Figure 4.2...164
Figure 4.3...166

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Stichwort	Stress Estradiol MRI Resting-State Rhesus
Committee Chair / Thesis Advisor	Wilson, Mark, Emory University Sanchez, Mar, Emory University
Committee Members	Wallen, Kim, Emory University Mayberg, Helen S, Emory University Rilling, James K, Emory University Toufexis, Donna, Emory University

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