Experiential and Developmental Factors Affecting Brain and Behavior in Female Rhesus Macaques Open Access

Godfrey, Jodi Ruth (2016)

Permanent URL: https://etd.library.emory.edu/concern/etds/6q182k37c?locale=en


Exposure to chronic social stressors during childhood, adolescence and adulthood leads to alterations in brain structure and circuitry. Importantly, these stress-induced alterations can lead to emotional dysregulation and psychopathology, particularly in women. However, the mechanisms underlying the emergence of, and the factors contributing to, these stress- induced alterations are poorly understood. Therefore, the primary goal of this thesis was to investigate what factors underlie and modify chronic stressor-induced changes in brain structure and function and resulting behavior. Social subordination in female rhesus macaque monkeys is an established translational animal model that produces a number of stress-related phenotypes, including stress-induced over-eating of an obesogenic diet. Using this social subordination model of chronic stressor exposure, we found that developmental suppression of estradiol (E2) and consumption of an obesogenic diet both modify chronic stressor alterations in brain structure, functional connectivity (FC) and behavior. In one study, chronic social subordination across pre- and peripuberty resulted in larger amygdala (AMYG) volume compared to dominant subjects, but experimental suppression of E2 neutralized this effect. In the next study, the effects of social subordination on regional brain volumes in adults were modified by dietary environment, where the availability of an obesogenic diet reversed the impact of social rank on bilateral prefrontal cortex white matter (PFC WM). In the final study, the effects of social subordination on brain FC in adults were also modified by dietary environment. These results are important as they provide evidence that (1) exposure to developmental increases in E2 modify the consequences of social subordination on the volume of cortico-limbic regions involved in emotional and stress regulation during maturation, and (2) exposure to an obesogenic diet in adulthood modifies the consequences of social subordination on the volume and FC of cortico-limbic regions involved in stress regulation, in addition to emotional and motivational behavior in female rhesus macaques.

Table of Contents

Chapter 1. Introduction.....1

1.1 Low social status as a psychosocial stressor.....2

1.1.2 Limbic-hypothalamic-pituitary-adrenal (LHPA) axis overview..... 3

1.1.3 Macaque model of social subordination.....4

1.1.4 Effects of social subordination on the LHPA axis.....8

1.1.5 Chronic stress and role of immune system function.....9

1.2 Effects of social subordination on limbic brain regions across the life span.....10

1.2.1 Postnatal development of amygdala, hippocampus and prefrontal cortex.....10

1.2.2 Effects of social subordination on brain structure and connectivity in adult non-human primates.....13

1.2.3 Effects of social subordination on brain structure and neurotransmission in juvenile non-human primates.....15

1.3 Modifiers of stress-induced effects on neurobehavioral outcomes.....18

1.3.1 Importance of estradiol on neurobehavioral outcomes.....18

1.3.2 Importance of dietary environment on brain and behavior and non-homeostatic brain regions involved in food intake.....20

1.3.3 Evidence of diet-induced obesity effects on brain structure.....22

1.3.4 Evidence of diet-induced obesity effects on brain functional connectivity.....24

1.3.5 Effects of dietary environment on social and emotional behavior.....25

1.3.6 Signals linking diet to neurobehavioral outcomes.....26

1.4 Overall goal and hypotheses.....28

Chapter 2. Effects of Social Rank and Experimental Delay of Puberty on Brain structure in Female Rhesus Macaques.....30

2.1 Abstract.....31

2.2 Introduction.....33

2.3 Methods.....39

2.3.1 Subjects.....39

2.3.2 Social Subordination.....40

2.3.3 Experimental Procedures.....41

2.3.4 Hormone Assays.....48

2.3.5 Statistical Analyses.....49

2.4 Results.....51

2.4.1 sMRI Data.....51

2.4.2 Behavior and Stress Physiology.....55

2.4.3 Multiple Regression Analyses.....57

2.5 Discussion.....59

Chapter 3. Chronic Social Stress and Consumption of a Palatable Diet Alter Brain Structure and Behavior in Female Rhesus Macaques.....88

3.1 Abstract.....89

3.2 Introduction.....91

3.3 Methods.....98

3.3.1 Subjects.....98

3.3.2 Dietary Intervention.....99

3.3.3 Behavior.....101

3.3.4 Stress Physiology and Immune Markers.....104

3.3.5 Cytokine/Immune Markers.....105

3.3.6 Structural MRI.....106

3.3.7 Statistical Analyses.....109

3.4 Results 110

3.4.1 Predictors of alterations in ROI volumes.....110

3.4.2 Functional behavioral outcomes.....112

3.5 Discussion.....114

Chapter 4. Cortico-Limbic-Striatal Functional Connectivity and Behavior Are Impacted by Dietary Environment and Exposure to Social Stressors in Female Rhesus Macaques.....132

4.1 Abstract.....133

4.2 Introduction.....136

4.3 Methods.....142

4.3.1 Subjects.....142

4.3.2 Dietary Intervention.....144

4.3.3 Behavior.....145

4.3.4 Stress Physiology and Immune Markers.....149

4.3.5 Cytokine/Immune Markers.....150

4.3.6 Rs-fMRI.....150

4.3.7 Statistical Analyses.....154

4.4 Results.....155

4.4.1 Predictors of alterations in ROI-ROI FC.....155

4.4.2 Functional behavioral outcomes..... 157

4.5 Discussion.....158

Chapter 5. General Discussion.....177

5.1 Summary of results.....178

5.1.1 Summary of Chapter 2.....178

5.1.2 Summary of Chapter 3.....179

5.1.3 Summary of Chapter 4.....181

5.2 Integration of findings.....182

5.3 Conclusions and future directions.....185

Chapter 6. References.....188

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