Impact of Stress, Pubertal Tempo, and Diet on Neurobehavioral Development in Female Rhesus Macaques Open Access

Abstract

Early life stress is one of the strongest risk factors for the emergence of psychopathology, particularly in women; yet, the mechanisms explaining how stress becomes biologically embedded remain poorly understood. Social subordination in rhesus macaques provides a naturalistic model for studying the impacts of chronic psychosocial stress on neurobehavioral development. This dissertation aims to investigate how chronic subordination stress in female macaques interacts with experiential factors, including pubertal timing and diet, to alter the development of corticolimbic circuitry and behavior. Puberty-induced increases in gonadal hormones are involved in shaping the brain during adolescence, and may modulate the effects of stress on brain development during this critical period. We examined the effects of social subordination and pharmacological delay of puberty in macaques at a postpubertal time point in adolescence and found that subordination was associated with decreased functional connectivity (FC) between dorsolateral prefrontal cortex (PFC) and amygdala (AMYG). Pharmacological delay of puberty resulted in increased FC between AMYG and orbitofrontal cortex (OFC), and both positive and negative effects on socioemotional behavior, but no interactions between experimentally-induced pubertal delay and subordination were detected. Given that stress is a cumulative risk factor for obesity in children and consuming an obesogenic diet impacts the corticolimbic circuits affected by stress, we then used this same social subordination model to study how social subordination and consumption of a high-calorie diet (HCD) interact to affect neurobehavioral development during infancy. Subordination in infancy was associated with higher AMYG-PFC FC, and higher FC between the insula (INS) and anterior cingulate cortex (ACC) at 6 months of age, and nursing from mothers consuming a HCD, obesogenic diet decreased AMYG-OFC FC at 2 weeks of age. Effects of subordination stress on corticolimbic FC, stress physiology, and inflammation were modified by diet during infancy. These results provide evidence that chronic social subordination stress, pubertal timing, and consumption of an obesogenic diet alters physiology, behavior, and the maturation of corticolimbic circuitry important to emotion regulation, reward processing, and interoception during primate development.

Table of Contents

Chapter 1. Introduction............................................................................................................................1

Acknowledgement of Reproduction.............................................................................................................................2

1.1 Chronic Stress in Development and Human Health............................................................................................2

1.2 Stress Response and Chronic Activation of the Hypothalamic-Pituitary-Adrenal (HPA) Axis........................3

1.2.1 Overview of the Autonomic and Endocrine Responses to Stress.............................................................3

1.2.2 Effects of Chronic Stress on the HPA axis and Regulatory Limbic Regions..........................................6

1.2.3 Chronic Stress and Functional Connectivity of Corticolimbic Circuits.................................................8

1.3 Macaque Model of Social Subordination............................................................................................................10

1.3.1 Subordination Status and Chronic Stress................................................................................................10

1.3.2 Social Subordination and Alterations of the HPA axis...........................................................................12

1.3.3 Chronic Stress and Immune Interactions..................................................................................................13

1.3.4 Normative Non-Human Primate Brain Development.................................................................................14

1.3.5 Effects of Social Subordination Stress on Brain Structure and Connectivity in Adult NHPs.............16

1.3.6 Biobehavioral  Effects of Social Subordination in Juvenile NHPs..........................................................18

1.4 Experiential Factors that Modify Effects of Stress on Brain and Behavior......................................................20

1.4.1 Estradiol and Puberty...............................................................................................................................20

1.4.2 Effects of E2 on Emotion and Mood.........................................................................................................23

1.4.3 Interactions between E2 and HPA Axis....................................................................................................25

1.4.4 E2 and Neural Remodeling During Adolescence.....................................................................................26

1.4.5 Pubertal Timing and Neurobehavioral Development................................................................................30

1.4.6 Dietary Environment and Neural Circuits Implicated in Nonhomeostatic Eating...................................31

1.4.7 Effects of Diet and Diet-induced Obesity on Brain Structure and Function..........................................34

1.4.8 Effects of Diet and Diet-induced Obesity on Functional Connectivity of Corticolimbic Circuits.........38

1.4.9 Impacts of Diet on Emotional Behavior.....................................................................................................41

1.4.10 Signals Linking Diet to Neurobehavioral Outcomes...............................................................................42

1.5 Overall Goal and Hypotheses...............................................................................................................................43

Chapter 2. Effect of Pubertal Delay and Social Status on Amygdala Functional Connectivity in Adolescent Rhesus Macaques: Associations with Behavior and Stress Physiology.............................................................................................................................................47

2.1 Abstract................................................................................................................................................................. 48

2.2 Introduction........................................................................................................................................................... 49

2.3 Methods...................................................................................................................................................................59

2.3.1 Subjects........................................................................................................................................................59

2.3.2 Determination of Social Rank.....................................................................................................................60

2.3.3 Lupron Administration.................................................................................................................................60

2.3.4 Functional MRI Data Acquisition...............................................................................................................61

2.3.5 Functional MRI data pre-processing...........................................................................................................62

2.3.6 Resting-state Functional Connectivity Analysis........................................................................................63

2.3.7 Quality Control Before Statistical Analysis.............................................................................................63

2.3.8 Behavioral Data...........................................................................................................................................64

2.3.9 Statistical Analysis......................................................................................................................................65

2.4 Results......................................................................................................................................................................68

2.4.1 Pubertal Timing.............................................................................................................................................68

2.4.2. Behavioral Data...........................................................................................................................................69

2.4.3 Resting-state Functional Connectivity........................................................................................................70

2.4.4 Associations between Resting-state Functional Connectivity and Behavior..............................................71

2.4.5 Secondary Analysis: Menarche Age.............................................................................................................71

2.4.6 Influence of Outliers....................................................................................................................................72

2.5 Discussion..................................................................................................................................................................72

CHAPTER 3. Social Subordination Stress and an Obesogenic Diet Affect Neurobehavioral Development and Physiology in Infant Rhesus Macaques.........104

3.1 Abstract..................................................................................................................................................................105

3.2 Introduction............................................................................................................................................................108

3.3 Methods...................................................................................................................................................................120

3.3.1 Subjects.......................................................................................................................................................120

3.3.2 Dam Selection and Prenatal Conditions....................................................................................................121

3.3.3 Infant Assignment and Cross Fostering.....................................................................................................121

3.3.4 Diet Intervention.........................................................................................................................................122

3.3.5. Emotional Behavior....................................................................................................................................123

3.3.6 Physiology...................................................................................................................................................124

3.3.7 Resting-state fMRI.....................................................................................................................................126

3.3.8 Statistical Analysis....................................................................................................................................130

3.4 Results....................................................................................................................................................................135

3.4.1 Predictors of Feeding..................................................................................................................................135

3.4.2 Resting-state FC..........................................................................................................................................136

3.4.3 Stress Physiology and Peripheral Inflammation........................................................................................137

3.4.4 Emotional Behavior.....................................................................................................................................139

3.4.5 Regression Models of Feeding behavior.....................................................................................................139

3.4.6 Associations between Outcomes with Significant Social Status or Diet effects......................................140

3.5 Discussion................................................................................................................................................................140

Chapter 4. General Discussion.................................................................................................................174

4.1 Summary of Results................................................................................................................................................175

4.1.1 Summary of Chapter 2.................................................................................................................................175

4.1.2 Summary of Chapter 3.................................................................................................................................177

4.2 Integration of Findings...........................................................................................................................................180

4.3 Conclusions and Future Directions........................................................................................................................186

Chapter 5. REFERENCES...................................................................................................................................188

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience Biology, Endocrinology
Keyword	Stress Development
Committee Chair / Thesis Advisor	Sanchez, Mar, Emory University
Committee Members	Wilson, Mark, Emory University Bachevalier, Jocelyne, Emory University Keilholz, Shella, Emory University Jovanovic, Tanja, Emory University

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