Effects of stress and estradiol on neural mechanisms of emotional memory Restricted; Files Only
Oliver, Katelyn (Fall 2025)
Abstract
Posttraumatic stress disorder (PTSD) is characterized by experiences of fear overgeneralization, fragmented trauma memories, and declarative memory deficits. However, there are gaps in the literature regarding how mechanisms of these memory differences develop and are maintained in relation to stressor-related disorders. I hypothesized that traumatic exposure might impact emotional memory processes as early as childhood. Additionally, since PTSD is more prevalent in females compared to males, I further hypothesized that sex-specific factors might influence emotional and threat-relevant memory mechanisms in participants with greater trauma burdens. First, I reviewed how fear neurocircuitry differs between men and women, which provides context for why trauma disorders may develop differently between sexes. Next, I investigated the impacts of childhood trauma load on neural and behavioral emotional memory processes, finding evidence of sex differences in emotional memory recall and that children with the highest amount of trauma exposure utilized alternative neural circuits to successfully encode emotional memories. Finally, in a randomized, placebo-controlled, crossover trial, I analyzed the influence of exogenous estradiol (E2) on mechanisms of threat-related memory among trauma exposed women during two low-E2 cycle phases. In the early luteal phase, I found that E2 interactions with progesterone may dampen threat-related memory facilitation effects. However, in the early follicular phase under E2 administration, participants with greater PTSD symptom severity showed better episodic memory for safety-associated images, which was accompanied by increased functional activations in the hippocampus and entorhinal cortex. Overall, results within this dissertation provide important insights about the effects of trauma and sex-related factors on mechanisms of emotional memory, which may confer increased risk for PTSD.
Table of Contents
CHAPTER 1: INTRODUCTION: NEUROBIOLOGICAL SEX DIFFERENCES IN FEAR AND ANXIETY THAT CONTRIBUTE TO WOMEN’S RISK FOR TRAUMA RELATED DISORDERS 1
1.1 Context, Authors’ Contribution, And Acknowledgement of Reproduction 2
1.2 Abstract 2
1.3 Introduction 3
1.4 Healthy Human Populations and Fear-Related Sex Differences 4
1.4.1 Unconditioned Fear and Anxiety Responses 4
1.4.2 Cortisol and Stress 8
1.4.3 Fear Conditioning and Extinction in Healthy Human Subjects 12
1.4.4 Hormone Effects in Fear Conditioning 15
1.5 Translational/Clinical: How Sex Differences are Related to Symptoms of Anxiety and Stress-Related Disorders 20
1.5.1 Prevalence of Anxiety and Stress-Related Disorders in Women and Men 20
1.5.2 Neuroimaging Studies of Anxiety and Stress-Related Disorders in Women and Men 22
1.6 Conclusions and Future Directions 29
1.7 Overview of the Dissertation 32
1.8 Figures 32
CHAPTER 2: IMPACTS OF EARLY LIFE ADVERSITY ON THE NEUROCIRCUITRY OF EMOTIONAL MEMORY IN CHILDREN 36
2.1 Context, Authors’ Contribution, And Acknowledgement of Reproduction 37
2.2 Abstract 37
2.3 Introduction 38
2.4 Methods 42
2.4.1 Participants 42
2.4.2 Trauma Load and Symptom Assessment 42
2.4.3 Procedures 43
2.4.4 Imaging acquisition and processing 46
2.4.5 Statistical Analyses 47
2.5 Results 50
2.5.1 Trauma and symptom assessments 50
2.5.2 Cued recall 51
2.5.3 Trauma load associations with regional brain activity and difference-in-memory recall performance 51
2.5.4 Effects of whole-brain activity during affective scene encoding on recall performance 53
2.5.5 Post-hoc associations between encoding-related brain activity and symptoms of PTSD, anxiety, and depression 54
2.6 Discussion 54
2.7 Supplemental Methods 61
2.8 Supplemental Results 65
2.9 Tables and Figures 67
CHAPTER 3: EXOGENOUS ESTRADIOL MODULATES ENTORHINAL CORTEX CONTRIBUTIONS TO EPISODIC ENCODING OF CONDITIONED THREAT IN WOMEN 80
3.1 Context, Authors’ Contribution, And Acknowledgement of Reproduction 81
3.2 Abstract 81
3.3 Introduction 82
3.4 Methods 85
3.4.1 Participants 85
3.4.2 Procedures 86
3.4.3 Neuroimaging 90
3.4.3 Statistical Analyses 92
3.5 Results 95
3.5.1 Task verification analyses 95
3.5.2 Recognition comparisons 96
3.5.3 E2 patch effects on encoding of conditioned threat cues 97
3.5.4 Exploratory and post-hoc analyses 97
3.6 Discussion 99
3.7 Supplemental Methods 103
3.8 Supplemental Results 109
3.9 Tables and Figures 111
CHAPTER 4: EXOGENOUS ESTRADIOL SHAPES MEMORY FOR CONDITIONED THREAT AND SAFETY IN WOMEN WITH TRAUMATIC STRESS SYMPTOMS 130
4.1 Context, and Authors’ Contribution 131
4.2 Abstract 131
4.3 Introduction 133
4.4 Methods 137
4.4.1 Participants 137
4.4.2 Procedures 139
4.4.3 Neuroimaging Protocol 144
4.4.4 Data Analytic Plan 146
4.5 Results 152
4.5.1 Impacts of exogenous estradiol and ovarian cycle phase on circulating hormone levels 152
4.5.2 Contingency awareness changes over threat conditioning: Behavioral responses 152
4.5.3 Task effects on whole-brain responses during CS+ and CS- trials 153
4.5.4 Post-scan recognition correlations with E2 supplementation x PTSS interactions 153
4.5.5 PTSS and E2 effects on regional encoding of threat and safety cues 154
4.5.6 Whole brain investigation of E2, PTSD symptom severity, and memory effects 155
4.6 Discussion 156
4.7 Tables and Figures 164
CHAPTER 5: CONCLUSIONS AND FUTURE DIRECTIONS 182
5.1 Summary of Findings 183
5.2 Contributions to the Field 183
5.3 Future Directions 188
5.4 Conclusion 191
References 192
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File download under embargo until 12 January 2032 | 2025-10-14 12:57:30 -0400 | File download under embargo until 12 January 2032 |
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