Long-term Impacts of Early Life Stress on the Functional Connectivity of Adult Emotional Neurocircuits in Rhesus Macaques 公开

Abstract

Child Maltreatment (MALT) is a traumatic form of early life adversity (ELA) with high prevalence in the United States and the grave physical threat it poses for infants and children. MALT is a major public health issue because it is associated with the development of physical illnesses, such as chronic inflammation and obesity, and mental illness later in life, including but limited to depression, anxiety, posttraumatic stress disorder -PTSD-, substance use disorder, and conduct disorder. This study examined the long-term effects of infant maltreatment (MALT) on adult functional connectivity (FC) between the amygdala (AMY), hippocampus (HIPP), and subregions of the prefrontal cortex (PFC) -mPFC, OFC, dlPFC, and vlPFC- due to the critical role of these circuits in emotional and stress regulation. For this, brain resting state functional MRI (rs-fMRI) scans were collected to examine ROI-ROI FC (AMY-AMY, AMY-PFC, AMY-HIPP, and HIPP-PFC). Our lab has previously reported greater anxiety in adult MALT animals using a measure of baseline amplitude of the acoustic startle reflex (Beesley et al, 2022), and the goal of this thesis was to identify alterations in PFC-AMY-HIPP FC that could underlie those effects. In addition, total COC intake during adolescence was added as a covariate to the statistical models to control for its potential developmental impact on FC in these cortico-limbic circuits during adolescence. The findings suggest that infant MALT did not have a long-term effect on adult AMY FC (AMY-AMY, AMY-PFC, or AMY-HIPP). The results also contrast with a previous publication from this cohort of animals studied from infancy to the juvenile, prepubertal, period (at 3, 6, 12 and 18 months of age), where weaker AMY-PFC FC was found in MALT than Control animals across development, particularly between AMY and subgenual cingulate (Area 25) anterior cingulate (Area 24), Area 13 in the OFC and Area 9 in the dlPFC, whereas left AMY-right AMY FC was stronger in MALT than Controls (Morin et al, 2020). The findings in this thesis suggest transient effects of MALT on AMY FC during infancy and the juvenile period, with recovery (“catch up”) of AMY-AMY and AMY-PFC typical FC underlying emotional regulation by adulthood. On the other hand, this study revealed long-term effects of MALT in HIPP-PFC FC, specifically between HIPP-Area 9 (dlPFC) and HIPP-Area 45 (vlPFC), and in both cases different in males than females; specifically, MALT females showed weaker negative FC than Control females, whereas the opposite directionality was observed in males. Adult anxiety was not associated with FC between HIPP and these two lateral PFC regions, suggesting functional alterations in other emotional regulation circuits that could underlie the exaggerated startle amplitude in the animals with ELS. Additional effects of Sex and Laterality were detected in the FC of AMY, PFC and HIPP circuits. Surprisingly, we did find a significant positive correlation between adolescence COC intake and AMY FC with vlPFC Area 47 FC , which is interesting given the vlPFC role in reward and reappraisal of addictive stimuli. Overall, these findings suggest long-term effects of infant MALT on specific HIPP-PFC circuit FC, but not AMY FC of adult rhesus monkeys, which contrasts with the weaker AMY-PFC FC reported in MALT animals compared to Controls during infancy and the juvenile period; this indicates that some effects of infant MALT on these corticolimbic functional development are temporary/transient, while others are long-term. 

Table of Contents

Table of Contents

Introduction. 1

The Effects of Child Maltreatment on Health Outcomes 1

Does Child Maltreatment Alter Neurocircuitry Implicated in Emotional Regulation? 2

Translational NHP Model 10

ELA Increased Risk for Substance Use Disorders during Adolescence 11

Aim and Hypotheses 12

Methods 13

Subjects and Housing 13

Adolescence: Cocaine Self-Administration (COC SA) 15

Adult brain Magnetic Resonance Imaging Data Acquisition, Processing & Analysis 17

Regions of Interest (ROIs) 18

Adult Amplitude of Startle Response 19

Statistical Analysis 19

Results 21

Functional Connectivity (FC) data 21

Left AMY-Right AMY FC 21

AMY-mPFC FC 21

AMY-OFC FC 23

AMY-dlPFC FC 24

AMY-vlPFC FC 25

HIPP-AMY FC 26

HIPP-mPFC FC 26

HIPP-OFC FC 28

HIPP-dlPFC FC 30

HIPP-vlPFC FC 32

Discussion 34

Effects of MALT on ROI-ROI FC 35

Effects of Sex and Laterality on ROI-ROI FC 39

Limitations & Future Studies 40

Significance 44

Tables & Figures 45

Table 1. Group and Sex breakdown based on biological mother group and randomized crossfostering assignment at birth to a Control or MALT foster mother 45

Table 2. Summary of Functional Connectivity (FC) Findings 45

Figure 1. Experimental Timeline 44

Figure 2. Anatomical location of Regions of Interest (ROIs) 44

Figure 3. Left amygdala (AMY)-Right AMY functional connectivity 47

Figure 4. Whole amygdala (AMY)- Area 14 functional connectivity 48

Figure 5. Whole amygdala (AMY)- Area 24 functional connectivity 48

Figure 6. Whole amygdala (AMY)-Area 25 functional connectivity 49

Figure 7. Whole amygdala (AMY)-Area 32 functional connectivity 49

Figure 8. Whole amygdala (AMY)-Area 11 functional connectivity 50

Figure 9. Whole amygdala (AMY)-Area 13 functional connectivity 50

Figure 10.Whole amygdala (AMY)-Area 9 functional connectivity 51

Figure 11. Whole amygdala (AMY)-Area 45 functional connectivity 51

Figure 12. Whole amygdala (AMY)-Area 46 functional connectivity 52

Figure 13A. Whole amygdala (AMY)-Area 47 functional connectivity 53

Figure 13B.Pearson Correlation between AMY-left Area 47 FC and Lifetime Cocaine Intake 53

Figure 14. Whole amygdala (AMY)-hippocampus (HIPP) functional connectivity 54

Figure 15. Whole hippocampus (HIPP)-Area 14 functional connectivity 54

Figure 16. Whole hippocampus (HIPP)- Area 24 functional connectivity 55

Figure 17. Whole hippocampus (HIPP)-Area 25 functional connectivity 55

Figure 18. Whole hippocampus (HIPP)-Area 32 functional connectivity 56

Figure 19. Whole Hippocampus (HIPP)-Area 11 functional connectivity 56

Figure 20. Whole hippocampus (HIPP)- Area 13 functional connectivity 57

Figure 21. Whole hippocampus (HIPP)-Area 9 functional connectivity 57

Figure 22. Whole hippocampus (HIPP)-Area 45 functional connectivity 57

Figure 23. Whole hippocampus (HIPP)-Area 46 functional connectivity 58

Figure 24. Whole hippocampus (HIPP)-Area 47 functional connectivity 59

References 60

 

About this Honors Thesis

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School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Health Sciences, Mental Health Biology, Neuroscience
关键词	Prefrontal Cortex Hippocampus Maltreatment Early Life Stress Emotion Amygdala Functional Connectivity
Committee Chair / Thesis Advisor	Dr. Mar Sanchez , Emory University
Committee Members	Dr. Kim Wallen , Emory University Dr. Megan Cole , Emory University Dr. Kristen Frenzel, Emory University Dr. Zsofia Kovacs Balint, Emory University

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