Long-term Impacts of Early Life Stress on the Functional Connectivity of Adult Emotional Neurocircuits in Rhesus Macaques Öffentlichkeit
Reddy, Vijaya (Spring 2023)
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
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