Early Maternal Care Modulates the Development of Adolescent Emotional Regulation and Neurocircuitry in Nonhuman Primates 公开
Morin, Elyse (Summer 2019)
Abstract
Maternal care is vital for proper primate socioemotional and cognitive development. Childhood maltreatment constitutes a major risk for psychopathology, including anxiety and mood disorders, and social and cognitive deficits, although the underlying neurodevelopmental mechanisms are not clearly understood. This dissertation tests the overall hypothesis that alterations in cortico-limbic circuits are involved, based on their critical role in emotional/stress regulation, and sensitivity to early experience. These studies utilized a well-established, spontaneous, nonhuman primate model of infant maltreatment (MALT) by the mother, which consists of comorbid physical abuse and rejection. In macaques, the highest rates of abuse/rejection happen in the first three months of life, a time of rapid brain development and maturation of prefrontal cortex(PFC)-amygdala circuits. We hypothesize that MALT impacts the developmental trajectory of amygdala circuits, including PFC-amygdala functional connectivity (FC) and relevant emotion/fear regulation behavior into adolescence. Adolescence is a crucial developmental period with physical, neuroendocrine, cognitive, and socioemotional changes linked to neural maturation and remodeling. We first examined long-term effects of MALT on attention bias to threat during adolescence, using cognitive touchscreen testing with the dot-probe task. MALT altered attentional processing of social threat, which could interfere with attention and cognitive processes. Next, acoustic startle testing was performed to measure baseline startle, fear/safety signal discrimination, fear modulation by safety cues, and extinction. Baseline startle in MALT animals was higher than controls, suggesting elevated state anxiety, but showed generalized blunted startle responses when safety and fear cues were presented together. Lastly, we examined the impact of MALT on amygdala FC longitudinally, from infancy through adolescence, using resting state fMRI. We found weaker amygdala FC with PFC and brainstem regions critical for arousal, stress and fear-learning throughout infancy and the juvenile period, some of which was predicted by elevated early exposure to cortisol. Interestingly, these effects on FC normalized by adolescence. Altogether these findings suggest that early adverse experience results in long-term alterations in emotional regulation beyond expected impacts in PFC-amygdala circuits. These studies uncovered lasting effects of MALT and its trajectory throughout development, to identify underlying neurobiological mechanisms that can be the target of and responsive to therapeutic intervention.
Table of Contents
Chapter 1 Introduction............................................................. 1
1.1 Early Life Stress and Childhood Maltreatment......................................................... 2
1.2 The stress response: neuroendocrine and emotional aspects, regulation and role of ELS on anxiety and mood disorders 5
1.3 Impact of ELS on brain development......................................................................... 7
1.4 Impact of ELS on brain connectivity in adolescence................................................ 9
1.5 Impact of ELS on emotional regulation/fear learning in adolescence................. 10
1.6 Translational ELS macaque model of infant maltreatment (MALT): elevated stress and emotional reactivity 11
Chapter 2 Effects of early maternal care on adolescent attention bias to threat in nonhuman primates............. 17
2.1 Abstract....................................................................................................................... 18
2.2 Introduction............................................................................................................... 18
2.3 Methods...................................................................................................................... 24
2.3.1 Subjects................................................................................................................ 24
2.3.2 Behavioral characterization of maternal care & measures of infant emotional reactivity 26
2.3.3 Dot-Probe Testing Procedure............................................................................. 27
2.3.4 Hair Cortisol........................................................................................................ 30
2.3.5 Statistical Analysis............................................................................................... 31
2.4 Results........................................................................................................................ 32
2.4.1 Early maternal care, emotional reactivity and cortisol................................... 32
2.4.2 Dot-probe test...................................................................................................... 33
2.4.3 Early predictors of Reaction Time in the Dot-probe....................................... 34
2.5 Discussion.................................................................................................................. 35
Chapter 3 Maternal Care Controls the Development of Fear Learning in Adolescent Nonhuman Primates......... 49
3.1 Abstract...................................................................................................................... 50
3.2 Introduction.............................................................................................................. 50
3.3 Methods...................................................................................................................... 57
3.3.1 Subjects................................................................................................................. 57
3.3.2 Fear-Potentiated Startle Testing Procedure..................................................... 59
3.3.3 Statistical Analysis.............................................................................................. 63
3.4 Results....................................................................................................................... 64
3.4.1 Baseline acoustic Startle Response................................................................... 64
3.4.2 Fear/safety signal discrimination learning: AX+/BX− training.................... 66
3.4.3 Transfer Test (Conditioned Inhibition)............................................................ 68
3.4.4 Extinction............................................................................................................ 69
3.5 Discussion.................................................................................................................. 69
Chapter 4 Developmental Outcomes of Early Adverse Care on Amygdala Functional Connectivity in Nonhuman Primates...... 90
4.1 Abstract....................................................................................................................... 91
4.2 Introduction.............................................................................................................. 92
4.3 Methods..................................................................................................................... 98
4.3.1 LONGITUDINAL (INFANCY THROUGH JUVENILE –PREPUBERTAL- PERIOD) RESTING STATE fMRI FUNCTIONAL CONNECTIVITY STUDIES.. 98
4.3.1.1 Subjects.............................................................................................................. 98
4.3.1.2 Behavioral characterization of maternal care........................................................ 99
4.3.1.3 Resting state functional MRI (rsfMRI) Image Acquisition..................................... 101
4.3.1.4 Structural MRI acquisition................................................................................. 103
4.3.1.5 Rs-fMRI data preprocessing............................................................................... 103
4.3.1.6 Definition of Amygdala and Prefrontal Cortex (PFC) Regions of Interest (ROI)...... 106
4.3.1.7 Whole Brain Voxel-wise Amygdala (AMY) functional connectivity (FC) Analysis.... 107
4.3.1.8 Amygdala-Prefrontal Functional Connectivity (FC): ROI-ROI analyses................. 107
4.3.2 ADOLESCENCE RESTING STATE fMRI FUNCTIONAL CONNECTIVITY STUDIES 108
4.3.2.1 Subjects............................................................................................................ 108
4.3.2.2 Rs-fMRI Image Acquisition during Adolescence.................................................. 109
4.3.2.3 Rs-fMRI data preprocessing: adaptation of the Human Connectome Project (HCP) Pipeline for macaques 110
4.3.2.4 Amygdala-Prefrontal Functional Connectivity (FC): ROI-ROI Analyses................. 111
4.3.2.5 Postnatal Hair Cortisol Measures........................................................................ 111
4.3.3 STATISTICAL ANALYSES.................................................................................. 112
4.3.3.1 Infancy-Juvenile Period Longitudinal PFC-Amygdala FC: ROI-ROI Analyses......... 112
4.3.3.2 Infancy-Juvenile Period Longitudinal Whole Brain Voxel-wise Amygdala FC......... 113
4.3.3.3 Adolescent PFC-Amygdala FC: ROI-ROI Analyses............................................... 113
4.4 Results...................................................................................................................... 114
4.4.1 LONGITUDINAL INFANCY-JUVENILE AMYGDALA FUNCTIONAL CONNECTIVITY STUDIES 114
4.4.1.1 Amygdala-PFC ROI-ROI Functional Connectivity................................................. 114
4.4.1.2 Associations between Postnatal Cortisol Exposure and MALT effects on PFC-AMY FC 120
4.4.1.3 Whole-brain Voxel-wise Amygdala FC................................................................ 120
4.4.1.4 Associations between Postnatal Cortisol Exposure and MALT effects on Whole Brain Voxel-wise Amygdala FC 122
4.4.2 ADOLESCENCE AMYGDALA-PREFRONTAL FUNCTIONAL CONNECTIVITY STUDIES 122
4.4.2.1 Amygdala-PFC ROI-ROI Functional Connectivity................................................ 123
4.5 Discussion................................................................................................................ 126
Chapter 5 Discussion, conclusions, and future directions 146
5.1 Summary of Results................................................................................................. 147
5.1.1 Effects of early maternal care on adolescent attention bias to threat in nonhuman primates 147
5.1.2 Maternal Care Controls the Development of Fear Learning in Adolescent Nonhuman Primates 149
5.1.3 Developmental Outcomes of Early Adverse Care on Amygdala Functional Connectivity in Nonhuman Primates 152
5.2 Integration of Findings............................................................................................ 153
5.3 Conclusions and Future Directions....................................................................... 154
Chapter 6 References............................................................. 157
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