Neurodevelopmental Consequences of Early Life Stress in Primates Open Access

Howell, Brittany Rollins (2013)

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Early life stress (ELS), particularly social stress, comes in many forms and has been implicated in the etiology of several psychopathologies. It is thought that the repeated activation of the stress response, and subsequent exposure to elevated levels of stress hormones (specifically the glucocorticoid cortisol in primates) during development, when the brain is especially vulnerable to insult, leads to alterations in the brain that result in alterations in behavior. Evidence suggests that white matter (WM) is sensitive to stress, and alterations in WM microstructure have been reported in several stress-related psychopathologies. Thus, it is the goal of this dissertation to investigate the development of WM in two nonhuman primate models of early social stress, social subordination stress and infant maltreatment, and how alterations in WM are related to behaviors related to those that are altered in human psychopathology. Diffusion tensor imaging (DTI) was employed to measure the microstructural integrity of WM tracts in these models at different ages from birth through adolescence. Findings in subordinate animals during prepuberty include increased FA in prefrontal and frontal regions. FA in these regions positively correlated with submissive behaviors in the social group. To investigate the effects of inherited factors on these measures serotonin transporter (5HTT) genotype polymorphism was included in the analysis, and showed interaction effects with dominance rank in several regions of WM, where subordinate animals with the s-allele had decreased FA. Anxious and aggressive behaviors measured during laboratory tasks negatively correlated with FA in these regions, suggesting a role for 5HTT polymorphism in these behaviors via effects on WM microstructure. Animals maltreated as infants showed alterations in FA throughout infancy and in adolescence. Both increases and decreases in FA were detected, with decreases predominating at the older ages. Affected regions included the internal capsule, cerebellar, frontal, parietal, temporal, and prefrontal WM. Maltreated animals showed increased emotional reactivity in the social group, but had blunted responses to threat during a laboratory task. These results provide evidence that WM is sensitive to ELS, that alterations in WM microstructure are related to behavior, and effects in these two domains appear to be experience specific.

Table of Contents

Chapter 1 : Introduction.. 1

1.1 Stress, early adversity and human health. 2

1.2 The stress response. 4

1.2.1 Behavioral, autonomic and endocrine responses to stress. 4

1.2.2 Central control of the stress response. 6

1.2.3 Effects of chronic stress on the HPA-axis and regulatory limbic regions 8

1.2.4 Stress regulatory neurocircuitry, chronic stress, and psychopathology 10

1.3 Neurobehavioral development in primates. 11

1.3.1 Brain development in primates. 11

1.3.2 Development of the HPA axis: GCs. 15

1.3.3 Sex differences in neurobehavioral development 17

1.4 Early social stress in humans. 18

1.4.1 Early social deprivation. 19

1.4.2 Low SES during childhood. 20

1.4.3 Childhood maltreatment 22

1.5 Nonhuman primate models of social stress early in life. 24

1.5.1 Social isolation and maternal deprivation. 25

1.5.2 Social subordination in rhesus monkeys. 27

1.5.3 Infant maltreatment in rhesus monkeys. 29

1.6 ELS effects on brain WM using DTI. 30

1.6.1 DTI as a measure of WM integrity. 31

1.6.2 Strengths and limitations of DTI. 32

1.6.3 Stress effects on brain WM: role of GCs. 33

1.7 Overall rationale and hypotheses. 34

Chapter 2 : Long-term effects of early life stress on brain white matter and behavior: juvenile period in a model of social subordination stress[1]. 40

2.1 Abstract 41

2.2 Introduction. 42

2.3 Methods. 45

2.3.1 Subjects. 45

2.3.2 Determination of social rank. 46

2.3.3 5HTT genotyping. 46

2.3.4 Coefficients of relatedness. 47

2.3.5 DTI data. 47

2.3.6 Behavioral data. 52

2.3.7 Cortisol data. 54

2.4 Results. 56

2.4.1 DTI data. 56

2.4.2 Behavioral data. 59

2.4.3 Behavioral correlations with FA measures. 60

2.4.4 Cortisol data: associations with status, 5HTT genotype and FA measures 62

2.5 Discussion. 62

Chapter 3 : Brain white matter microstructure alterations in adolescent rhesus monkeys exposed to early life stress: associations with high cortisol during infancy[2] 81

3.1 Abstract 82

3.2 Introduction. 83

3.3 Methods. 88

3.3.1 Subjects and housing. 88

3.3.2 HPA axis basal activity: cortisol in infancy. 89

3.3.3 Behavioral data collection during adolescence. 90

3.3.4 In vivo neuroimaging. 90

3.3.5 Statistical analyses. 93

3.4 Results. 94

3.4.1 Group differences in FA.. 94

3.4.2 Group differences in RD and AD in regions with significant FA effects 95

3.4.3 Correlations of biobehavioral measures with FA.. 95

3.5 Conclusions. 96

Chapter 4 : Longitudinal effects of infant maltreatment from birth using a cross-foster paradigm: experiential effects on brain white matter and emotional reactivity during infancy. 111

4.1 Abstract 112

4.2 Introduction. 113

4.2.1 Why studying childhood maltreatment is important 113

4.2.2 Effects of maltreatment on emotion regulation and social behavior. 114

4.2.3 Prefrontal-amygdala circuits regulate behaviors altered in maltreatment 115

4.2.4 Early life stress lead to alterations in the development of limbic regions: possible mechanisms?. 118

4.2.5 Nonhuman primate model of infant maltreatment 120

4.3 Methods. 121

4.3.1 Subjects and housing. 121

4.3.2 Training and capture. 123

4.3.3 Experimental design: cross-foster design. 123

4.3.4 Behavioral data collection in the social group. 125

4.3.5 Hair cortisol 126

4.3.6 Physical growth. 126

4.3.7 Human Intruder paradigm... 126

4.3.8 DTI data. 128

4.3.9 Statistical analyses. 131

4.4 Results. 133

4.4.1 Maternal behavior: physical abuse and rejection during the first 3 months of life 133

4.4.2 Cortisol accumulation in hair. 134

4.4.3 Physical growth. 134

4.4.4 Behavior in social group. 135

4.4.5 Human Intruder paradigm... 136

4.4.6 DTI: White matter microstructure. 138

4.5 Discussion. 141

4.5.1 Cross-fostering does not affect maternal behavior: maltreatment is a maternal trait 141

4.5.2 Infant maltreatment is a chronic stressor. 142

4.5.3 Infant maltreatment does not affect physical growth in this model 143

4.5.4 Infant maltreatment increases emotional reactivity in the social group 144

4.5.5 Infant maltreatment decreases emotional reactivity during the HI paradigm 145

4.5.6 Sex differences in emotional reactivity during the HI. 148

4.5.7 Alterations in brain WM development 149

Chapter 5 : Discussion, conclusions, and future directions. 192

5.1 Summary of results. 193

5.1.1 Effects of social subordination stress in the juvenile period. 193

5.1.2 Effects of infant maltreatment in adolescence. 193

5.1.3 Effects of infant maltreatment in infancy. 194

5.2 Integration of findings. 195

5.3 Conclusions and future directions. 197

References 199

[1] Modified slightly from Howell BR, Godfrey J, Gutman DA, Michopoulos V, Zhang X, Nair G, Hu X, Wilson ME, Sanchez MM. (2013) Social subordination stress and serotonin transporter polymorphisms: associations with brain white matter tract integrity and behavior in juvenile female macaques. Cerebral Cortex. In press.

[2] Modified slightly from Howell BR, McCormack KM, Grand AP, Sawyer NT, Zhang X, Maestripieri D, Hu X, Sanchez MM. Brain white matter microstructure alterations in adolescent rhesus monkeys exposed to early life stress: associations with high cortisol during infancy. Biology of Mood & Anxiety Disorders. Submitted.

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