Megan R. Gunnar - US grants

Four groups of studies are proposed to examine the human infant's behavioral and physiological responses to stress. The focus of the work is on the pituitary-adreno-cortical system, a neuroendocrine system that plays a central role in stress-resistance. The goals of the research are 1) to characterize the infant's behavioral and adrenocortical responses to stimulation, particularly with role of novelty/uncertainty as primary psychological triggers of stress responses; 2) to examine infant and maternal characteristics that may influence that infant's psychobiological response to stressful events; 3) to begin to extend our analyses to consideration of Ill and Well premature infants who must cope with the stressors of illness and/or necessary NICU procedures; and 4) to develop paradigms to examine the relations between adrenocortical and a) brain evoked potentials b) activity of the immune system, and c) activity o the autonomic nervous system in human infants. Subjects will be male and female infants aged birth to 15 months. Ecologically relevant stressor will be examined in these studies, including: gavage feeding (premature infants), PKU blood-test, discharge exam, circumcision, (full-term newborns), inoculations, maternal separation, entering daycare, strangers, and novel experiences (infants 2 months and older). Activity of the adrenocortical system will be examined using measures of salivary cortisol. Observational techniques will be used to score behavioral state, coping strategies, and sensitivity/responsivity of caregiving. Collaborative efforts with other laboratories will be used to examine the linkages between adrenocortical activity and other stress-relevant systems as listed above. The proposed studies will provide basic data in the areas of psychobiology as such information pertains to child development and pediatric behavioral medicine. The long-term goals are to gain a better understanding of stress and coping in human infants.

Three groups of experiments are proposed to (1) characterize the human infant's adrenocortical and behavioral responses to stressors and their interrelationships during the neonatal period and later during infancy; (2) examine individual differences in reactivity of the adrenocortical system with regard to social-emotional development; and (3) examine the dynamics of plasma (total) saliva (free, unbound) cortisol and their relations to behavioral responses to stressors and determine the effects of substituting saliva cortisol measures for plasma cortisol measures in research on children. Male and female infants (birth to 12 mos) will serve as subjects. In the experiments with newborns, ecologically relevant stressors such as circumcision, Guthrie blood-tests, weighing and measuring, and discharge examinations will be studied. behavioral state will be examined using a 30-sec coding interval and the Brazelton Neonatal Behavioral Assessment Scale will be used to measure the organization of the newborn's behavior. Activity of the pituitary-adrenocortical system will be examined using measures of plasma and saliva cortisol. Plasma samples will be obtained via heel-stick. In older infants, behavioral and adrenocortical responses to psychosocial stressors such as strangers and separation will be examined. In addition, factors mediating the infant's biobehavioral response to stressors will be explored, including characteristics of mother-infant interaction, maternal perceptions of infant temperament, and maternal support systems. Finally, behavioral correlates of plasma and saliva cortisol indices of adrenocortical activity will be examined in a population of children with phenylketonuria (PKU) during regularly scheduled clinic visits. The proposed experiments will provide basic data in the area of psychobiology as such information pertains to child development and pediatric behavioral medicine. The long-term goals are to gain a better understanding of stress and coping in human infants.

Three years of support are requested for the Minnesota Symposia in Child Psychology. This annual symposium, now in its 24th year, typically involves five to six speakers and me to two discussants. Topics are chosen two years in advance to reflect cutting-edge issues in the field. The two topics proposed are "Modularity and Constraints in Language and Cognition" and "Coping and Adaptation in Childhood, Process and Prognosis." In addition to symposium presentations, presenters also contribute chapters published in the Minnesota Symposia on Child Psychology series currently published by Lawrence Erlbaum and Associates.

The research to be performed during the project period is designed to extend our understanding of the psychobiology of stress and coping in human newborns, infants and toddlers. Three groups of studies are proposed to examine young children's behavioral and physiological responses to stress. The focus of the research is on the pituitary-adreno-cortical system, a neuroendocrine system that plays a central role in stress resistance. The goals of the research include characterizing the adrenocortical response to normally occurring stressors in the lives of young children. These stressors include heelsticks, inoculations, and handling in early infancy, and psychosocial stressors such as interaction with strangers, separation, and approach-avoidance conflicts in older infants and toddlers. A second goal is to examine basal adrenocortical activity and its relations to the stress response. A third goal is to examine the relations between adrenocortical activity and infant behavioral responses to stress and to understand these relations Within the context of individual differences in temperament, parentinfant interaction, and parental personality and temperament. A final, major goal is to begin to develop paradigms for examining the links between adrenocortical activity and other stress- and emotion-sensitive physiological systems. Finally, pilot studies are proposed to extend the research to "at risk" populations of infants and young children. The research offers considerable promise in increasing our understanding of stress and coping processes in the developing child.

This proposal describes studies of the development of behavioral and hormonal responses to stressors during infancy and early childhood. In addition to a longitudinal study (prenatal period to age 3), a large study of children responding to the challenges of preschool, and several smaller studies are also proposed. This research is organized around examination of the hypothalamic-pituitary-adrenocortical (HPA) system, a neuroendocrine system central to mammalian stress resistance. A major goal of this work is to integrate studies of the psychobiology of this system with research on the biological substrate of temperament in children. To this end, the studies described examine components of a proposed temperament-coping resources-physiological stress model. According to this model, the biological substrate of temperament (assessed through measures of baseline EEG asymmetry, vagal tone, basal HPA activity, and positive late components of the ERP) influences the child's likelihood of perceiving events as potentially threatening. However, activation of physiological stress reactions are presumed to follow from expectations that the threat will be realized. Mediating these perceptions are the coping resources available to the child. The studies will take advantage of both lab-based and naturalistic-ecological stressors and challenging situations. The proposed studies are designed to integrate 3 major literatures: (1) the physiology of infant/child temperament, (2) socioemotional development, including attachment research, and (3) psychoendocrine studies of infant/child stress. Finally, preliminary investigations of a noninvasive measure of immune functioning (salivary interleukin-1b) are also proposed that would extend this integration to research on individual differences in children's physical health and susceptibility to illness.

The research to be performed during the project period is designed to extend our understanding of the psychobiology of stress and coping in human newborns, infants and toddlers. Three groups of studies are proposed to examine young children's behavioral and physiological responses to stress. The focus of the research is on the pituitary-adreno-cortical system, a neuroendocrine system that plays a central role in stress resistance. The goals of the research include characterizing the adrenocortical response to normally occurring stressors in the lives of young children. These stressors include heelsticks, inoculations, and handling in early infancy, and psychosocial stressors such as interaction with strangers, separation, and approach-avoidance conflicts in older infants and toddlers. A second goal is to examine basal adrenocortical activity and its relations to the stress response. A third goal is to examine the relations between adrenocortical activity and infant behavioral responses to stress and to understand these relations Within the context of individual differences in temperament, parentinfant interaction, and parental personality and temperament. A final, major goal is to begin to develop paradigms for examining the links between adrenocortical activity and other stress- and emotion-sensitive physiological systems. Finally, pilot studies are proposed to extend the research to "at risk" populations of infants and young children. The research offers considerable promise in increasing our understanding of stress and coping processes in the developing child.

DESCRIPTION (Adapted from applicant's abstract): The overarching goal of this line of research is to examine the role of the hypothalamic-pituitary-adrenocortical (HPA) system in (1) Attention Regulation and (2) Inhibitory Control, aspects of functioning that are potentially related to emotion regulation, behavior problems, and behavior disorders, particularly ADHD. Cortisol, the hormone produced by the HPA system, is known to affect cognitive functioning, particularly declarative and spatial memory and selective attention. The results of two studies provide evidence suggestive of an association between high cortisol concentrations and poorer Inhibitory Control/Attention Regulation in children. The specific goal of the proposed studies is more closely examine the possible linkages between cortisol and attention/inhibitory control to determine that these relations exist before embarking on more expensive, time-consuming longitudinal research. To this end, three studies are proposed, all of which take advantage of existing data sets and "add" either the cortisol measures or the behavior measures. Study 1 uses cortisol measures and Rothbart CBQ (temperament questionnaire) measures already being collected on nursery school children and "adds" observational tests of attention/inhibitory control. Study 2 uses behavioral measures of inhibitory control collected as part of an ongoing longitudinal study (ages 2, 4, and 6) and "adds" measures of cortisol at age 6 years. While Study 3 uses cognitive neuroscience measures of selective attention and executive function being collected to determine norms in 4 to 8 year olds and "adds" cortisol and the Rothbart CBQ temperament questionnaire measures. Studies 2 and 3 are collaborative studies with the investigators responsible for the primary data sets: Grazyna Kochanska (Study 2) and Charles A. Nelson/Monica Luciana (Study 3).

This award was made as a Small Grant for Exploratory Research. The project investigates a possible link between cortisol and inhibitory or effortful control in young children. The PI (M. Gunnar) studies the role of cortisol in behavioral adaptation and its impact on the central nervous system and behavior. The co-PI (G. Kochanska) studies effortful control, self-regulation, affectivity, and temperament in young children. The two investigators will link their programs of research to study whether dysregulation of the daily rhythm in cortisol, and/or elevated cortisol responses to stressors might be related to poor inhibitory control in preschool children. Repeated assessments of cortisol levels (derived from samples of saliva) will be related to childrens' inhibitory/effortful control, also measured repeatedly over time. Preliminary data indicate that children who score consistently low on inhibitory control competencies over the preschool years show a marked suppression of the first morning cortisol values compared to other children. As a result, the daily rhythm in cortisol production is dampened in these children. It is not known whether the childrens' poor inhibitory control abilities preceded or followed the alteration in their daily cortisol rhythm. This project is designed to gain further insight into this relationship between glucocorticoids and attention regulation and inhibitory control.

The overarching goal of this network on Early Experiences and Glucocorticoids is to strengthen the conceptual and empirical linkages between: (1) animal research on early experiences and development of the Limbic-Hypothalamic-Pituitary-Adrenocortical (L-HPA) axis, and (2) human research on the emotional, social, and cognitive sequelae of early psychosocial adversity. The long-term goal is to develop collaborative research programs designed to: (1) describe the neurobiology of stress system development in relation to cognitive, social, and emotional functioning of children deprived and/or abused early in development, and (2) to develop animal paradigms that appropriately model and potentially explicate the molecular and neurobiological processes underlying response patterns observed in the human research. Four conceptual issues have been identified that form the specific aims and short-term goals of this network. These issues are used to organize the first 4 of the 6 planned network meetings, with the last 2 meetings devoted to discussing and refining research and grant proposal plans. Ten network members spanning expertise from molecular to behavioral levels and rodent, monkey, and human child populations have been assembled with 4 consultants who will join the group for specified topics/meetings. Network members are: Megan Gunnar (PI), Paul Plotsky, Seymour Levine, Delia Vazquez, Ned Kalin, Ronald G. Barr, Mary Dozier, Philip Fisher, James Black, and Nathan Fox. Consultants are: Dante Cicchetti, Charles Zeanah, Myron Hofer and Ron Dahl.

Since 1990, nearly 73,000 international children have been adopted by American families with the numbers increasing annually by about 18%. Over these years, the percentage of children adopted out of orphanages or baby homes has increased from 20 to 65%. Two studies are proposed. The first is designed to improve understanding of the health and well being of these children, with an eye to describing the sampling frame for planned future studies of neurophysiology-behavior development and "recovery" in these children. The second is designed toe examine whether pre-adoption institutional cre experiences are associated with tonic increased in cortisol, a stress-sensitive hormone, whose activity is known to be affected in animals by adverse conditions early in development. Thus, in Study 1, in collaboration with the Minnesota's Adoption and Guardianship Division we will abstract data on all international children adopted in Minnesota from 1990 through 1998. We will then survey the families (@ N=4,000) to obtain demographic data, children's pre-adoption histories, health at placement and current health, behavioral and emotional functioning, enrichment experiences and negative life events post-adoption. These data will be used to examine hypotheses regarding factors expected to affect the risk for poor behavioral and health outcomes in these children. In addition, an on- going registry of families interested in future studies will be established. In Study 2 we will examine evening salivary cortisol levels in 300, 5- to 9-year-old registry children selected for differing amounts of pre-adoption institutional care experience. In addition to examining pre- and post-adoption factors related to cortisol levels, associations between cortisol levels and behavior problems will be examined. This work will add significantly to our understanding of the health and behavioral sequelae of early adversity and th potential impact of early adversity on stress-sensitive limbic-hypothalamic processes.

DESCRIPTION (provided by applicant): This "developing grant" application unites a group of 13 productive investigators in order to facilitate translation of basic research on early experience and the development of stress-sensitive neurobiological systems into preventive intervention research with young children who are growing up under conditions of adversity-in particular, children who have experienced maltreatment and relationship disruption. The investigators and pilot studies described herein cover a wide breadth ranging from animal (rodent and non-human primate) research to clinical studies of children in the foster care system. The proposed research will be conducted at 7 research sites, 2 of which involve randomized treatment trials of theoretically driven interventions for at-risk populations of infants and young children. By bringing together this diverse group of investigators we are able to address questions about early experience and stress neurobiology from molecular to social levels of analysis. The specific aims and the research designs proposed herein are based on 1.5 yrs of initial networking by our group during which time we determined that translational research in this area is likely to be productive, while noting the many questions that still need to be addressed before such research is likely to be successful. Five years of research is proposed, the outcome of which will provide the conceptual and methodological basis needed for studying the impact of early experience on stress neurobiology in randomized treatment interventions designed for infants and young children. As a component of this goal, in addition to the research proposed, we have established a significant training component to this application to enhance integration of prevention/intervention research and developmental neurobiological research in very young children.

Since 1990, nearly 73,000 international children have been adopted by American families with the numbers increasing annually by about 18%. Over these years, the percentage of children adopted out of orphanages or baby homes has increased from 20 to 65%. Two studies are proposed. The first is designed to improve understanding of the health and well being of these children, with an eye to describing the sampling frame for planned future studies of neurophysiology-behavior development and "recovery" in these children. The second is designed toe examine whether pre-adoption institutional cre experiences are associated with tonic increased in cortisol, a stress-sensitive hormone, whose activity is known to be affected in animals by adverse conditions early in development. Thus, in Study 1, in collaboration with the Minnesota's Adoption and Guardianship Division we will abstract data on all international children adopted in Minnesota from 1990 through 1998. We will then survey the families (@ N=4,000) to obtain demographic data, children's pre-adoption histories, health at placement and current health, behavioral and emotional functioning, enrichment experiences and negative life events post-adoption. These data will be used to examine hypotheses regarding factors expected to affect the risk for poor behavioral and health outcomes in these children. In addition, an on- going registry of families interested in future studies will be established. In Study 2 we will examine evening salivary cortisol levels in 300, 5- to 9-year-old registry children selected for differing amounts of pre-adoption institutional care experience. In addition to examining pre- and post-adoption factors related to cortisol levels, associations between cortisol levels and behavior problems will be examined. This work will add significantly to our understanding of the health and behavioral sequelae of early adversity and th potential impact of early adversity on stress-sensitive limbic-hypothalamic processes.

stress; social psychology; early experience; psychobiology; psychophysiology; preschool child (1-5); cortisol; child psychology; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; psychological stressor; parasympathetic nervous system; parent offspring interaction; limbic system; child care; hormone metabolism; sympathetic nervous system; anxiety; fear; personality; behavioral /social science research tag; clinical research; electrophysiology; human subject;

DESCRIPTION (provided by applicant): This proposal is an application for a Senior Scientist Award (K05) for Megan R. Gunnar. The award is requested to sustain Dr. Gunnar's continuing efforts to produce independent research and to enter into multi-disciplinary, integrative collaborations designed to foster our understanding of stress and its role in human development. Dr. Gunnar is one of the pioneers of stress physiology-behavior research in human development with 100+ publications on this topic. She is a chaired professor in the Institute of Child Development at the University of Minnesota, a world-renowned site for research on human development. Both in the Institute and through participation in multi-disciplinary centers at the University of Minnesota, Dr. Gunnar has access to a vibrant and rich environment to support her career development. Her career has been characterized by increasing integration of the literature on and methods of studying cortisol-behavior relations, with the literature and methods in the study of psychophysiological, neuroscience, and clinical/high-risk children. During this award period, she will focus on developing skills in several domains relevant to our understanding of stress and its effects early in life. These include: measurement of sleep, assessment of cognitive/emotional processes supported by prefrontal-limbic circuits, and epidemiologically-sensitive, prevention/intervention research theory and methods. She will also administer 2 large, currently funded, NIMH individual research grants and devote time to directing an NIMH-funded, multidisciplinary, multi-site network designed to foster translation of the animal research on stress neurobiology and early experience to prevention/intervention research with high-risk human populations. The preparatory work currently underway to guide the development of a multi-site ROl on orphanage-adopted children is also described. Finally, Dr. Gunnar will continue to devote roughly 25% of her time to science education and advocacy. These latter activities include mentoring of postdoctoral, doctoral, and undergraduate students, graduate-level teaching, participation in activities that follow-up on her role in the National Academy of Science panel that produced Neurons to Neighborhoods participation in organizations such as Zero to Three whose missions are to "give child development information away" for use by practitioners, parents, and policy makers.

[unreadable] DESCRIPTION (provided by applicant): This collaborative R01 involves parallel studies at the Universities of Wisconsin and Minnesota. The work explores the neurobiological bases of problems in attention/executive functions, sensory integration, and emotion/stress regulation exhibited by children who have experienced neglect/privation early in life. This project is motivated by renewed interest the effects of early deprivation/neglect on development, precipitated by the last decade's increase in international adoptions. In addition, it reflects concerns with brain development and neural plasticity coupled with continued controversies over the importance of early experiences and questions about sensitive periods. The marked change in living environments experienced with adoption allows a reasonable way to estimate both the duration and ages during which deprivation was experienced. To date, studies of these children have employed global measures that are difficult to map to specific neural systems. The General Aim of this project is to build upon extant studies and examine specific cognitive and affective systems. The specific aims identify (a) aspects of neural circuitry that are linked to the development of cognitive processes and self-regulatory behaviors and (b) later-developing neural systems that are likely to be affected by early deprivation/neglect. Specific Aim 1 examines frontally mediated systems believed to underlie aspects of attention, inhibitory control, and working memory. Specific Aim 2 examines sensory-motor processing including sensory integration, acquisition, and praxis. Specific Aim 3 explores systems thoughts to be compromised based upon the animal literature on early neglect: cortico-limbic-hypothalamic-brainstem systems that are involved in stress reactivity and regulation. Together, these studies will provide a relatively comprehensive and more specific picture of the potential neural compromises resulting from early deprivation in human children as well as highlighting those aspects of brain-behavior development that appear to be spared. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The purpose of the proposed program is to train predoctoral and postdoctoral students in research in developmental psychology. The application is to continue a research training program that has had continuous NIMH support since 1959. The training site, the Institute of Child Development (founded in 1925), holds a unique position as an internationally known, premier center of research in developmental science. The community of scholars at the Institute engages in substantive and significant basic research on the development of biological, sensory, perceptual, cognitive, social, and emotional processes. Simultaneously, the Institute faculty and students seek to "give away" knowledge of human development; and to engage in collaborative work across several disciplines, including the interface between brain and behavior, and between individuals and the contextual systems in which their development is embedded, such as family, peers, schools, community, and cultural systems. The training program would provide support for four predoctoral scholars per year, at least one of whom would be engaged in interdisciplinary research in the critical fields of developmental psychopathology or developmental neuroscience; appointments are for two years. Predoctoral trainees entering the program will have completed baccalaureate studies in psychology or a related field and occasionally will have had some graduate training. Predoctoral trainees complete a full major and minor program, including coursework, research and teaching apprenticeships, and examinations. The training program also would provide support for two postdoctoral trainees per year; appointments are for two years. Postdoctoral trainees would be recruited from two categories of individuals: those whose doctoral studies were not in developmental psychology, but who desire research training in developmental science; and those whose training was in development science, but who seek expanded interdisciplinary training in developmental psychopathology or developmental neuroscience. The primary engagement of postdoctoral trainees is research. The training site is located on the main campus of the University of Minnesota. It includes state-of-the-art computer, laboratory, and library facilities, as well as offices for staff, students, and trainees. The faculty includes 17 professors, whose work ranges across the entire discipline.

[unreadable] DESCRIPTION (provided by applicant): The purpose of the proposed program is to train predoctoral and postdoctoral students in research in developmental psychology. The application is to continue a research training program that has had continuous NIMH support since 1959. The training site, the Institute of Child Development (founded in 1925), holds a unique position as an internationally known, premier center of research in developmental science. The community of scholars at the Institute engages in substantive and significant basic research on the development of biological, sensory, perceptual, cognitive, social, and emotional processes. Simultaneously, the Institute faculty and students seek to "give away" knowledge of human development; and to engage in collaborative work across several disciplines, including the interface between brain and behavior, and between individuals and the contextual systems in which their development is embedded, such as family, peers, schools, community, and cultural systems. The training program would provide support for four predoctoral scholars per year, at least one of whom would be engaged in interdisciplinary research in the critical fields of developmental psychopathology or developmental neuroscience; appointments are for two years. Predoctoral trainees entering the program will have completed baccalaureate studies in psychology or a related field and occasionally will have had some (typically 2 yrs) graduate training. Predoctoral trainees complete a full major and minor program, including coursework, research and teaching apprenticeships, and examinations. The training program also would provide support for two postdoctoral trainees per year; appointments are for two years. Postdoctoral trainees would be recruited from two categories of individuals: those whose doctoral studies were not in developmental psychology, but who desire research training in developmental science; and those whose training was in development science, but who seek expanded interdisciplinary training in developmental psychopathology or developmental neuroscience. The primary engagement of postdoctoral trainees is research. The training site is located on the main campus of the University of Minnesota. It includes state-of-the-art computer, laboratory, and library facilities, as well as offices for staff, students, and trainees. The faculty includes 16 professors, whose work ranges across the entire discipline. [unreadable] [unreadable] [unreadable]

Faced with persisting disparities in educational achievement, there is a pressing need to understand processes that promote early school success in children at risk for academic problems. Promising evidence indicates that executive function (EF) skills play a central role in successful transitions to school among young children, especially disadvantaged children. EF skills are those involved in cognitive self-control of behavior, including directing and shifting attention, resisting distractions, and inhibiting impulses. Children with good EF skills fare better in the school context, both in terms of learning and social competence. There is also evidence that EF can be improved through strategic intervention. This project will examine the role of EF skills in the school success of young homeless/highly mobile students who represent a substantial proportion of the low-income children at highest risk for academic problems in urban school districts. Chronic adversities associated with poverty and mobility may alter physiological stress response systems and undermine the early development of neural systems associated with EF. As a result, children may face the challenges of school and life with poor EF skills, as well as difficulties regulating stress. Nonetheless, some children growing up in adversity succeed in school, and their resilience may be related to protections afforded by good parenting and the development of effective stress regulation and EF skills. To examine the role of EF in school success among homeless/highly mobile children, this study will assess children entering kindergarten from shelters for homeless families and follow their adjustment during this important school year. Through assessments of child, parent, and parent-child interactions, this study will test the connections of family adversity, risk, and parenting to EF skills, stress regulation, and success in school. Cortisol, a stress hormone, will be sampled from the children's saliva to assess stress reactivity. School outcomes will be assessed through teacher reports and school records of standardized tests and attendance. Better EF skills are expected in children with lower family risk, better parenting, and good stress regulation, who consequently will do well in school. EF skills are expected to show protective effects for learning and social adjustment in these high-risk children.

Results are expected to inform developmental theory on EF, risk and resilience, and the design of educational programs and interventions to address achievement disparities and promote early school success in disadvantaged children. The project will provide insights into processes that may enhance or inhibit learning and adaptation in a context of high adversity and change. Results will elucidate how EF skills may facilitate successful transitions to school in an under-studied population of low-income, highly mobile children whose success may prove crucial to closing achievement gaps in American education.

DESCRIPTION (provided by applicant): This is the first revision of a proposal to study the effects of early life stress (ELS) in the form of orphanage/institutional rearing on children's threat- and stress-response systems and aspects of parenting post-adoption that support recovery of these systems and decreases subsequent risk of emotional and attentional problems. 150 children internationally-adopted from orphanages/institutions and their families will be studied at four 8-mo intervals beginning 2 mos post-adoption for the child's first 2 yrs in the family with a 5th outcome assessed at 4.5-5.5. yrs (2.5-3.5 yrs post-adoption). Previous work documents the first yrs post-adoption as ones of rapid rebound/recovery. However, children adopted post-infancy (18-30 mos in this study) exhibit great heterogeneity in outcomes. Based on animal studies of ELS, we will test the hypothesis that sensitization of threat- and stress-response system functioning at adoption and the capacity of these systems to recover underlies heterogeneity in emotional and attentional problems. Further, we will test the hypothesis that variations in post-adoption parenting interacts with sensitization of these systems to affect recovery trajectories. A multi-method, multi-level approach will be used with home and laboratory assessments of behavioral and physiological indices of threat- and stress-system functioning: behavioral measures of negative emotionality, salivary measures of cortisol, and electrophysiological measures of ANS functioning. Outcome measures will include parent, teacher and child reports augmented by laboratory assessments of EEG power and asymmetry, fear-potentiated startle (EMG startle), and ERP and behavioral measures of executive attention. Parent behavior will be assessed using structured laboratory assessments and measures derived from parent diary reports. Finally, we will also explore whether the serotonin transporter gene polymorphism, shown to moderate risk for depression in maltreated children and HPA axis reactivity in animal models, moderates children's vulnerability to early institutional care and/or capacity to recover. The ultimate goals of this work are (1) to establish a better understanding of the mechanisms through which early life stress increases risks of emotional and behavioral problems, (2) identify children at the greatest risk of emotional and attentional problems and (3) identify patterns of parenting to target in subsequent randomized intervention trials to improve outcomes for these and similar children. PUBLIC HEALTH RELEVANCE: The proposed study examines effects of early life stress (ELS) in the form of orphanage/institutional rearing on children's threat- and stress-response systems and aspects of parenting post-adoption that support recovery of these systems and decrease subsequent risk of emotional and attentional problems. The goals of this work are (1) to establish a better understanding of the mechanisms through which early life stress increases risks of emotional and behavioral problems, (2) identify children at the greatest risk of emotional and attentional problems and (3) identify patterns of parenting to target in subsequent randomized intervention trials to improve outcomes for these and similar children.

Project 2 examines 150 children who experience early life stress (ELS) in the form of institutional rearing during their first 18-30 postnatal months and then are adopted into families. It builds on a funded R01 that was initially developed for this Center by examining how our Center model predicts attention- and emotion- regulatory problems when these post-institutionalized children adjust to the increased demands of formal schooling. Reflecting the Center's 2 specific aims, Project 2 will: (1) test the hypothesis that ELS sensitizes developing stress- and threat-response systems with decreasing capacity for recovery and hence more significant impacts on later attention- and emotion-regulatory competence with age at adoption; (2)examine whether post-adoption parenting interacts with pre-adoption adversity and changes in stress- and threat- system functioning to predict attention- and emotion-regulatory problems. For Project 2, we will collect measures of attention- and emotion-regulatory problems at 12-mos post adoption and kindergarten. Because the R01 funded project will obtain measures of parenting and stress- & threat-system functioning that are identical to those obtained in Project 1 (foster care), adding this 12-month assessment will allow us to fully integrate the data from both projects to examine the Center's model. The kindergarten assessment allows us to evaluate the model's ability to predict children's functioning at a critical developmental juncture; the onset of formal schooling creates a developmental context where competent attention- and emotion-regulation are more significant. Project 2 will use measures collected as part of the funded R01 [parenting, autonomic and neuroendocrine regulation, and fear behavior collected repeatedly over the first two years post-adoption, along with electrophysiologicaland neurocognitive measures obtained the year before kindergarten] to predict emotion- and attention-regulatory problems. In addition to paralleling measures in Project 1 (foster care), Project 2 involves measures of parenting, neuroendocrine, and neurocognitive functioning that are being obtained in a species-comparable fashion in Project 3 (Rhesus monkey), thus permitting this project to contribute to the integrative aims of our Center work, this project draws on all 5 cores of the Center. RELEVANCE (See instructions): Project 2 contributes uniquely by studying early stress effects in children who experience marked and permanent improvement in care when adopted from orphanages. Comparable data collection with Project 1 permits examination of similarities and differences in recovery trajectories of fostered and orphanage- adopted children. Comparable neurobehavioral measures with Project 3 enhances translation of animal data.

We describe a mature multi-site IDSC, "Early Experiences, Stress, and Neurodevelopment" focused on understanding the impacts of early life stress (ELS). We use ELS as a framework to encompass adverse early care conditions: separation/loss, neglect, abuse. We integrate basic developmental behavioral neuroscience using various models to a) increase understanding of the behavioral and neurobiological impacts of ELS, b) identify care experiences that support recovery, and c) approach these questions guided by preventive intervention researchers so that future interventions can benefit from this more comprehensive knowledge base. In 3 projects we test the hypothesis that adverse conditions of early caregiving result in chronic activation of neurohormonal stress systems, shapes more reactive threat response system functioning, and impacts the development of cortico-limbic attention- and emotion regulatory systems. These neural systems are plastic during early life;improved care can normalize their functioning. However, because young children exposed to these ELS conditions often confront caregivers with disordered attachment behaviors &disruptive behavior problems, therapeutic parenting must provide nurturance the child needs but may not signal, and reduce behavior problems through firm, non-hostile, structure/limit-setting. Even so, children exposed to the most severe, prolonged ELS may sustain neurodevelopmental vulnerabilities that increase risk of pathology long after care conditions improve. Our projects involve (1) young children in domestic foster care (2) those adopted from orphanages overseas, as well as (3) another model that allows random assignment to maltreating care and tracking of neurodevelopmental impacts in ways not feasible with young children. The work is supported by 5 Cores: Administrative, Behavioral Coding, Neuropsychological/ Electrophysiological, Data Management, and Assay. We use behavioral observations, electrophysiology (EEG, ERPs, EMG, ECG), neuroendocrine activity (HPA axis) under basal conditions and in response to psychological &pharmacological challenges, in vivo neuroimaging (MRI, DTI, MRS), and neurobehavioral tasks of amygdala (fear-potentiated startle) &prefrontal functioning. Our Center also includes a cross-training program in basic developmental science and developmental psychopathology &prevention science.

The Administrative, Training and Data Sharing Core is charged with the overall planning, administration, support, and integration of the Center activities, as well as oversight of trainee selection and activities. Its specific aims are to 1) provide the planning, policy, and oversight for the Center; 2) organize major Center meetings; 3) facilitate communication among Center members, including between projects and their cores; 4) arrange for Center review in years 2-4, and oversee implementation of our Advisory Board's advice; 5) oversee Center budgets in relation to the scope and progress of Cores and Projects; 6) oversee trainee selection, policies, and 3-day training institutes; 7) oversee policies and budgets of pilot studies; 8) facilitate synergies between our Center and related NIMH Centers/networks through joint meetings, cross-fertilization of speaker programs, establishing web-site links; 9) oversee the timeliness of data collection at all sites and facilitate data analysis through coordination of data analytic plans among statisticians involved in each of the center projects; and 10) guide Center faculty on issues of data sharing and conceptual interpretation of findings across projects. The Center will be directed by Megan Gunnar, who directed our initial network (MH60766), developing center (MH65046), and guided the work culminating in this proposal. As the Center Director, Professor Gunnar will be responsible for providing overall Center guidance and vision. She will be guided by the Associate Director, the Executive Committee and supported by the Core's staff and Center's statistician. The Core will oversee the recruitment and training of Center trainees. Fourteen trainees will work on Center related projects, attend Center meetings and annual training institutes, which alternate between: (1) Developmental Neurobiology and Psychobiology of Early Life Stress and (2) Developmental Psychopathology and Prevention Science. It will be the responsibility of the Core to insure a diversity of trainees with regard to basic developmental science, developmental psychopathology, and prevention science and with regard to race/ethnicity; to that end mechanisms are described to enhance minority recruitment and we describe the history of our network in enhancing the careers of minority scientists. Each project will have its own statistician; however, the Core will also support a statistician to work with the projects and advise the Center's Director in order to support the Director's oversight of analytic plans across the Center. RELEVANCE (See instructions): Core A, Adiminstrative, serves all projects in the Center. It is charged with overseeing all critical aspects of Center functioning including planning, policies and budgets, organizing Center meetings, facilitating communication within the Center and with the outside community of scholars and practitioners, insuring the timliness of data collection at all sites, and management of the Center's training program.

DESCRIPTION (provided by applicant): Youth with severely adverse early life histories are at double the risk of increased emotional problems as they transition from childhood into adolescence. This risk may reflect the calibration of stress-mediating systems to harsh conditions during sensitive periods early in life. Yet, not all youth with such histories are affected. The proposed study tests the novel pubertal stress recalibration hypothesis; specifically puberty opens a second sensitive period for calibration of stress-mediating systems to current life conditions at the approach of sexual maturity. For youth who experienced adverse early care, pubertal development allows a shifting of stress-system activity to that seen among youth without such histories if concurrent stressors are low and a hyper-sensitization of stress activity if current life conditions are stressful. Our target participants will be youth adopted internationally from orphanages (post-institutionalied, PI) youth, compared to youth reared in their families of origin (non-adopted,NA). We will follow 368 youth examining them annually over 3 time points (0, 1 and 2 yrs). The use of an accelerated longitudinal design (4 grps: 7-8, 9-10, 11-12, 13-14 yrs) and growth curve modeling allows examination of a broad range of the pubertal period (7 through 16 yrs). Annual measures will be made of the HPA axis (salivary cortisol), the SAM system (pre-ejection period) for PI and NA youth in relation to current life stress (Youth Life Stress Interview completed annually) and pubertal stage (annual nurse-conducted Tanner Staging). Measures of stress-mediating systems activity will be obtained using the Trier Social Stress Test for Children and home assessment of the cortisol awakening response (CAR). Our prior research with PI youth showed a normalization of the CAR by Tanner stage 3-5, compared to same aged youth at stages 1-2. This proposal is a logical extension of that work that will also test the hypothesis that shifts in stress-system activity mediates the increase in emotional problem symptoms in adolescence. The results of this study should help determine whether the peripubertal period is a critical time to intervene with children exposed to early life adversity.

The burden of stress and fear of threats to our well-being are parts of modern society that sap productivity and induce mental and physical diseases. The child is particularly hard hit by stress and fear because it can change the actual structure of the brain and produce strong vulnerability to crime, addiction and pathology later in life. Recent research suggest that social support can greatly reduce stress and fear by suppressing the physiological effects of stress, but also by actually preventing some of the brain's response to fear and stress. This ability of social cues to prevent the brains's immediate and enduring response to stress and fear is most pronounced in children and the caregiver is most effective in influencing the impact of stress. Thus, understanding mechanism of the physiology of stress, the psychology of fear and its rescue by caregivers and romantic partners (called social buffering) is critical for developing social policies and interventions to support child development and life long wellbeing. Significant advances in this area can be made via improved communication between researchers who typically work separately due to historical reason. Dr. Megan Gunnar at the University of Minnesota will lead a steering committee consisting of leading scientists from several disciplines to conduct a series of three workshops to break down barriers and unite researchers across previously disparate disciplines to transform our current understanding of the neurobiology of fear. This workshop series will bring together researchers from the behavioral sciences (social, cognitive, and developmental sciences), biological sciences (neurophysiology, neuroendocrinology, neuroimaging), as well as researchers involved in the development of new technologies and computational modeling (engineering and mathematics) to generate innovative ideas and transformative projects to significantly advance our understanding of fear and its management by social context. Such advance is expected to have broader societal impact by informing policy making and by suggesting effective behavioral methods and technological supports for reducing stress and fear.

Specifically, this workshop series aims to break down disciplinary boundaries and historical norms to address the problem of how fear is acquired and controlled by social stimuli throughout all stages of development across life span and across different species (humans and non-human animals) and what neural mechanisms underlie these psychological, social, and developmental processes. The aim for the first year is to develop a platform for dialogue among researchers from behavior, brain science, computational scientists, and engineers to develop a shared vision to tackle this grant challenge for society. We will assess recent development in nanotechnology that can transform the way scientists observe and measure stress related behavioral and psychological changes and the way biological scientists to obtain neural and physiological indices of stress regulation. The outcome of the first workshop will be a joint vision statement in a high profile journal and joint selection of major research themes for subsequent workshops' scientific sessions and methodological tutorials. The aim of the second and third years will be systematically transforming this shared vision (in terms of major thematic areas) into concrete collaborative projects and conduct pilot studies and identifying major technological, scientific, and organization challenges and considerations of possible solutions, and actively involving postdoc and graduate students in creating sustainable training plan for interdisciplinary research across the newly expanded collaborating research communities. While the focus of the second year will be on developing pilot studies and coordinated effort in obtaining funding to support the jointly developed projects, the focus of the third year will be on developing long-term training mechanisms to support the newly formed community. The final outcome of this workshop series will be the development of large-scale and cross-cutting collaborative project proposals, possibly international, that link multiple research centers within the US and on the global scale.

This Science of Learning Collaborative Research Network project is a partnership among the University of Minnesota, the Children and Nature Network, the North American Association of Environmental Education and the University of Illinois Urbana-Champaign. The network is composed of researchers from across the country, as well as practitioner leaders in the non-profit, professional society, public education and museum sectors, who have an interest in accelerating the pace of research to understand if, and how, nature exposure influences children's learning, cognitive development and academic performance. The network serves three functions 1) to develop a long-term interdisciplinary research agenda about nature and learning, 2) to conduct exploratory research to understand possible mechanisms explaining how time spent in nature influences children's classroom learning and behavior, and 3) to synthesize and disseminate existing knowledge about nature and learning as well as the network's research findings. Enhancing our understanding of the mechanisms of the nature-learning connection, and particularly the questions of what works, for whom, how, and under what circumstances, will inform the practice of educators, educational administrators, policy makers, planners and designers, among others. Our best chances of enhancing our understanding of this complex phenomenon is to accelerate research progress on the science of nature-based learning. The Science of Nature-based Learning Collaborative Research Network aims to provide the structure and resources to permit such acceleration.

There is increasing evidence that time spent in nature produces a host of developmental benefits, including enhanced learning and academic achievement. What are the mechanisms that underlie the relationship between nature and learning? This is the focal scientific question grounding the funded network and exploratory research. This Science of Learning Collaborative Research Network project is a partnership among the University of Minnesota, the Children and Nature Network, the North American Association of Environmental Education and the University of Illinois Urbana-Champaign. The network is composed of researchers from across the country, as well as practitioner leaders in the non-profit, professional society, public education and museum sectors, who have an interest in accelerating the pace of research to understand if, and how, nature exposure influences children's learning, cognitive development and academic performance. The network serves three functions 1) to develop a long-term interdisciplinary agenda appropriate for sustained collaborative research, 2) to conduct collaborative, exploratory research to ground future rigorous studies of the impact of nature on learning and of the explanatory mechanisms of this effect, particularly for disadvantaged students, and 3) to synthesize and disseminate existing knowledge about nature and learning as well as the network's research findings.

The exploratory research study embedded in within this project is intended to begin to elucidate the mechanisms that explain why nature exposure enhances learning. In addition, building on others' preliminary findings of differential impact of nature on learning based on economic disadvantage, this study examines socioeconomic status as an independent variable and attempts to elucidate possible explanations for this effect. Three mechanisms - stress dysregulation, attention fatigue, and behavioral disruption - are hypothesized as mediators of the relationship between nature exposure and learning. In each case, there is a rationale for why economically disadvantaged students might experience the mediating effect to a greater degree than more advantaged students.

? DESCRIPTION (provided by applicant): There is a dearth of evidence in humans definitively showing that stress confined to the prenatal-infancy period has programming-like effects on the immune system. In addition, human studies of immune correlates of adverse childhood conditions have not focused specifically T-cell phenotypes involved in immune regulation that may compromise the ability to respond to infection. Both of these gaps in the literature are highly significant in that they limit our ability to understand the mechanisms through which early life stress (ELS) impairs health across the life span. This R21 addresses these lacunae by conducting sophisticated immunophenotyping and functional immune assays in a unique population of youth (14 through 17 years of age) who as infants (< 36 months) were adopted from orphanages/institutions in Russia/Eastern Europe into well-resourced and generally stable, low-life-stress families in the US. The early life stress (ELS) for these youth, thus, was confined to the prenatal-infancy period. There are two aims. Aim 1: Determine the impact of ELS on immune responses of these youth now that they are adolescents. Blood samples will be obtained from 30 post-institutionalized (PI) and 30 comparison adolescents. Sophisticated multi-color immunophenotyping will be used to characterize lymphocyte subsets and mononuclear cell responses will be probed in vitro with stimulants, and cytokine levels in supernatants determined with multi-cytokine arrays. Complete blood counts and C-reactive protein levels also will be determined. Saliva cortisol collected at testing will assess whether transient cortisol elevations in response to blood sampling contribute to the immune differences between groups. Aim 2. Delineate factors that account for differential vulnerability among ELS youth, including distorted hormone biorhythms and severity of the ELS. The second phase of this project will expand the sample size to include 30 additional PI's (total=60), providing sufficient diversity to determine the influence of the severity and duration of institutional care and the mediating influence of dysregulated HPA diurnal rhythms to predict variation in the T cell repertoire and cellular responses in stimulated cultures. This work is highly significant because, by focusing on youth who experience radical improvements in care post-infancy, it will provide the strongest evidence to date of prenatal-infancy programming-like effects on the human immune system and underscores the importance of preventing early deprivation and neglect. It also has potential significance for improving the preventive care of individuals with a history of early adverse care, by delineating specific immune alterations that may underlie potential health risks later in adulthood. It is highly innovative in being the first study of ELS in humans to employ such a sophisticated immune panel and to combine measures that are integral to a pro-inflammatory bias and immune competence. This R21 project will lay the groundwork for a new avenue of ELS-immune research that is focused on lingering sequelae of childhood experiences.

The effectiveness of social buffering in regulating stress appears to wane for a period with puberty at the same time that stress-reactivity increases and young adolescents become more vulnerable to stress-related affective pathology. However, there is a dearth of knowledge regarding the neural underpinnings of social buffering in children and the changes in neural responses to potential social buffers with puberty. Two of the proposed experiments address this gap in knowledge. In addition, to date, the loss of social buffering effectiveness with puberty has primarily been examined using activity of the hypothalamic-pituitary-adrenocortical (HPA) axis as the stress measure. All three proposed experiments will examine the pervasiveness of the effect by examining sympathetic and parasympathetic responses, in addition to salivary cortisol. Urinary oxytocin will also be examined because of its role as an anti-stress hormone. Finally, the effectiveness of parents and friends as social buffers during the peripubertal period has only been examined for social evaluative stressors. The proposed experiments will determine whether the loss of social buffering also extends to threat stimuli as it does in adults and to situations in which two friends are both experiencing the stressful event together. Finally, all three proposed studies will explore whether puberty is associated with an emergence of sex differences in social buffering by parents and friends. Participants will be 11-14 years old and Tanner staging by nurse exam along with self-report and testosterone and DHEA will index pubertal status. Our prior research uncovered the waning of the effectiveness of parents to serve as social buffers of the HPA axis over the pubertal transition and the concomitant failure of friends to ?step in? as stress buffers. The proposed experiments are the logical extension of this work. The results will have the potential to drive significant attention to the role of developmental disruptions in social stress buffering as possible contributing factors in the rise of affective problems in the early teen years.

Abstract Poor cardiometabolic health, encompassing both cardiovascular and metabolic diseases, is the leading cause of preventable death worldwide. There is growing evidence that childhood exposure to stress increases lifespan cardiometabolic risk. The proposed study addresses 4 gaps in the literature recently identified by the American Heart Association: (1) the need for prospective studies, (2) the need to better specify periods of greater vulnerability to stress with regards to cardiometabolic health, (3) the need for more evidence on mechanistic pathways, and (4) the need for more studies that explore sex differences. Our central hypothesis that infancy is a important period for setting in motion processes that increase cardiometabolic disease risk. Our model of early life stress (ELS) will be orphanage-rearing experienced by children adopted internationally. We will assess cardiometabolic functioning in adolescence, the earliest age period when these assessments are associated with adult cardiovascular health. We will compare adolescents adopted as infants or very young children from orphanages into well-resourced homes with youth reared in their natal families of comparable educations and incomes. We will address three specific aims: 1) Determine the relationship between significant ELS in the first few years of life and cardiometabolic functioning in adolescence, 2) determine factors that mediate or partially mediate the association of ELS with cardiometabolic function and changes in functioning during adolescence, and 3) explore the sex differences in ELS- cardiometabolic risk associations. Under the first aim, arterial stiffness and fasting glucose, insulin, and lipids levels will be examined. For the second aim, the impact of ELS on cardiometabolic functioning in adolescence will be examined with the mediators of altered stress system activity, indices of immune aging, increased trunk fat mass and poorer health behaviors. In the third aim, sex differences will be examined in the outcomes in aim 1 and associations with potential mediators in aim 2. These aims are based on significant preliminary data. The impact of this study will be (1) improved understanding of the importance of the first few years of life for cardiometabolic health, (2) a deeper characterization of the mechanisms and pathways through which ELS-cardiometabolic risk is instantiated and (3) determination of whether there are sex differences in either the association or the pathways mediating cardiometabolic risk. These contributions are significant because they will demonstrate the need to begin interventions earlier in development and will identify novel treatment targets to mitigate future cardiometabolic risk and ultimately shift the odds for children experiencing ELS.