Kimberly Andrews Espy - US grants

DESCRIPTION (provided by applicant): More women use tobacco during pregnancy than any other substance, yet little is known about the effects of on early human development. Prenatal tobacco exposure is the single largest preventable risk factor for low birth weight and prematurity, resulting in increased healthcare costs. Nicotine acts on the developing fetal nervous system directly through effects on neurotransmitter systems and indirectly by vasoconstriction of placental blood flow. In animals, prenatal nicotine exposure prematurely signals cell differentiation by altered dopamine and acetylcholine activity that results in disrupted cell development, reduced cell number, and aberrant synaptic connections, with particularly marked effects on dopaminergic systems. Because dopaminergic systems are related to motor, attention, and temperament behavior in infants, children, and adults, these behaviors are particularly susceptible to disruption by prenatal tobacco exposure. Because of the vulnerable nervous system, the added risk of prenatal tobacco exposure in preterm infants may be doubly deleterious. Alternatively, preterm birth typically shortens the duration of in utero exposure in the third trimester, with attenuated prenatal tobacco exposure effects. Finally, specific gene variants that result in net reductions in dopaminergic activity may render these infants more vulnerable to prenatal tobacco exposure effects. This study will examine the effects of prenatal tobacco exposure as a function of perinatal risk and genetic vulnerability, while accounting for the social environment. A large sample of preterm and full term infants (n = 360) will be recruited (with oversampling on prematurity and exposure level) and carefully selected on background characteristics to maximize tobacco exposure-related differences. Thorough maternal interviews and biochemical analysis of cotinine level (maternal and infant urine, infant meconium) will be used to measure prenatal tobacco exposure. Postnatal tobacco exposure, in addition to alcohol, caffeine, and other substance exposure, also will be measured through similarly thorough multi-methods. Neonatal outcome will be assessed longitudinally to more reliably determine effects on early development; both in the hospital where the effects of postnatal exposure and social environment are minimized, and after discharge where these effects are more prominent. Multiple methods are used to assess different neonatal outcome domains, with instruments that capture age-dependent neurobehavioral skill and physical growth. Sophisticated statistical methods will uncover prenatal tobacco exposure effects on developmental processes, including level and growth rates.

[unreadable] DESCRIPTION (provided by applicant): Executive control is a significant cause or contributor to poor outcome in a host of neurological, psychiatric, and developmental disorders with origins in the preschool period, yet little is known about the nature or development of executive control in young children, or how to adequately measure such abilities in this age range. To address this problem, Miller and Cohen's comprehensive, yet parsimonious, context representation model of executive control was used. Because the level of analysis here is neuropsychological test performance, classic psychometric test theory was utilized to operationalize these environmental context representations as the latent task demands that are represented by the true score or common factor variance shared across tasks, i.e., latent EF constructs or factors. These latent EF constructs (labeled Working Memory, Inhibition, and Flexible Shifting factors) are separable, yet highly interrelated; and symbolize the unobservable representations of the larger environmental context that invoke executive control to produce regulated thought and behavior. A cohort-sequential, longitudinal design is used to test the utility of this postulated model. A large longitudinal cohort of 3-year-old children, stratified by sex, will be recruited (using a comprehensive strategy to assure diversity) and administered an executive test battery every 9 months through age 6-0 years, to adequately model skill development during this period of rapid brain and cognitive growth. Four smaller, sequential cohorts with staggered ages of entry also will be recruited and followed subsequently at 9 month intervals until age 6-0 years. The cohort-sequential design permits simultaneous longitudinal modeling of cognitive development, while assessing directly the impact of repeated test administration. The latent EF constructs are defined a priori by multiple tests that are designed specifically for use in young children. Sophisticated statistical analyses are used to a) contrast the fit of the hypothesized structural model to simpler and alternative models developed from test specific characteristics that have confounded previous investigations, b) determine development with age by examining individual and group differences in the level [intercept] and rates [slope] of change, and c) characterize dynamic relations to everyday behavior. Because of the potential application in clinical contexts, changes in individual executive test performance also will be examined with hierarchical growth models, and growth mixture modeling will be used to identify latent groups of children whose developmental trajectories differ from peers that may relate to parental ratings of everyday behavior. Understanding the nature and development of executive control, and its relation to everyday behavior, ultimately will yield important information regarding the processes that may be impaired in a number of neurodevelopmental disorders. [unreadable] [unreadable]

Humans live in large social units and often care deeply about the rules governing life in those units (politics) even if those rules are unlikely to affect them personally. In fact, they sometimes care so deeply that differences of opinion over politics can be the cause of small-scale arguments and large-scale violence. This project examines the multiple influences on people's political preferences, using a wide range of techniques across different samples. Traditionally, it has been assumed that environmental factors, like parental socialization, lead some people to adopt positions associated with the left and others to adopt positions associated with the right (while still others refrain from adopting any political positions at all). The field of behavioral genetics, however, modifies this assumption in an important way by providing empirical evidence, mostly from twin studies, showing that genetics also plays a role in shaping political orientations. This research extends this work by using multiple levels of analyses including genotyping, brain imaging, physiological tests, surveys, and hormonal assays, applied to large samples of people in the United States and in Australia. Not only does identifying the specific genes, biological systems, and cognitive processing biases relevant to various political temperaments make the gene-political temperament link more convincing, it elucidates the nature and sources of political orientations. This project will also provide interdisciplinary training opportunities to undergraduate and graduate students.

DESCRIPTION (provided by applicant): Based on widely replicated associations, it is now clear that prenatal exposure to tobacco exposure is either a risk marker for, or a causal contributor to, early onset disruptive behavior in offspring. However, the nature and mechanisms of exposure-related behavioral disruptions are poorly understood due to limitations of previous research. Moving beyond replication to testing alternative models and mechanisms requires a translational approach that (1) accurately measures exposure in close proximity to outcome;(2) integrates examination of exposure-related disruptive behavior and its neuropsychological substrates using direct assessment methods and;(3) examines exposure "in context," particularly elucidating the complex interplay of exposure, genetic susceptibility to disruptive behavior and, parenting behavior in these pathways. To this end, we propose a preschool follow-up of a pregnancy cohort oversampled for exposure to examine the following specific aims: (I) Establish the nature and independence of effects of exposure on disruptive behavior patterns and their neuropsychological substrates at preschool age using developmentally sensitive, direct assessments and, testing whether independent effects of exposure remains when passive gene- environment correlations (rGE) are modeled in tandem;(II) Examine whether responsive parenting modifies the relation of exposure, disruptive behavior patterns and their neuropsychological substrates, including testing the robustness of this interaction with rGE controlled;(III) Characterize how the association of exposure, disruptive behavior patterns and their neuropsychological substrates varies in children with differing dopaminergic and serotonergic genotypes, including testing for the robustness of these interactions when rGE is controlled. The study proposes an age 5 follow-up of the participants of the Midwest Infant Development Study (MIDS: DA014661, K. Espy, PI) (n=375). Exposure was assessed with repeated biologic and self-reported measures. Laboratory assessments of both disruptive behavior patterns and neuropsychological substrates, direct observations of maternal responsiveness and measured genotype will be utilized to assess the preschoolers. In this revised application, we will also collect questionnaire data on disruptive behavior patterns and responsive parenting for the siblings of the subjects (n=500) and measured genotype in the mothers and these siblings in order to conduct within-family analyses. This translational approach is designed to move beyond a scientific perspective that juxtaposes teratologic genetic and contextual processes as mutually exclusive alternative explanations to one that examines them in concert to explicate their relative contributions and mutual influence in pathways to emergent disruptive behavior. As a window on how prenatal insults to the brain and biologic and contextual risks interact in the early-onset of psychopathology, the study has substantial public health significance. PUBLIC HEALTH RELEVANCE: While there is strong evidence that prenatal exposure to cigarettes is a risk marker for disruptive behavior, exposure related patterns and mechanisms are not well understood. Specifying exposure-related disruptive behavior patters and their neuropsychological substrates in young children and establishing mechanisms of effect, including the complex interplay of exposure, genetic susceptibility and parenting, will importantly advance understanding of the impact of this modifiable, prenatal risk factor on the emergence of the most common mental health problem of childhood.

DESCRIPTION (provided by applicant): Our goal is to expand and renovate core animal facilities at the University of Oregon (UO) to increase productivity and impact of PHS funded research, promote safety and welfare of research animals, researchers, and animal care staff, and expand a cryopreservation repository for genome-wide research. The UO is a pioneer in using fish models for research in vertebrate development, genetics, genomics, evolution, and genetic contributions to human disease. Because of this expertise, UO houses the Zebrafish International Resource Center (ZIRC). UO has begun to translate discoveries made in these models into mammals, with an ambitious program in mouse genetics, involving new hires and current junior and senior faculty. The success of UO research programs has put serious pressure on the Zebrafish, Stickleback, and Mouse Facilities, and on ZIRC. We propose to alleviate this pressure by a synergistic program of construction, renovation, and equipment purchase, including innovative sustainable design strategies to increase energy savings. (1) We propose new construction, renovation, and purchase of new aquaculture equipment in our Zebrafish Facility. This will increase the number of lines we can maintain and improve work flow efficiency. (2) We propose renovation of existing space and purchase of new equipment to establish a new Stickleback Facility. The new facility will complement our very small existing facility that houses the only inbred lines worldwide, increase the number of lines we can maintain, and improve work flow. (3) We propose to purchase equipment for a new Mouse Facility in a building UO is constructing. This will increase the number of lines we can maintain, alleviate stress on the mice, and enable several senior faculty to expand their research programs to include mice. (4) We propose to purchase new cryopreservation equipment for ZIRC. This equipment will be housed in a building UO is constructing adjacent to ZIRC. Recent technological breakthroughs are enabling researchers to mutate and functionally annotate every zebrafish gene. The new equipment will allow ZIRC to cryopreserve sperm from the extensive genetic and genomic resources created by this effort.

? DESCRIPTION (provided by applicant): The preschool years mark a critical period for the emergence of developmental psychopathology, including symptom dimensions consistent with ADHD. However, the availability of assessment tools to effectively detect such mental health problems early in childhood is limited, in part because the early precursors and neural bases are not well understood. The preschool period is characterized by rapid neurocognitive development reflected in young children's executive control (EC) capabilities, and individual differences in EC figure prominently into mental health disorder and functional impairment, making it a potentially important candidate to target for early assessment/intervention. Recent developmental models of EC suggest that executive task performance in younger preschoolers is driven primarily by bottom-up stimulus/response processing before a qualitative shift occurs around age four, after which top-down executive processes begin to contribute to behavioral performance. It is unknown what the precise neurophysiological mechanisms of these complimentary processes are before and after this critical transition, and how they might differ in children at risk for metal health problems. The long-term goal is to explicate the neurophysiological mechanisms underlying these processes across this developmental transition and understand how they relate to risk for child psychopathology. The objective of the proposed research is to characterize distinct neurophysiological signatures of the respective mechanisms in typically developing children before and after the transition, and to identify differences in these signatures in children displaying ADHD symptoms after the transition. The rationale is that this knowledge will inform how these mechanisms function at different developmental stages and in a clinical sample to lay the groundwork for future longitudinal study and intervention. The central hypothesis is that distinct neurophysiological signatures of bottom-up stimulus/ response processing will be identifiable before and after the transition, but neural activity related to to-down EC will only be observed at later ages and further be diminished in children with ADHD symptoms. The specific aims of the research are to: 1) Characterize the neurophysiological signatures of bottom-up and top-down processes in younger and older preschoolers; 2) Determine the relative power of the neurophysiological signatures reflecting both bottom-up and top-down processes in predicting specific and general ADHD symptom dimensions in 3.5- and 5-year-olds. The project is innovative in its objective to measure brain activity related to EC and ADHD risk in this critical age range, and to do so within the framework of sophisticated statistical models which form the basis of the hypotheses. The significance of this research is that it will explicate the mechanisms underlying the qualitative shift in preschool EC development and identify how individual differences in these mechanisms correspond to risk for child psychopathology. This work will clarify the importance of EC as a critical target for early assessment/intervention and ultimately enhance national mental health.