Eileen M. Moore, Ph.D. - US grants

DESCRIPTION (provided by applicant): Initiation of alcohol consumption during early adolescence (before age 14) is related to an increase in lifetime prevalence of alcohol dependency (Grant &Dawson, 1997). The risk for future alcoholism also increases with a positive family history of alcohol abuse (Schuckit &Smith, 1996). However, in order to fully understand the impact of adolescent exposure to ethanol and the genetic factors associated with alcoholism, use of animal models are necessary. The proposed research will examine: differences in ethanol intake between adult and adolescent mice, as well as the differences in drinking between adult mice that were either previously exposed to ethanol during adolescence or adulthood in 8 inbred mouse strains (Aim 1);the extent to which a conditioned taste aversion (CTA) can be induced in adolescents as well as the degree to which prior ethanol exposure (either in adolescence or adulthood) alters sensitivity to the aversive properties of alcohol in adulthood in the same 8 inbred mouse strains (Aim 2) and lastly, the extent to which alcohol intake and CTA to alcohol in adolescence and adulthood will correlate across the 8 inbred mouse strains. Male adolescent (early: P28-32 and late: P38-42) and-adult (P70-74) mice ofthe C57BL/6J, DBA/2J, 129S1/SvlmJ, A/J, BALB/cByJ, BTBR T+tf/tf, C3H/HeJ, and FVB/NJ inbred strains will be given access to a 20% (v/v) ethanol solution for 2-h a day, for 5 consecutive days. Mice will then be reassessed for ethanol intake, 37 days after the completion of the initial ethanol exposure, when the adolescents reach adult-age (Aim 1). Next, male adolescent and adult mice (ofthe same genotypes and age-ranges) will be given access to a 10% (w/v) sugar-water solution for 1-h, and immediately after sugar-water access mice will be intraperitoneally (ip) injected with saline or ethanol (2 or 4 g/kg) to produce an ethanol-induced CTA to the tastant. Mice will receive this tastant/ethanol pairing 3 times, with one day of recovery between each sugar-water access/ethanol injection treatment. Again, after a 37 day abstinence period animals will be re- exposed to the CTA procedure in adulthood, this time using a different tastant (0.05% sodium-chloride) to determine whether previous ethanol treatment in adolescence will alter adult sensitivity to the aversive properties of ethanol (Aim 2). Lastly, ethanol drinking and CTA phenotypes will be correlated across genotypes for both adolescent and adult mice. This work will examine both developmental exposure/sensitivity to ethanol as well as differences in ethanol intake/sensitivity due to genotype;examining both of these influences together may yield important and interesting interactions which could result in a greater understanding of alcohol use and abuse from adolescence into adulthood in humans.

DESCRIPTION (provided by applicant): This proposal outlines research and training to occur with funding from a Pathway to Independence Award (K99/R00). The training objective during the first two years of the award is to foster training in neuroimaging and human behavioral assessment to prepare me for a translational research career in academia, and accelerate my progress towards independence. During the K99 phase, I will complete research projects with the following goals: (1) determine the utility of olfactory function measures for distinguishing children with prenatal alcohol exposure (PAE) from non-exposed typically developing control children (CON) and children with idiopathic attention deficit/hyperactivity disorder (ADHD); and (2) understand the neural dissimilarities in these groups of children that contribute to their behavior. I will undertake an intensive training regimen to obtain the necessary expertise to conduct neuroimaging research. I will also begin studies using functional magnetic resonance imaging (fMRI) to investigate differences in central olfactory processing systems in PAE, ADHD and CON children. I will promote my career development by attending relevant seminars and scientific conferences, publishing my research findings, and interviewing for independent faculty positions. The proposed mentors, Drs. Edward Riley, Claire Murphy, and Jay Giedd are experts in the fetal alcohol spectrum disorders, chemical senses, and pediatric neurodevelopment fields, respectively. The collaborative research and training environments at the Center for Behavioral Teratology, San Diego State University, and University of California, San Diego will provide me with the necessary resources to complete the aims outlined in this proposal. In the 3-year R00 phase of the award, I will establish myself in my new role as an independent researcher and continue my research on olfactory functioning in children with PAE and ADHD with the following goals: (1) examine the relationship between attention deficits, olfactory function, neural activation patterns and stimulant treatment responses; and (2) determine the value of olfactory function measures in predicting chronic responses to psychostimulant treatments in children with PAE using a mouse-model. The work described in this proposal is in line with NIAAA's mission for improving diagnosis of FASD, increasing the understanding of the effects of alcohol on the unborn child, and developing effective interventions to mitigate the health effects on those prenatally exposed to alcohol.

Project Summary Exposure to alcohol in utero can have devastating effects on the developing fetus, including growth deficits, cognitive and behavioral anomalies, alterations in brain, and distinct facial characteristics; collectively these are referred to as fetal alcohol spectrum disorders (FASD). While research over the last 40 years has characterized these alterations and provided numerous potential mechanisms for the effects of prenatal alcohol exposure (PAE), very little data exists on long-term consequences as the majority of clinical research has focused on children and adolescents. Many of the consequences of PAE are thought to be lifelong, yet data on individuals past young adulthood are rare, despite animal model data suggesting long-term consequences and altered trajectories of behavioral development. The goal of this application is to address this significant shortfall in our knowledge by evaluating the protracted effects of prenatal alcohol exposure on the brain. Previous large studies from Seattle, WA developed well-characterized research samples of individuals with a classification of having an FASD who are now adults between 30 and 60 years of age. These individuals are currently being recruited into a registry of research participants. Over 150 of these individuals have had previous structural MRI scans conducted while in their teens and twenties. A subset of subjects and matched controls (N=90) will be recruited to have another MRI session in which structural, DTI, and connectivity assessments will be conducted. Comparisons between these and earlier scans will provide insight into the changes in overall brain structure, white matter integrity, and function with age in subjects with alcohol exposure histories. We postulate that brain maturation following PAE follows an altered trajectory relative to normal developing controls. This work will begin to examine a major gap in our knowledge about the impact of PAE by addressing for the first time the longitudinal changes in brain during the adult period, and identify gaps in knowledge regarding FASD in adulthood.

Project Summary Prenatal alcohol exposure can have devastating effects on the developing fetus, including growth deficits, cognitive and behavioral anomalies, alterations in brain, and distinct facial characteristics; collectively these are referred to as fetal alcohol spectrum disorders (FASD). While there has been much research examining the brain and behavior in children with FASD, very little data exists on adults. Many of the consequences of PAE are thought to be lifelong, yet data on individuals past young adulthood are rare. Previous large studies from Seattle, WA developed well-characterized research samples of individuals with a classification of having an FASD and age- and sex-matched controls. One-hundred-eighty of these subjects completed T1- weighted MRI scans approximately 20 years ago. Fifty of these previously scanned subjects have already been recruited to complete a follow-up T1-weighted MRI scan as part of the parent award. The aim of the parent award is to evaluate the protracted effects of prenatal alcohol exposure on the brain, particularly within the frontal executive system from the aforementioned dataset. This project expands upon the parent grant by evaluating additional age-related changes in the brain within subcortical regions of interest (ROIs). This supplement will support the trainee, Lindsey Aguilar, as she acquires skills in human neuroimaging research and contributes to the goals of the parent award, ?Brain maturation in adults with FASD.? More specifically, Ms. Aguilar will utilize available neuroimaging software programs to apply a Bayesian model of shape to subcortical ROIs for baseline and follow-up scan data. For Aim 1, she will process the baseline data with two different techniques for estimating probable shape (FSL/FIRST and FreeSurfer with Enigma pipeline) to determine which pipeline is most effective. After choosing the more appropriate pipeline, she will compare shape differences in adults with FASD as compared to matched controls using the follow-up data. As part of her training plan, she will complete tutorials and short courses offered by both FreeSurfer and FSL, attend and present her data at the Human Brain Mapping and Research Society on Alcoholism conferences. Additionally, she will be completing career development activities as she earns her master?s degree and pursues a research career studying the impact of prenatal alcohol exposure on the brain.