Jennifer D. Thomas - US grants

DESCRIPTION: Prenatal alcohol exposure can produce central nervous system dysfunction, resulting in a wide range of behavioral alterations. The mechanisms by which ethanol disrupts brain and behavioral development, however are currently unknown. Preliminary data demonstrate that administration of MK-801, a noncompetitive NMDA receptor antagonist, during ethanol withdrawal in neonatal rats can attenuate ethanol-induced deficits on a spatial discrimination reversal task. These results suggest that withdrawal-related NMDA receptor-mediated excitotoxicity may be one mechanism producing alcohol's adverse effects on behavioral development. This project proposes to investigate the factors that determine the effectiveness of MK-801 in mitigating ethanol induced behavioral alterations. Rat pups are exposed to ethanol during the neonatal brain growth spurt, a period of development equivalent to a portion of the human's third trimester in utero, via an artificial rearing procedure. MK-801 is administered during withdrawal and behavioral performance is examined with two behavioral tasks: open field activity and serial spatial discrimination reversal learning. These two tasks are sensitive to early alcohol exposure and are believed to rely on the functional integrity of the hippocampus, an area sensitive to both neonatal ethanol exposure and NMDA receptor-related excitotoxicity. Preliminary evidence suggests that MK-801 can either exacerbate or protect against ethanol-related teratogenic effects, depending on the dose and timing of administration. Thus, the dose-response and time course of the effects of MK-801 are evaluated to determine the parameters that control the interaction of ethanol and MK-801. Secondly, given that chronic ethanol treatment has been shown to produce a greater upregulation of NMDA receptors, the comparative effects of MK-801 following acute vs. chronic ethanol exposure is examined. Finally, a preliminary exploration into the effects of postnatal ethanol and MK-801 administration on hippocampal neuropathology is conducted. Characterization of the behavioral consequences of blocking NMDA receptors during developmental ethanol withdrawal lays an important foundation for future studies on the role of withdrawal-related neurotoxicity in fetal alcohol effects.

DESCRIPTION (provided by applicant): Prenatal alcohol exposure can disrupt development, leading to a spectrum of disorders that include facial dysmorphology, growth deficiencies and central nervous system dysfunction. Alcohol's adverse effect on brain development and consequent cognitive abilities are among the most devastating. Yet, although alcohol- related neurodevelopmental disorders are completely preventable, women continue to drink alcohol during pregnancy. Thus, it is critical that we identify effective treatments and interventions for reducing the adverse consequences of prenatal alcohol exposure. Many behavioral alterations associated with prenatal alcohol exposure may be related to altered cholinergic functioning. Interestingly, perinatal choline supplementation in control subjects can lead to long-lasting enhancements in cholinergic functioning and cognitive abilities. Thus, we hypothesized that perinatal choline supplementation may reduce the severity of some fetal alcohol effects. Using an animal model system, we demonstrated that perinatal choline supplementation attenuates the hyperactivity and learning deficits associated with alcohol exposure during development. In fact, choline supplementation is effective even when administered after the alcohol exposure is complete and during a period of brain development equivalent to early postnatal development in humans. This proposal continues our investigation of choline as a potential treatment for fetal alcohol effects. Using an animal model of third trimester alcohol exposure, we first plan to examine the temporal windows of choline's effectiveness. Elucidation of the developmental periods when choline is effective will produce further hypotheses of its mechanisms of action and indicate if choline can be administered and still be effective later in life. Secondly, we will examine if perinatal choline supplementation leads to long-lasting changes in cholinergic functioning in our alcohol-exposed subjects. This will allow us to correlate behavioral changes with neurochemical substrates. Finally, we will examine if choline supplementation can enhance the efficacy of other behavioral treatments, specifically environmental enrichment. If choline potentiates the effects of environmental enrichment, it would suggest that combinations of treatments may be the most effective for children with FASD. Importantly, choline supplementation may serve as a relatively safe and effective treatment that could be administered after birth in humans.

[unreadable] DESCRIPTION (provided by applicant): The purpose of the Research Society on Alcoholism (RSA) Lecture Series is to provide educational information on a wide range of important topics in the field of alcohol research to a broad audience that includes practitioners, scientists, students and the public. The Lecture Series will include 16 lectures on topics ranging from alcohol's pharmacological action to epidemiology, treatment, and translation of science to the clinic. These lectures will be presented on the two days prior to the 2008 annual RSA meeting (June 27 & 28) and then educational materials, including Powerpoint slides, notes and podcasts of the lectures, will be made available to the public via the RSA website. The lectures will be translated both into Spanish and lay language to increase accessibility to a broader audience. As a resource to researchers, the Lecture Series can enhance the interchanges between clinical and basic scientists, as well as social and biomedical scientists, by developing a common knowledge base. It is also an excellent series of lectures for someone new to the alcohol research field (whether at the level of graduate student, postdoctoral scientist or scientist from an area outside of alcohol research). In addition, the Lecture Series serves as an educational forum to enhance and develop bridges between the treatment and research communities, providing accurate, up-to-date information on what is known of alcohol's effects and treatments for alcohol use disorders. Finally, by translating the talks into lay language, the Lecture Series creates an interface through which the public can become aware of the current state of alcohol research. Thus, the Lecture Series serves as an educational tool, providing a cost-effective means of disseminating accurate scientific information to researchers, clinicians, Universities, outreach programs and the general public. The Research Society on Alcoholism (RSA) Lecture Series will provide educational materials on alcohol's effects and alcohol use disorders. These materials will be available in scientific, Spanish and lay language, allowing accurate and current information on alcohol-related topics to be disseminated to students, educators, researchers, practitioners, and the public. [unreadable] [unreadable] [unreadable]

This application requests funding for partial support of the 2010-2014 Fetal Alcohol Spectrum Disorders Study Group (FASDSG) meetings. The FASDSG meeting is held annually as a satellite conference preceding the Research Society on Alcoholism (RSA) meeting. The FASDSG meeting provides a unique opportunity for a broad range of researchers, including basic, clinical and social scientists, to meet and discuss fetal alcohol spectrum disorders. As such, the FASDSG meeting allows cross-fertilization between animal, human, clinical and epidemiological FASD-related research efforts and research progress. The meeting allows its members to provide updates on new research, discuss and debate issues in the field, stimulate interest among new investigators (including students), and to interact and form scientific collaborations. The goal of the meeting is to move the research field forward and, ultimately, to identify means to prevent and treat fetal alcohol spectrum disorders. As the FASDSG membership continues to grow, partial support from NIAAA has been critical to bring in high quality speakers that are leaders in their field, including areas outside of alcohol research. This support has also been essential to grow the cadre of young scientists entering the alcohol field through travel awards for the brightest and most promising students/new investigators. This application requests funding for travel and registration fees for 6 young investigators (students and postdoctoral fellows), and all meeting- related expenses plus speaker fees for invited keynote speakers each year. Support for the website, which provides a mode of communication both within the FASDSG and with the public, is also being requested. Publication of a meeting synopsis, as proposed herein, will document the annual proceedings and afford availability of the meeting content to the larger scientific community and public.

DESCRIPTION (provided by applicant): The Congress of the International Society for Biomedical Research on Alcoholism (ISBRA) provides a critical venue for alcohol researchers from around the world to provide updates on scientific findings, exchange ideas, discuss and debate issues in the field, and to interact and form scientific collaborations. As the premier international scientific meeting devoted to alcohol research, this Congress brings together a range of basic and clinical scientists that study the biomedical, psychosocial, and clinical aspects of alcohol use, abuse and addiction. This scientific exchange is invaluable for both established and developing research programs around the world. Alcohol is currently the 3rd highest risk factor for disease burden globally, affecting not only the drinker, but their families and communities as well. Given the immense public health cost of alcohol use and abuse, cooperation and scientific exchange among international researchers is critical for informing public policy as well as addressing important research questions. The ISBRA Congress has been held biennially since 1982, shortly after ISBRA was founded. Meetings have been held around the world, in Asia, Europe, Australia, and North America. This application requests funding for support of the 2014 and 2016 ISBRA Congresses. The 17th Congress will be held on June 21- 25, 2014 as a joint meeting with the Research Society on Alcoholism (RSA) in Seattle, Washington, USA. This will be the sixth time that ISBRA has met in North America and the fourth joint meeting between ISBRA and RSA. The 18th Congress will be held in the fall of 2016 at a European destination to be determined by the ISBRA Board. This application would provide partial travel support for scientists to attend these important Congresses, scientists who might otherwise not be able to attend. Funds would be directed primarily to individuals outside the U.S. for the 2014 meeting and to U.S. scientists for the 2016 meeting. Funding support is prioritized to ensure that junior investigators can attend the meeting, to foster the cadre of youn scientists that will develop into the leaders of the field. Furthermore, funds are allocated to ensure the on the contribution from women and underrepresented populations. Funds are requested to offset travel, registration fees as permitted and partial living expenses. The application also requests partial publication costs for the Congress abstract book, program, and published proceedings. Publication of scientific abstracts and summaries allows the content of the Congresses to be communicated to the larger research community and public.

DESCRIPTION (provided by applicant): This application requests funding for partial support of the 2015-2019 Fetal Alcohol Spectrum Disorders Study Group (FASDSG) meetings. The FASDSG meeting is held annually as a satellite conference preceding the Research Society on Alcoholism (RSA) meeting. The FASDSG meeting provides a unique opportunity for a broad range of researchers, including basic, clinical, and social scientists, to meet and discuss fetal alcohol spectrum disorders (FASD). As such, the FASDSG meeting allows for interdisciplinary integration among basic science, human, clinical, and epidemiological FASD-related research efforts and progress. The meeting allows its members to provide updates on new research, discuss and debate issues in the field, stimulate interest among new investigators (including students), and interact and form scientific collaborations. The goal of the meeting is to move the field forward and, ultimately, to identify means to prevent and treat FASD. As the FASDSG membership continues to grow, partial support from NIAAA has been critical for inviting high quality speakers who are leaders in their field, including areas outside of alcohol research, to the FASDSG meeting. Outside expertise stimulates novel ideas and approaches that may be applicable to FASD research. This support has also been essential to grow the cadre of young scientists entering the alcohol field, by providing travel awards for the brightest and most promising students and new investigators. More specifically, this application requests funding for travel and registration fees for young investigators (students and postdoctoral fellows), as well as meeting-related expenses, such as fees for invited keynote speakers. Additionally, this application requests support for the FASDSG website, which provides a mode of communication both within the FASDSG and with the public. Finally, publication of a meeting synopsis documents the annual proceedings and affords availability of the meeting content to the larger scientific community. In sum, the FASDSG meeting provides a critical venue for communication and collaboration among FASD researchers, fostering progress in the FASD research field.

Project Summary/Abstract Alcohol abuse and alcoholism constitute a serious public health concern across the globe. In fact, alcohol is currently the 3rd highest risk factor for disease burden around the world, and its adverse effects influence not only the drinker, but also their families, employers, and communities. Given the immense public health cost of alcohol use and abuse, scientific exchange among international alcohol researchers is critical for addressing important issues in the field and for informing public policy. The International Society for Biomedical Research on Alcoholism (ISBRA) Congress provides an important venue for alcohol researchers from around the world to share scientific findings, discuss and debate issues in the field, and to interact and form scientific collaborations. As the premier international scientific meeting devoted to alcohol research, this Congress brings together a range of basic and clinical scientists that study the biomedical, psychosocial, and clinical aspects of alcohol use, abuse and addiction. The scientific exchange that occurs during the Congress is invaluable for both established and developing research programs around the world. ISBRA Congresses are held biennially and their meeting locations have rotated among Asia/Australia, Europe, and the Americas. This grant requests funding to support travel to the 19th and 20th ISBRA Congresses. The 19th Congress will be held in September 2018 in Kyoto, Japan and the 20th Congress will be held in June 2020 as a joint meeting with the Research Society on Alcoholism (RSA) in New Orleans, LA, USA. In addition, support is being requested for ISBRA members to participate in meetings of ISBRA's affiliate societies, such as the European Society for Biomedical Research on Alcoholism (ESBRA) and the Asian Pacific Society on Alcohol and Addiction Research (APSAAR), which meet biennially in years opposite the ISBRA Congresses. This grant requests partial travel, lodging and registration support for scientists to attend these important Congresses. In particular, this grant seeks to provide support for junior investigators and individuals from underrepresented groups and countries. This support will foster the cadre of young scientists that will develop into the leaders of the field and assist investigators who might otherwise not be able to attend the Congresses. Partial support for Congress publication costs is also requested so the scientific abstracts and summaries can be communicated to the larger research community and the public.

PROJECT SUMMARY Prenatal exposure to alcohol can lead to a range of physical, neurological, and behavioral alterations referred to as fetal alcohol spectrum disorders (FASD). Despite increased education efforts urging pregnant women to not consume alcohol, estimates indicate that as much as 2% to 4% of all live births in the U.S. may be affected by prenatal alcohol exposure. Thus, FASD pose a serious public health problem. In addition, pregnant women who drink may also be consuming other illicit drugs. Cannabis is the most commonly used illicit drug among pregnant women, with overall prevalence rates ranging from 3% to 4%, and even higher rates in teen pregnancies. Furthermore, over half of pregnant women who are consuming cannabis are also consuming alcohol. Given the increase in availability of cannabis, combined with the increasing potency of ?9- tetrohydrocannabinol (THC), the principle psychoactive component of cannabis, prenatal exposure is likely to increase. However, the consequences of combined prenatal alcohol and cannabis exposure on brain and behavioral development are not well understood. Preclinical evidence indicates that THC increases alcohol- induced neurodegeneration, particularly during a model of late gestational exposure. In fact, alcohol's teratogenic effects can be attenuated by blocking CB1 receptors, suggesting that the cannabinoid receptors may mediate some of alcohol's effects on development. However, it is not clear how these interactions translate to behavioral alterations. Using an animal model, this proposal will examine the functional consequences of combined alcohol and THC. First, we will establish parameters of THC administration to model clinically relevant levels of THC exposure. Secondly, we will examine the effects of developmental exposure to alcohol, THC, and their combination on learning and memory, motor function, and emotional behaviors. These studies will lay a foundation so that future studies can strategically investigate the interaction of alcohol and cannabis on brain development, elucidate mechanisms of action, and determine if intervention effectiveness varies with co-exposure. Importantly, understanding the effects of prenatal exposure to both drugs has major implications, not only for the lives of affected individuals and families, but also for public health and establishing public policy.

ABSTRACT Caregivers of children with fetal alcohol spectrum disorders (FASD) often report that their child has problems with sleep. However, despite decades of research on the consequences of prenatal alcohol exposure, sleep behaviors are grossly understudied, even though sleep disturbances may mediate or exacerbate some of the cognitive and emotional effects of prenatal alcohol exposure and could serve as a potential target for intervention. In fact, sleep difficulties are related to neurobehavioral deficits in typically developing populations and may have more robust effects on neurobehavioral functioning among individuals with developmental disorders. We hypothesize that children with FASD will demonstrate greater sleep disturbance compared to controls. We also predict that sleep disturbance will be related to increased emotional reactivity, hyperactivity, aggression, and depression, and greater deficits in executive functioning, memory, and attention. Moreover, preclinical studies indicate that prenatal alcohol exposure can disrupt the clock genes that control circadian rhythmicity at a cellular level. Thus, we hypothesize that clock genes will be expressed differently in children with prenatal alcohol exposure. First, this proposal will examine sleep in children with FASD with both wearable technology and subjective measures. Secondly, the relationship between sleep quality and neurobehavioral outcome will be examined. Finally, as an exploratory aim, we will determine if children with FASD exhibit differential expression of clock genes. These data will allow us to better understand the effects of prenatal alcohol exposure on sleep and lay the foundation for developing targeted interventions that may not only improve sleep, but also have the potential for enhancing functioning in other cognitive and emotional domains as well.