Brain Endophenotypes Modulating Drug Abuse Risk

调节药物滥用风险的大脑内表型

• 批准号: 8447114
• 负责人: ROBERT ALPERT ZUCKER
• 金额: $ 61.58万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447114
• 关键词: 10 year old; Address; Adolescence; Adult; Affect; Affective; Age; Alcohols; Area; Behavior; Behavioral; Brain; Brain region; Brain-Derived Neurotrophic Factor; California; Candidate Disease Gene; Cannabis; Child; Child Behavior Checklist; Childhood; Complex; DNA; Development; Diffuse; Drug Addiction; Drug Use Disorder; Drug abuse; Early identification; Early treatment; Emotional; Emotions; Environment; Event; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Gene-Modified; Genes; Genetic; Genetic Risk; Genetic Variation; Genotype; Goals; Haplotypes; Impulsivity; Individual; Individual Differences; Instruction; Life; Life Stress; Link; Longitudinal Studies; Measures; Mediating; Memory; Methaqualone; Michigan; Modeling; Neural Pathways; Neurobiology; Neurons; Nicotine; Participant; Performance; Pharmaceutical Preparations; Phenotype; Predisposition; Prefrontal Cortex; Prevention; Process; Q-Sort; Regulation; Research Personnel; Risk; Role; Sampling; Scanning; Sex Characteristics; Signal Transduction; Social Environment; Staging; Statistical Models; Stress; Structure; Substance Use Disorder; Substance abuse problem; Substance of Abuse; System; Task Performances; Techniques; Time; Tobacco; Variant; aged; base; behavior measurement; blood oxygen level dependent; blood oxygenation level dependent response; boys; design; disorder risk; endophenotype; genetic analysis; genetic variant; girls; high risk; longitudinal design; neural circuit; neuroimaging; neuronal circuitry; neurophysiology; programs; relating to nervous system; response; statistics; trait

This project examines the intermediate neural systems that mediate the gene-behavior relationships involv- ed in risk for development of substance use disorders (SUDs) with special focus on alcohol, cannabis, and nicotine. We will characterize this circuitry, study its interaction with two intermediate behavioral phenotypes (behavioral undercontrol and negative affectivity), and examine the contribution of selected genetic variants, and early-life stress on the neural correlates of impulsivity and negative emotionality in children with varying risk for development of SUDs in adulthood [G2 sample of the Michigan Longitudinal Study(MLS)]. We will examine these correlates during childhood and begin to characterize changes that occur during adolesc- ence. The general hypothesis is that dysregulation of the brain networks involved in processing and regula- tion of behavior and affect during childhood underlies a heightened predisposition to develop SUDs at a later age. Both behavioral undercontrol and affective dysregulation at an early age are strong predictors of SUDs later in life, and these processes are regulated by complex neuronal circuits. We will use fMRI to investigate these neural systems in a sample of 8-10 year old boys & girls (n=129) from the ongoing MLS in a longitud- inal design in which scanning occurs at 2-year intervals. It is expected that children at high risk for develop- ment of SUDs based on the risk conferred by behavioral phenotypes (measured initially as externalizing and internalizing behavior and later by developmental trajectory classes), will demonstrate alterations in the functional responses of neuronal circuitry involved in impulse control and emotional regulation. It is also ex- pected that this effect will be modified by genes and early-life stress. Changes in brain functional responses over time are expected to be influenced by risk conferred by genetic variants and early stress. As models of gene-trait-environment interaction over time are developed in the MLS, we will investigate the relationship between brain responses and these developmental phenotypes. As substance abuse problems develop in this sample, this information will be available during subsequent funding periods to determine dysfunctions in neural circuitry associated with the early development of SUDs during adolescence. RELEVANCE (See instructions): This project will provide in-depth understanding about the intermediate neural pathways underlying susceptibility to drug use disorders, their genetic basis, and the possible interactive role of the social environment in producing variations in risk over time. Findings will have direct implications for early identific- ation, prevention, and early treatment of at-risk individuals as well as those in early stages of drug addiction.

该项目检查介导基因行为关系的中间神经系统，涉及- 有发生物质使用障碍 (SUD) 的风险，特别关注酒精、大麻和 尼古丁。我们将表征该电路，研究其与两种中间行为表型的相互作用 （行为失控和负面情感），并检查所选遗传变异的贡献， 以及早期生活压力对不同儿童的冲动和消极情绪的神经相关性的影响 成年后发生 SUD 的风险 [密歇根纵向研究 (MLS) 的 G2 样本]。我们将 检查童年时期的这些相关性，并开始描述青春期发生的变化的特征 恩斯。一般的假设是，参与处理和调节的大脑网络失调 童年时期的行为和情感影响是以后发展 SUD 的更高倾向的基础 年龄。幼年时期的行为失控和情感失调都是 SUD 的有力预测因素 在以后的生活中，这些过程受到复杂的神经元回路的调节。我们将使用功能磁共振成像来调查 这些神经系统来自正在进行的 MLS 中的 8-10 岁男孩和女孩样本（n = 129） 最终设计中每隔 2 年进行一次扫描。预计处于发育高风险的儿童 SUD 的评估基于行为表型所赋予的风险（最初测量为外化和 内化行为，然后通过发展轨迹课程），将展示 涉及冲动控制和情绪调节的神经回路的功能反应。它也是前 预计这种效应将被基因和早期生活压力所改变。大脑功能反应的变化 随着时间的推移，预计会受到遗传变异和早期压力带来的风险的影响。作为模型 随着时间的推移，基因-性状-环境相互作用在 MLS 中得到发展，我们将研究这种关系 大脑反应和这些发育表型之间的关系。随着药物滥用问题的发展 该样本，该信息将在后续资助期间可用，以确定功能障碍 与青春期 SUD 早期发育相关的神经回路。 相关性（参见说明）： 该项目将深入了解潜在的中间神经通路 对吸毒障碍的易感性、遗传基础以及社会因素可能的相互作用 随着时间的推移，环境会产生风险变化。研究结果将对早期识别产生直接影响 对高危人群以及处于毒瘾早期阶段的人群进行预防和早期治疗。