Brain Endophenotypes Modulating Drug Abuse Risk

调节药物滥用风险的大脑内表型

• 批准号: 8245909
• 负责人: ROBERT ALPERT ZUCKER
• 金额: $ 9.66万
• 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/8245909
• 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.

该项目研究了介导基因-行为关系的中间神经系统， 艾德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。我们将描述这种回路，研究它与两种中间行为表型的相互作用， （行为控制不足和消极情感），并检查选定的遗传变异的贡献， 和早期生活压力对神经冲动和消极情绪的影响， 成年期SUD发展风险[密歇根纵向研究（MLS）G2样本]。我们将 在儿童时期检查这些相关性，并开始描述在儿童时期发生的变化， 恩塞。一般的假设是，参与加工和调节的大脑网络失调， 儿童时期的行为和情感的改变是日后发展SUD的高度倾向性的基础。 年龄早期行为控制不足和情感失调都是SUD的强预测因子 这些过程是由复杂的神经回路调节的。我们将使用功能性磁共振成像来研究 这些神经系统在8-10岁的男孩和女孩（n=129）的样本，从正在进行的MLS在一个神经系统， 以2年为间隔进行扫描的最终设计。预计高风险儿童将发展- 基于行为表型（最初测量为外化和 内化行为和后来的发展轨迹类），将证明在改变 神经元回路的功能反应涉及冲动控制和情绪调节。它也是前- 预计这种影响将被基因和早期生活压力所改变。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。了模型 随着时间的推移，基因-性状-环境相互作用在MLS中发展，我们将研究它们之间的关系。 大脑反应和这些发育表型之间的联系。随着药物滥用问题在 在随后的供资期间，将提供这一信息，以确定功能障碍 与青春期SUD早期发展相关的神经回路。 相关性（参见说明）： 这个项目将提供关于中间神经通路的深入了解， 药物使用障碍的易感性，其遗传基础，以及社会因素可能的相互作用 环境中产生的风险随着时间的推移而变化。研究结果将对早期识别有直接影响- 预防和早期治疗处于危险中的个体以及处于药物成瘾早期阶段的个体。