Brain Endophenotypes Modulating Drug Abuse Risk

这个项目研究了调节基因-行为关系的中间神经系统。 ED有发生物质使用障碍(SODS)的风险，特别关注酒精、大麻和 尼古丁。我们将描述这个回路，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， 不同情绪障碍儿童早期应激对冲动和负性情绪神经相关的影响 成年后患肥皂症的风险[密歇根纵向研究(MLS)的G2样本]。我们会 研究儿童时期的这些相互关系，并开始描述发生在青春期的变化。 安斯。一般的假设是，参与加工和调节的大脑网络的失调- 童年时期的行为和情感是日后产生肥皂泡的更高的易感性的基础 年龄。早年的行为控制不良和情感失调都是肥胖症的有力预测因素 在生命的后期，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 这些神经系统在8-10岁的男孩和女孩(n=129)的样本中，来自正在进行的MLS在一个纵向上- 每隔两年扫描一次的原始设计。预计高危儿童会患上- 基于行为表型赋予的风险(最初测量为外化和 将行为内化，然后通过发展轨迹类别)，将显示出 参与冲动控制和情绪调节的神经回路的功能反应。它也是前- 预计这一效应将被基因和早期应激所改变。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。作为……的榜样 随着时间的推移，基因-性状-环境的交互作用在MLS中得到发展，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关系。随着药物滥用问题的发展 此样本、此信息将在随后的资助期间可用来确定功能障碍 与青春期肥胖症早期发展相关的神经回路。 相关性(请参阅说明)： 这个项目将提供对潜在的中间神经通路的深入理解 药物使用障碍的易感性，其遗传基础，以及社会因素可能的交互作用 随着时间的推移，风险会发生变化。这些发现将对早期识别有直接影响- 对高危人群以及吸毒成瘾早期患者进行预防和早期治疗。

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.