Neurobehavioral pathways of polygenic and polyenvironmental effects on the onset and maintenance of substance involvement

多基因和多环境影响的神经行为途径对物质参与的发生和维持

• 批准号: 10317570
• 负责人: ARPANA AGRAWAL
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10317570
• 关键词: Accounting; Adolescence; Adolescent; Adolescent and Young Adult; Adult; Age; Alcohols; Architecture; Attenuated; Behavior; Behavioral; Behavioral Mechanisms; Brain; Cessation of life; Childhood; Corpus striatum structure; Cues; Data; Data Analyses; Development; Disease; Education; Emotional; Emotions; Environment; Environmental Exposure; Environmental Risk Factor; Etiology; Genetic; Genetic Risk; Genomics; Impulsivity; Individual; Intoxication; Investigation; Link; Machine Learning; Maintenance; Manuscripts; Mediating; Methods; Modeling; Neurobiology; Pathway interactions; Pattern; Phenotype; Plant Roots; Policies; Prevention; Risk; Risk Factors; Risk-Taking; Sampling; Siblings; Structure; Substance Use Disorder; Testing; Thick; Tobacco; Twin Multiple Birth; Variant; Withdrawal; Youth; addiction; association cortex; base; behavioral phenotyping; brain behavior; burden of illness; cognitive control; cognitive development; cognitive reappraisal; comorbidity; cost; disease classification; disorder risk; early adolescence; early onset substance use; emerging adult; emotion regulation; executive function; fetal substance exposure; improved; indexing; multimodality; negative affect; neural correlate; neurobehavioral; neurodevelopment; neuromechanism; novel; polygenic risk score; prenatal; relating to nervous system; risk sharing; social; socioeconomics; substance misuse; substance use; young adult

PROJECT SUMMARY/ABSTRACT Problematic substance use is associated with significant personal and socioeconomic costs (accounting for approximately 5% of global disease burden and worldwide deaths). Substance use initiation, progression to heavy use, and early onset substance use disorders (SUDs) commonly emerge during adolescence and young adulthood. This developmental period of risk is theorized to result from typical patterns of regionally asynchronous brain maturation (i.e., rapid and early development of limbic regions alongside relatively immature prefrontal and multimodal association cortices) resulting in a diminished ability to suppress inappropriate emotions, desires, and actions when salient environmental cues are present. During later young adulthood the stabilization, reduction, or desistance of heavy use typically occurs alongside maturing cognitive control and emotional regulation abilities coinciding with cortical development. Brain and behavioral maturation may also be influenced by substance use. As genetic and environmental risk factors for substance involvement are predominantly shared across substances, understanding the behavioral and neural mechanisms underlying these shared risk factors in a developmental context will broadly improve our etiologic understanding of substance involvement liability and refine treatment and prevention. In this 5-year R01 (responding to PAR-19- 162), we propose to test whether putative behavioral and neural mechanisms of stage-based addiction may link broad spectrum SUD genomic liability and environmental risk to substance involvement trajectories from childhood – young adulthood using longitudinal data from the Adolescent Brain and Cognitive Development (ABCD) Study (N=11,875 followed from ages 9-16) along with other samples that uniquely extend the temporal scope of ABCD to comprehensively examine brain-behavior developmental interplay related to substance use and misuse (e.g., National Consortium on Alcohol and Neurodevelopment in Adolescence followed 830 individuals from ages 12-32). Disentangling the behavioral and neural mechanisms underlying broad spectrum genetic and environmental liability to SUD will inform our etiologic understanding of substance use initiation, escalation, and desistence that may ultimately contribute to substance-related policy, education, nosology, prevention, and treatment. Primary deliverables from this project will be manuscripts evaluating whether behavior and neural phenotypes may represent mechanisms underlying polygenic and polyenvironmental risk for substance use disorders.

项目总结/摘要 有问题的物质使用与重大的个人和社会经济成本有关（占 约占全球疾病负担和全球死亡人数的5%）。开始使用药物，进展至 大量使用和早发性物质使用障碍（SUD）通常出现在青春期和年轻时 成年理论上，这种风险的发展期是由区域性的典型模式造成的。 异步脑成熟（即，边缘区的快速和早期发展， 前额叶和多模态联合皮层），导致抑制不适当的 情绪、欲望和行动时，突出的环境线索存在。在后来的青年时期， 稳定、减少或停止大量使用通常伴随着认知控制的成熟而发生， 情绪调节能力与大脑皮层发育一致大脑和行为的成熟也可能是 受物质使用的影响。由于涉及药物的遗传和环境风险因素 主要是跨物质共享，了解行为和神经机制， 这些共同的风险因素在发展的背景下将广泛提高我们的病因学理解， 物质涉入责任和精细化治疗与预防。在本5年R 01（响应PAR-19- 162），我们建议测试是否假定的行为和神经机制的阶段为基础的成瘾可能链接 广谱SUD基因组责任和环境风险，以物质参与轨迹， 使用青少年大脑和认知发展的纵向数据， （ABCD）研究（N= 11，875，9-16岁）沿着其他样本，这些样本独特地延长了时间 ABCD的范围，全面检查与物质使用相关的大脑行为发展相互作用 和滥用（例如，全国酒精和青少年神经发育联盟跟踪调查了830名 年龄在12-32岁之间）。解开广泛的行为和神经机制 SUD的遗传和环境易感性将告知我们对物质使用开始的病因学理解， 升级和停止，最终可能有助于物质相关的政策，教育，疾病分类， 预防和治疗。从这个项目的主要成果将手稿评估行为是否 和神经表型可能代表多基因和多环境风险的机制， 物质使用障碍