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

项目摘要/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%)。物质使用开始，进展到 过度使用和早发性物质使用障碍(SODS)通常出现在青春期和青年时期 成人期。理论上说，这种风险发展期是由典型的地区性 大脑不同步成熟(即边缘区域快速和早期发育，同时相对不成熟 前额叶和多模式联合皮质)导致抑制不适当的能力减弱 当有明显的环境提示时，情绪、欲望和行为。在年轻的成年后期， 稳定、减少或停止大量使用通常伴随着成熟的认知控制和 情绪调节能力与大脑皮层发育相吻合。大脑和行为的成熟也可能是 受物质使用的影响。因为涉及物质的遗传和环境风险因素是 主要是跨物质共享，了解潜在的行为和神经机制 这些共同的风险因素在发育背景下将广泛地提高我们对 物质牵涉责任，细化治疗和预防。在本5年R01(响应PAR-19- 162)，我们建议测试基于阶段的成瘾的假定的行为和神经机制是否可能联系 广谱SOD基因组易感性和环境风险对物质参与轨迹的影响 用青春期大脑和认知发展的纵向数据研究儿童-成年期 (ABCD)研究(N=11,875，从9-16岁开始)以及其他独特延长颞叶的样本 ABCD的范围是全面检查与物质使用有关的大脑行为发育相互作用 和滥用(例如，国家酒精与青春期神经发育联合会跟踪830 12-32岁的个人)。解开广谱背后的行为和神经机制 对SUD的遗传和环境责任将有助于我们对物质使用开始的病因学理解， 升级和停止，这最终可能有助于与物质有关的政策、教育、病因学、 预防和治疗。该项目的主要交付成果将是评估行为是否 神经表型可能代表了多基因和多环境风险的潜在机制 物质使用障碍。

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.