Project 3: Adolescent Nicotine

项目3 -青少年尼古丁 尼古丁是青少年最常用的药物之一。一些研究将烟草与 尼古丁在人类青春期的使用和成年后的问题，包括后来的烟草，酒精， 可卡因和其他非法药物使用。15岁以前吸烟的人估计 使用可卡因等非法药物的可能性是不使用毒品的人的80倍。此外，研究 动物研究表明，青少年尼古丁暴露会影响尼古丁和可卡因的奖赏和敏感性， 啮齿类动物;我们已经证明，在青春期反复接触低剂量的尼古丁明显会导致衰老， 尼古丁和其他滥用药物的奖励作用的具体增强，在 停止尼古丁暴露。然而，尼古丁的分子和遗传机制- 对奖励效应的诱导增强仍然不清楚。该项目将确定风险相关基因 以及使用高度多样化的小鼠遗传种群的基因网络。我们将使用近亲繁殖的协作杂交 (CC)/多样性异交（DO）建立者和CC菌株使用条件化位置测量尼古丁奖励 在青春期早期暴露于尼古丁后的CPP测试。这些数据将用于 行为之间的遗传相关性，包括冲动，可卡因自我管理（IVSA），急性和 致敏可卡因诱导的运动激活和昼夜节律，以确定共同的遗传 特征之间共享的架构。我们还将研究CC株纹状体多巴胺（DA）信号的变化 对尼古丁表现出极端的行为反应其次，我们将尼古丁CPP行为与 基因表达的变化，以进一步确定潜在的候选基因，基因 网络和生物机制，可能介导青少年尼古丁暴露的影响。最后我们 将在早期暴露于尼古丁后，在大型DO队列中绘制CPP测试中的尼古丁奖励 青春期基因型数据将用于揭示青春期尼古丁特异性QTL，并确定 冲动、可卡因自我给药、可卡因致敏和昼夜节律之间共享的共同QTL 系统神经遗传学中心内的各种项目和核心产生的节律表型 上瘾。遗传作图数据沿着表达研究将用于鉴定候选基因， 通过基因组编辑技术制作的新型小鼠模型的验证研究。如果成功，这 应用有望通过识别对人类健康产生重大的积极影响， 遗传高风险个体将受益于尼古丁暴露后的积极干预， 青春期

PROJECT SUMMARY PROJECT 3 – ADOLESCENT NICOTINE Nicotine is one of the most commonly used drugs among adolescents. Several studies link tobacco and nicotine use in human adolescence and subsequent problems in adulthood, including later tobacco, alcohol, cocaine and other illicit drug use. Individuals who smoke cigarettes before the age of 15 are estimated to be eighty times more likely to use illegal drugs such as cocaine than those who do not. In addition, studies in animals have shown that adolescent nicotine exposure affects nicotine and cocaine reward and sensitivity in rodents; we have shown that repeated exposure to low doses of nicotine in adolescence clearly induces age- specific enhancement of the rewarding effects of nicotine and other drugs of abuse that persisted long after the termination of nicotine exposure. However, the molecular and genetic mechanisms underlining nicotine- induced enhancements to the reward effects are still unclear. This project will identify risk associated genes and gene networks using highly diverse mouse genetic populations. We will use inbred Collaborative Cross (CC)/ Diversity Outcross (DO) founder and CC strains to measure nicotine reward using the conditioned place preference (CPP) test after exposure to nicotine in early adolescence. These data will be used to conduct genetic correlations across behaviors including impulsivity, cocaine self-administration (IVSA), acute and sensitized cocaine induced locomotor activation and circadian rhythms to determine common genetic architecture shared among traits. We will also study changes in striatal dopamine (DA) signaling in CC strains that exhibit extreme behavioral responses to nicotine. Secondly, we will correlate nicotine CPP behaviors with gene expression changes in the striatum of CC mice to further identify potential candidate genes, gene networks and biological mechanisms that may mediate the effects of adolescent nicotine exposure. Finally, we will map nicotine reward in the CPP test in a large DO cohort after exposure to nicotine during early adolescence. Genotype data will be used to reveal QTLs specific to nicotine in adolescence as well as identify common QTLs shared between impulsivity, cocaine self-administration, cocaine sensitization and circadian rhythms phenotypes generated by the various projects and cores within the Center for Systems Neurogenetics of Addiction. Genetic mapping data along with expression studies will be used to identify candidate genes for validation studies in novel mouse models made through genome editing technologies. If successful, this application promises to have a significant positive impact on human health through the identification of genetically high-risk individuals who would benefit from proactive interventions following nicotine exposure in adolescence.