Interstrain variability in long-term cognitive effects of adolescent nicotine exposure

青少年接触尼古丁对长期认知影响的不同种间变异

• 批准号: 9978032
• 负责人: Thomas J Gould
• 金额: $ 7.99万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978032
• 关键词: Address; Adolescence; Adolescent; Adult; Age; Alcohol or Other Drugs use; Alleles; Anxiety; Area; Behavior; Behavioral; Brain; Chromosome Mapping; Chronic; Cigarette; Cognition; Cognitive; Cognitive deficits; Cotinine; Data; Data Set; Databases; Development; Drug abuse; Estrogens; Exposure to; Female; Foundations; Genes; Genetic; Genetic Variation; Genetic study; Goals; Heritability; Hippocampus (Brain); Impaired cognition; Inbred Strain; Inbreeding; Learning; Link; Longitudinal Studies; Measures; Mental Health; Metabolism; Motor Activity; Mus; Neurobiology; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Parents; Phenotype; Predisposition; Preventive treatment; Public Health; Rattus; Recombinant Inbred Strain; Recombinants; Sex Differences; Smoke; Smoker; Smoking; Smoking Behavior; Substance abuse problem; Time; Twin Multiple Birth; United States; Variant; Withdrawal; Youth; addiction; adolescent smoking; behavioral response; cognitive function; conditioned fear; critical period; drug of abuse; electronic cigarette use; environmental tobacco smoke; forward genetics; genetic analysis; genetic variant; genotypic sex; high risk; male; mouse genome; mouse model; nicotine exposure; nicotine use; phenome; relating to nervous system; sex; tool; trait

PROJECT SUMMARY Adolescent smoking is a serious public health concern. Earlier initiation of smoking is a key factor in the development of nicotine dependence and associated mental health problems. Increasing evidence suggests that nicotine exposure during this critical period of development may have long-term cognitive consequences. Mouse models represent an important tool for identifying neural and genetic underpinnings of behavioral response to nicotine exposure across development, permitting experimental control over time course and genetic factors. The primary objective of this proposal is to identify sex and strain variability in long-term cognitive effects of adolescent nicotine exposure. We previously identified that adolescent C57BL/6J male mice exposed to nicotine display long-term cognitive deficits, as assessed by contextual fear conditioning, during adulthood. However, the effect of genetics (i.e. strain) and sex on these long-term consequences of adolescent nicotine exposure have not yet been investigated. Here, we aim to determine the interstrain variability in long-term cognitive effects of adolescent nicotine exposure in the founder strains of the Collaborative Cross (CC), a panel of recombinant inbred lines derived from eight genetically diverse inbred strains: five classical inbred strains (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ) and three wild-derived strains (CAST/EiJ, PWK/PhJ, WSB/EiJ). The CC panel represents far greater genetic diversity than previous recombinant inbred panels, and thus, represents an unprecedented opportunity for genetic analyses. Additionally, sex differences exist in smoking behaviors and the impact of smoking on cognition; therefore both male and female mice from each strain will be examined to identify sex effects and interactions with strain. Studies in this proposal will use the founders of the CC to characterize phenotypic differences across inbred strains (Aim 1) and to investigate sex differences within and across strains (Aim 2). The goal of this proposal is to demonstrate feasibility of using the CC panel for a forward genetics mapping study of the long-term detrimental effects of adolescent nicotine exposure. This proposal represents an important step in investigating an understudied area of the genetic underpinnings of the long-term consequences of adolescent nicotine exposure. Ultimately, investigating the genetic and neurobiological factors that underlie susceptibility to these long-term consequences may aid in the development of preventative treatments.

项目摘要 青少年吸烟是一个严重的公共健康问题。早期吸烟是一个关键因素 尼古丁依赖性和相关心理健康问题的发展。越来越多的证据表明 在这个关键发展期间，尼古丁的暴露可能会带来长期的认知后果。 鼠标模型代表了识别行为的神经和遗传基础的重要工具 对整个开发中尼古丁暴露的反应，允许对时间过程进行实验控制和 遗传因素。该提案的主要目的是长期确定性别和应变变异性 青少年尼古丁暴露的认知作用。我们先前确定了青少年C57BL/6J男性 暴露于尼古丁的小鼠表现出长期的认知缺陷，如上下文恐惧调节所评估， 在成年期。但是，遗传学（即菌株）和性别对这些长期后果的影响 青少年尼古丁暴露尚未研究。在这里，我们旨在确定跨境 青少年尼古丁暴露在创始人菌株中的长期认知效应的可变性 协作十字架（CC），一个重组近交系的小组，源自八个遗传多样的近交易 菌株：五种经典的近交菌株（A/J，C57BL/6J，129S1/SVIMJ，nod/shiltj，nzo/hlltj）和三个野生菌株（Cast/eij，pwk/phj，phj，wsb/eij）。 CC面板代表的遗传多样性要大得多 以前的重组近交易合板，因此代表了遗传分析的前所未有的机会。 此外，吸烟行为中存在性别差异以及吸烟对认知的影响。因此，这两者兼而有之 将检查来自每种菌株的雄性和雌性小鼠，以识别与菌株的性别影响和相互作用。 该提案中的研究将使用CC的创始人来表征近交的表型差异 菌株（AIM 1）并调查菌株内部和跨菌株之间的性别差异（AIM 2）。该提议的目的是 为了证明使用CC面板进行长期的正向遗传学映射研究的可行性 青春期尼古丁暴露的有害影响。该提案代表了调查的重要一步 青少年尼古丁长期后果的遗传基础的研究区域 接触。最终，研究了对这些敏感性的基础的遗传和神经生物学因素 长期后果可能有助于开发预防治疗。