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.

项目概要 青少年吸烟是一个严重的公共卫生问题。早期开始吸烟是导致吸烟的一个关键因素 尼古丁依赖的发展和相关的心理健康问题。越来越多的证据表明 在这个发育的关键时期接触尼古丁可能会产生长期的认知后果。 小鼠模型是识别行为的神经和遗传基础的重要工具 在整个发育过程中对尼古丁暴露的反应，允许对时间过程进行实验控制， 遗传因素。该提案的主要目标是确定长期的性别和菌株变异性 青少年接触尼古丁对认知的影响。我们之前发现青少年 C57BL/6J 男性 根据情境恐惧条件评估，暴露于尼古丁的小鼠表现出长期认知缺陷， 成年期间。然而，遗传（即菌株）和性别对这些长期后果的影响 尚未对青少年尼古丁暴露情况进行调查。在这里，我们的目标是确定间应变 青少年接触尼古丁对长期认知影响的变异性 协作杂交 (CC)，一组源自八个遗传多样性近交系的重组自交系 菌株：五种经典近交菌株（A/J、C57BL/6J、129S1/SvImJ、NOD/ShiLtJ、NZO/HlLtJ）和三种野生菌株（CAST/EiJ、PWK/PhJ、WSB/EiJ）。 CC 组代表的遗传多样性远大于 以前的重组自交系面板，因此代表了遗传分析的前所未有的机会。 此外，吸烟行为以及吸烟对认知的影响存在性别差异；因此两者 将检查每个品系的雄性和雌性小鼠，以确定性别影响以及与品系的相互作用。 本提案中的研究将利用 CC 的创始人来描述近交系之间的表型差异 菌株（目标 1）并研究菌株内部和菌株之间的性别差异（目标 2）。该提案的目标是 证明使用 CC panel 进行长期正向遗传学图谱研究的可行性 青少年接触尼古丁的有害影响。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尚未得到充分研究 接触。最终，研究导致这些疾病易感性的遗传和神经生物学因素 长期后果可能有助于预防性治疗的发展。