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

项目摘要 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 在这个关键的发展时期，尼古丁暴露可能会产生长期的认知后果。 小鼠模型是识别行为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，允许在时间过程中进行实验控制， 遗传因素本提案的主要目的是确定长期试验中的性别和菌株变异性。 青少年尼古丁暴露的认知影响。我们以前发现青少年C57 BL/6 J男性 暴露于尼古丁的小鼠表现出长期的认知缺陷，如通过情境恐惧条件反射评估的， 在成年期。然而，遗传（即应变）和性别对这些长期后果的影响， 尚未对青少年尼古丁暴露进行调查。在这里，我们的目标是确定 青少年尼古丁暴露的长期认知效应的变异性 协作杂交（CC），一组重组自交系，来自8个遗传多样的自交系 菌株：5个经典自交系（A/J、C57 BL/6 J、129 S1/SvImJ、NOD/ShiLtJ、NZO/HlLtJ）和3个野生衍生系（CAST/EiJ、PWK/PhJ、WSB/EiJ）。CC组代表了比其他组更大的遗传多样性。 先前的重组近交系组，因此代表了遗传分析的前所未有的机会。 此外，吸烟行为和吸烟对认知的影响存在性别差异;因此， 将检查每种品系的雄性和雌性小鼠，以确定性别效应和与品系的相互作用。 本提案中的研究将使用CC的创建者来表征近交系之间的表型差异 菌株（目的1），并调查性别差异内和跨菌株（目的2）。这项提案的目的是 证明使用CC面板进行长期正向遗传学作图研究的可行性 青少年尼古丁暴露的有害影响。这一建议是调查的重要一步 青少年尼古丁的长期后果的遗传基础研究不足的领域 exposure.最后，研究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。

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.