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Role of Chrna5 genotype on outcomes of developmental nicotine exposure

Chrna5 基因型对发育期尼古丁暴露结果的作用

基本信息

批准号：
9086317
负责人：
JERRY A STITZEL
金额：
$ 19.06万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9086317
关键词：
Acetylcholine Address Adolescence Adolescent Affect Amino Acids Area Behavior Behavioral Brain Child Consumption Data Development Environment Exhibits Exposure to Genes Genetic Genetic Polymorphism Genetic Risk Genetic Variation Genotype Goals Habenula Health Heterozygote Human Human Genetics Inherited Intake Investigation Laboratories Lateral Measures Mediating Morphology Mothers Mus Names Neurons Nicotine Nicotine Dependence Nicotinic Receptors Nucleus Accumbens Outcome Pathway interactions Perinatal Exposure Pharmaceutical Preparations Play Pregnancy Pregnant Women Property Protein Subunits Pyramidal Cells Reporting Rewards Risk Risk Factors Rodent Role Smoke Smoker Smoking Structure Testing Tobacco Tobacco use Variant Woman conditioning fetal tobacco exposure genetic variant hippocampal pyramidal neuron in utero insight motivated behavior mouse model neurophysiology novel offspring pregnant research study response risk variant smoking cessation

项目摘要

DESCRIPTION (provided by applicant): Despite warnings of the teratogenic effects of tobacco use during pregnancy, estimates show that between 15 and 30% of all pregnant women in the US smoke. This leads to an alarming 700,000 children each year that are exposed to tobacco constituents in utero. Among the many reported negative outcomes of in utero nicotine exposure is a 3-5 fold elevated risk for the development of nicotine dependence. Rodent studies have supported the findings that developmental nicotine exposure increases negative outcomes, including increased risk for nicotine consumption. The mechanism(s) underlying the increased rate of smoking among in utero exposed children have not been elucidated. However, the women most prone to continue smoking during pregnancy are those at elevated genetic risk for nicotine dependence. Therefore, the elevated risk of nicotine dependence in their offspring could be due to inherited risk factors, in utero exposure, or both. Our laboratory recently has developed a mouse model that carries a human genetic variation in a gene named CHRNA5. Importantly for this application, women who have the risk version of this gene are less likely to stop smoking during pregnancy. Preliminary data from the mouse model indicate that mice with the risk version of the gene and exposed to nicotine in utero will consume the highest levels of nicotine suggesting an additive effect of genetic risk and environment. Strikingly and unexpectedly, however, offspring with the non-risk variant that were developmentally exposed to nicotine exhibited a dramatic reduction in nicotine intake during adolescence as compared to their genotype matched controls. This novel finding indicates that the direction of effect of developmental nicotine exposure on subsequent risk for nicotine intake is genotype dependent and challenges the notion that prenatal nicotine exposure alone is a risk factor for the development of nicotine dependence. To better appreciate how genotype and developmental nicotine exposure interact to dramatically alter outcomes, this exploratory project proposes two specific aims. Because alterations in nicotine consumption can be through altered reward or/and aversion to nicotine, we will determine the impact of nicotine exposure and genotype on these motivated behaviors. We also will assess whether the interaction between genotype and nicotine exposure to alter nicotine intake is due to the genotype of the offspring. In addition, we will assess the effect of genotype and prenatal nicotine exposure on the functional properties and structure of layer VI prefrontal cortical pyramidal cells that project to select brain areas relevant to reward and aversion. Understanding how genotype modifies the effect of developmental nicotine exposure on nicotine reward and brain circuits that modulate these behaviors will provide unique insight into the behavioral and neurophysiological mechanisms through which prenatal nicotine exposure alters risk for nicotine dependence.

描述（由申请人提供）：尽管妊娠期间使用烟草的致畸作用的警告，估计显示，在美国所有孕妇吸烟的15%至30%之间。这导致每年有70万儿童在子宫内暴露于烟草成分。在许多报告的子宫内尼古丁暴露的负面结果中，尼古丁依赖的发生风险增加了3-5倍。啮齿类动物研究支持发育中的尼古丁暴露会增加负面结果的发现，包括尼古丁摄入风险增加。子宫内暴露儿童吸烟率增加的潜在机制尚未阐明。然而，最容易在怀孕期间继续吸烟的女性是那些尼古丁依赖遗传风险较高的女性。因此，他们后代尼古丁依赖的风险升高可能是由于遗传风险因素、子宫内暴露或两者兼而有之。我们的实验室最近开发了一种小鼠模型，该模型在名为CHRNA 5的基因中携带人类遗传变异。对于这种应用来说，重要的是，具有这种基因风险版本的女性在怀孕期间戒烟的可能性较小。来自小鼠模型的初步数据表明，具有该基因风险版本并在子宫内暴露于尼古丁的小鼠将消耗最高水平的尼古丁，这表明遗传风险和环境的叠加效应。然而，令人惊讶和意外的是，与基因型匹配的对照组相比，发育暴露于尼古丁的非风险变体的后代在青春期表现出尼古丁摄入量的显著减少。这一新的发现表明，发育尼古丁暴露对随后尼古丁摄入风险的影响方向是基因型依赖性的，并挑战了产前尼古丁暴露单独是尼古丁依赖发展的风险因素的观点。为了更好地理解基因型和发育尼古丁暴露如何相互作用以显著改变结果，这个探索性项目提出了两个具体目标。由于尼古丁消耗的改变可以通过改变奖励或/和厌恶尼古丁，我们将确定尼古丁暴露和基因型对这些动机行为的影响。我们还将评估基因型和尼古丁暴露之间的相互作用是否改变尼古丁摄入量是由于后代的基因型。另外我们将评估基因型和产前尼古丁暴露对第六层前额叶皮质锥体细胞功能特性和结构的影响，这些细胞投射到选择与奖赏和厌恶相关的大脑区域。了解基因型如何改变发育尼古丁暴露对尼古丁奖励和调节这些行为的大脑回路的影响，将为产前尼古丁暴露改变尼古丁依赖风险的行为和神经生理机制提供独特的见解。