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：
8950029
负责人：
JERRY A STITZEL
金额：
$ 22.38万
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 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8950029
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 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 public health relevance 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（由适用提供）：尽管警告怀孕期间烟草使用的致病作用，但估计表明，美国所有孕妇中有15％至30％的烟雾。这导致每年有70万儿童在子宫内构成烟草。在尼古丁尼古丁暴露的尼古丁尼古丁暴露的众多负面结果中，尼古丁依赖性的风险增加了3-5倍。啮齿动物的研究支持了这样的发现，即发展尼古丁暴露会增加负面结果，包括增加尼古丁消耗的风险。尚未阐明子宫内暴露儿童吸烟率增加的基础机制。但是，在怀孕期间最容易继续吸烟的女性是尼古丁依赖性遗传风险升高的女性。因此，尼古丁在后代的依赖风险升高可能是由于遗传的风险因素，子宫曝光或两者兼而有之。我们的实验室最近开发了一种小鼠模型，该模型携带了一个名为ChRNA5的基因中的人类遗传变异。重要的是，对于此应用，具有该基因的风险版本的女性在怀孕期间不太可能停止吸烟。来自小鼠模型的初步数据表明，具有该基因风险版本并暴露于子宫内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额外作用。然而，与其基因型相匹配的对照组相比，与非风险变体相比，与尼古丁的非风险变体相比，它与尼古丁的尼古丁摄入量显着降低，令人惊讶地出乎意料的是尼古丁的非风险变体的后代。这一新颖的发现表明，发育性尼古丁暴露对随后的尼古丁摄入风险的影响方向取决于基因型，并且挑战了单独的产前尼古丁暴露是尼古丁依赖性的危险因素。为了更好地理解基因型和发展性尼古丁的暴露如何与大大改变结果相互作用，该Explorer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/和对尼古丁的厌恶，因此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于尼古丁摄入的相互作用是否归因于后代的基因型。另外，我们了解基因型如何改变发展性尼古丁对尼古丁奖励的影响和调节这些行为的大脑回路的影响将为行为和神经生理学机制提供独特的见解，从而改变了产前尼古丁暴露会改变尼古丁依赖性的风险。