Adolescent brains, nicotine and endogenous prototoxins

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）转化科学和特定的挑战主题，15- DA-110：确定青少年行为是否以及如何影响发育中大脑的连接。吸烟对健康的不利影响是一种世界性的流行病，每年造成400万人死亡，预计到2030年，全世界每年将增加到1 000万人。烟草依赖被视为一种“儿科疾病”，因为大多数人开始吸烟在青春期。青少年对尼古丁的成瘾作用表现出更大的敏感性，比成年人更快地依赖吸烟。研究还表明，从青少年开始吸烟的人吸烟更频繁，戒烟率更低。尽管有许多报告表明青少年大脑对尼古丁的敏感性更高，但这种更高敏感性的根本基础以及尼古丁暴露对大脑布线和神经化学的长期后果尚不清楚。大多数针对青少年的动物研究将尼古丁暴露的结局指标局限于单一方面，如行为、激动剂结合或电生理结局。此外，没有一项研究在单个神经元水平上检查基底前脑正常内源性胆碱能系统的可塑性变化，我们也不知道有任何研究将动物系统的信息与人类行为相结合。因此，这项挑战补助金是一项多学科方法，涉及动物行为，人类认知，遗传流行病学和分子细胞生物学领域的研究人员，以测试以下模型的有效性：青少年对尼古丁的敏感性增强是由于内源性胆碱能系统和烟碱乙酰胆碱受体（nAChRs）功能之间的不平衡。我们预测，从基底前脑到皮质和海马的胆碱能通路在青少年中尚未功能成熟，然而，过多的具有nAChR的末端与nAChR的原毒素调节剂水平降低相结合，使得外源性给予尼古丁导致增强奖赏通路的长期变化，同时阻止完全的胆碱能成熟，导致尼古丁在认知表现中的有益效果，从而加强尼古丁的使用。本申请的具体目的是：1）使用青少年和成年转基因Thy-1-eYFP小鼠，其显示尼古丁诱导的条件性位置，以确定是否发生第5层中eYFP标记的树突的树枝化的变化以及丘脑核中eYFP末端的变化;以确定是否发生胆碱能神经支配或多巴胺能与含eYFP的结构的相互作用的相关变化; 2）确定缺乏或仅携带一个拷贝的原毒素基因psca的小鼠是否对尼古丁表现出更大的生理和行为反应，并确定这是否与目的1中检查的参数相关; 3）对已经筛选并测试过冲动性、尼古丁暴露、和药物滥用，以确定原毒素基因的特定等位基因是否与冲动性增加或尼古丁依赖相关。 吸烟对健康的不利影响是一种世界性的流行病，每年导致400万人死亡。研究表明，从青少年开始吸烟的人吸烟更频繁，戒烟率更低。尽管有许多报告表明青少年大脑对尼古丁的敏感性更高，但这种更高敏感性的根本基础以及尼古丁暴露对大脑布线和神经化学的长期后果尚不清楚。更好地了解这些将导致可能的预防措施和治疗，对人类健康产生重大的长期影响。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15- DA-110: Determining if and how Adolescent Behaviors Affect Connections in the Developing Brain. The adverse impact of smoking on health is a world-wide epidemic that contributes to four million deaths a year, with an expected increase to 10 million per year world-wide by 2030. Tobacco dependence is viewed as a "pediatric disease" because most people begin smoking during adolescence. Adolescents display a greater sensitivity to the addictive effects of nicotine, becoming dependent upon smoking more rapidly than adults. Studies also show that smokers who began as adolescents smoke more frequently with a lower rate of quitting. Despite the many reports establishing a greater sensitivity of adolescent brains to nicotine, the fundamental basis of this greater sensitivity together with the long-term consequences of nicotine exposure on the wiring and neurochemistry of the brain is unknown. Most animal studies on adolescents have limited outcome measures of nicotine exposure to a single aspect such as behavior, agonist binding, or electrophysiological outcomes. Furthermore, none of the studies have examined plastic changes at the level of individual neurons with respect to the normal endogenous cholinergic system of the basal forebrain, and we know of no studies that integrate information from animal systems with human behavior. Thus, this Challenge Grant is a multidisciplinary approach that involves investigators from the fields of animal behavior, human cognition, genetic epidemiology, and molecular cell biology to test the validity of the following model: that the enhanced sensitivity of adolescents to nicotine is due to an imbalance between the endogenous cholinergic system and the function of nicotinic acetylcholine receptors (nAChRs). We predict that the cholinergic pathway from the basal forebrain to the cortex and hippocampus is not yet functionally mature in adolescents, yet an overabundance of terminals with nAChRs combined with a reduced level of prototoxin modulators of nAChRs allows exogenously administered nicotine to lead to long term changes that enhance reward pathways, while preventing full cholinergic maturation, leading to a beneficial effect of nicotine in cognitive performance that reinforces the use of nicotine. The specific aims of this application are: 1) to use adolescent and adult transgenic Thy-1-eYFP mice that demonstrate nicotine-induced conditioned place to determine whether changes in arborization of eYFP- labeled dendrites in layer 5 as well as changes in eYFP-terminals in nucleus accumbens occur; to determine if correlative changes in cholinergic innervation or dopaminergic interaction with eYFP-containing structures occur; 2) to determine whether mice that lack or carry only one copy of the prototoxin gene psca exhibit a greater physiological and behavioral response to nicotine and to determine whether this correlates with parameters examined in Aim 1; 3) to genotype human adolescent subjects that have been screened and tested for impulsivity, nicotine exposure, and drug abuse to determine whether specific alleles of prototoxin genes are correlated with increased impulsivity or nicotine dependence. PUBLIC HEALTH RELEVANCE: The adverse impact of smoking on health is a world-wide epidemic that contributes to four million deaths a year. Studies show that smokers who began as adolescents smoke more frequently with a lower rate of quitting. Despite the many reports establishing a greater sensitivity of adolescent brains to nicotine, the fundamental basis of this greater sensitivity together with the long-term consequences of nicotine exposure on the wiring and neurochemistry of the brain is unknown. A greater understanding of these will lead to possible preventive measures and therapies, having a significant long-term impact on human health.