CHILDREN AT RISK: HIGH FIELD MRI OF STIMULANT EFFECTS

描述(由申请人提供)： 这一修订的导师研究科学家发展奖(K01)是围绕三年的质子(1H)和碳(13C)磁共振波谱(MRS)培训、药物滥用研究以及接触正在接受药物滥用障碍治疗的临床青少年人口而设立的。 使用刺激性尼古丁的实验经常发生在儿童时期，并与健康风险增加和非法物质使用有关。青少年对尼古丁的依赖与第一次吸入香烟后出现的以下行为体征之一密切相关：放松、头晕和/或恶心(DiFranza等人，2004年)。这些行为迹象与尼古丁对脑干和小脑的影响是一致的，特别是前庭系统大量支配蚯蚓的区域，称为前庭小脑(VC)。这一区域富含谷氨酸(Glu)神经元，在条件化过程中整合来自上半身的内感感觉，并协调心血管脑干。大鼠小脑星形胶质细胞在体外尼古丁暴露下释放谷氨酸。人类的VC含有发育中的星形胶质细胞，这些星形胶质细胞会持续生长到成年早期。PET、MRS和体外研究表明，小脑组织对氧、谷氨酸和谷氨酰胺(Gin)的代谢需求较高，但己糖激酶活性较低。因此，尼古丁可以在发育过程中改变小脑神经胶质细胞与神经元的代谢关系。 候选人通过在4特斯拉学习进行1H-MRS，建议研究青少年VC中Glu、Gln和GABA浓度的变化。研究培训部分将在尼古丁依赖青少年中测试这一假设，即在尼古丁戒断过程中VC中的Glu浓度下降，并在30名(15M/15F)青少年吸烟者(当地高中14至17岁)接受尼古丁口香糖挑战后增加。30名不含尼古丁的对照受试者、匹配的饲料、性别和药物滥用家族史中的代谢物变化也将被研究。耶鲁大学在人类13C-MRS技术方面的额外培训，允许对神经元或星形胶质细胞中的大脑谷氨酸流量进行直接评估和代谢建模，建议用于未来研究尼古丁的特定发育影响。这项阶段性职业发展培训计划的核心，包括密集的MRS基础课程，以及在导师指导下进行青少年MRS研究的培训、药物成瘾研究方法、烟草治疗的专业培训，以及与药物依赖青少年的临床接触。 目前，很少有药物滥用研究人员具有发育神经科学的背景和对MRS的实际了解，MRS是一种非侵入性的、强大的工具，用于研究刺激剂暴露在人体内引起的神经递质变化。因此，这项应用为候选人提供了一个最佳的科学环境，用于培训、职业发展和专注于青少年尼古丁依赖这一长期问题的研究。

DESCRIPTION (provided by applicant): This revised Mentored Research Scientist Development Award (K01) is structured around 3-years of training in proton (1H)- and carbon (13C)-magnetic resonance spectroscopy (MRS), drug abuse research, and exposure to a clinical population of adolescents undergoing treatment for substance abuse disorders. Experimentation with the stimulant nicotine frequently occurs in childhood, and is associated with increased risks for health and illegal substance use. Adolescent nicotine dependence is strongly linked with the experience of one of the following behavioral signs after the first inhaled cigarette: increased relaxation, dizziness, and/or nausea (DiFranza et al., 2004). These behavioral signs are consistent with nicotine's effects on brainstem and cerebellum, particularly regions of the vermis heavily innervated by the vestibular system, called the vestibulocerebellum (VC). This region, enriched in glutamatergic (Glu) neurons, integrates interoceptive sensations from the upper body during conditioning and coordinates the cardiovascular brainstem. Rat cerebellar astrocytes release Glu upon nicotine exposure in vitro. The human VC contains developing astrocytes, which continue growth into early adulthood. PET, MRS and in vitro studies show that cerebellar tissue has high metabolic demands for oxygen, Glu and glutamine (Gin), but low hexokinase activity. Thus, nicotine could developmentally alter cerebellar glia-neuron metabolic relationships. The candidate, by learning to conduct 1H-MRS at 4 Tesla, proposes to study changes in Glu, Gln, and GABA concentrations in the adolescent VC. The research training component will test the hypothesis in nicotine dependent adolescents that Glu concentrations in the VC decline during nicotine withdrawal and increase after a nicotine-gum challenge in 30 (15M/15F) adolescent smokers (14 to 17 years from local area high schools). Metabolite variation in 30 nicotine-free comparison subjects, matched forage, sex, and family history of substance abuse will also be studied. Additional training at Yale University in human 13C-MRS techniques, which permit direct assessment and metabolic modeling of brain Glu flux in neurons or astrocytes, is proposed for future studies examining specific developmental effects of nicotine. Intensive course work in the fundamentals of MRS, coupled with mentor-guided training in conducting MRS studies of adolescents, drug addiction research methods, professional training in tobacco treatment, and clinical exposure to drug dependent adolescents form the core of this staged career development training plan. Currently, few substance abuse researchers have a background in developmental neuroscience and a practical understanding of MRS, a noninvasive, powerful tool to study neurotransmitter changes induced by stimulant exposure in humans. The application, therefore, provides the candidate with an optimal scientific environment for training, career development and research focused on the persistent problem of adolescent nicotine dependence.