CHILDREN AT RISK: HIGH FIELD MRI OF STIMULANT EFFECTS

描述（由申请人提供）： 这个修订后的指导研究科学家发展奖（K 01）是围绕质子（1H）和碳（13 C）-磁共振光谱（MRS），药物滥用研究，并暴露于正在接受药物滥用障碍治疗的青少年临床人群的3年培训。 儿童时期经常尝试尼古丁刺激剂，这与健康风险增加和非法物质使用有关。青少年尼古丁依赖与第一次吸入香烟后以下行为体征之一的经历密切相关：放松增加、头晕和/或恶心（DiFranza等人，2004年）。这些行为体征与尼古丁对脑干和小脑的影响一致，特别是受前庭系统严重支配的蚓部区域，称为前庭小脑（VC）。该区域富含谷氨酸能（Glu）神经元，在条件反射期间整合来自上身的内感受性感觉，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后释放Glu。人类VC包含发育中的星形胶质细胞，其持续生长至成年早期。PET、MRS和体外研究表明，小脑组织对氧、Glu和谷氨酰胺（Gln）有较高的代谢需求，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-神经元的代谢关系。 候选人通过学习在4特斯拉下进行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检验假设，即在尼古丁戒断期间VC中的Glu浓度下降，并在30名（15 M/15 F）青少年吸烟者（14至17岁，来自当地高中）中进行尼古丁口香糖挑战后升高。还将研究30名无尼古丁对照受试者、匹配饲料、性别和药物滥用家族史的代谢物变异。在耶鲁大学进行的人类13 C-MRS技术的额外培训，允许直接评估和神经元或星形胶质细胞中大脑Glu通量的代谢建模，建议用于未来研究尼古丁的特定发育影响。在MRS的基础知识密集的课程工作，再加上导师指导的培训进行MRS研究的青少年，药物成瘾的研究方法，在烟草治疗的专业培训，和临床接触药物依赖的青少年形成这个阶段的职业发展培训计划的核心。 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的实际理解，MRS是一种非侵入性的，强大的工具，用于研究人类刺激剂暴露引起的神经递质变化。因此，该申请为候选人提供了一个最佳的科学环境，用于培训，职业发展和研究，重点是青少年尼古丁依赖的持续问题。

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.