Functional Imaging of the Habenula in Tobacco Smokers

描述（由申请人提供）：烟草成瘾并发症是美国可预防死亡的头号原因。在小鼠中，烟碱乙酰胆碱受体（nAChR）的α 2、α 5和β 4（但不是β 2）亚基是尼古丁戒断所必需的。在人类中，α 3，α 5和β 4亚基的遗传变异与烟草成瘾风险有关。在脑中，这些亚基主要在缰核（Hb）及其主要靶点脚间核（ipn）中表达。微量注射烟碱受体阻滞剂到Hb或ipn，而不是在其他地区，沉淀尼古丁治疗小鼠的戒断症状。如果在人类身上也是如此，那么帮助人们戒烟的新药物疗法的设计应该从根本上改变焦点。我们建议使用功能磁共振成像研究在不同的吸烟条件下，人类的血红蛋白的激活。我们的假设是，缰核激活是尼古丁戒断的关键介质。我们将使用非常独特的感兴趣区域分析和高分辨率图像来专门研究Hb，因为该区域太小，使用通常应用于大脑其余部分的技术无法轻易看到。我们还将研究其他对成瘾很重要的区域的激活，如壳核。因此，我们将研究已知对成瘾重要的区域的活动如何与烟草戒断期间Hb的活动相关。我们的初步数据表明，在对照人群中，人类缰在负回报预测错误（即结果比预测的更糟糕）的时刻是活跃的，这与猴子的实验数据一致。我们将使用两种范式来激活满足、禁欲和不吸烟者的缰活动：使用果汁作为奖励的被动学习，以及受试者赚钱和赔钱的市场任务。 公共卫生相关性：烟草滥用是一种很难打破的行为模式，主要是因为戒断症状。为了帮助设计更好的反烟草滥用疗法，我们将研究大脑的哪些部分与烟草滥用行为和戒断症状有关。

DESCRIPTION (provided by applicant): Complications from tobacco addiction are the number one cause of preventable death in America. In mice, the alpha 2, alpha 5 and beta 4 (but not the beta 2) subunits of the nicotinic acetylcholine receptors (nAChR) are necessary for nicotine withdrawal. In humans, genetic variants in the alpha 3, alpha 5 and beta 4 subunits are associated with tobacco addiction risk. In the brain, these subunits are expressed mainly in the habenula (Hb) and its main target, the interpeduncular nucleus (ipn). Microinjection of nicotinic blockers into the Hb or the ipn, but not in other areas, precipitates withdrawal in nicotine treated mice. If the same is true in humans, the design of new pharmacotherapies to help people quit smoking should radically change focus. We propose to study the activation of the Hb in humans under different smoking conditions, by using fMRI. Our hypothesis is that habenular activation is a critical mediator of nicotine withdrawal. We will specifically study the Hb using a very unique region of interest analysis and high resolution images because this area is too small to be readily visible using the techniques usually applied to the rest of the brain. We will also study activation in other areas important for addiction such as the putamen. Thus, we will study how activity in areas known to be important for addiction, is related to activity in the Hb during tobacco withdrawal. Our preliminary data showed that in a control population, the human habenula is active at moments of negative reward prediction error (i.e. the outcome is worst than predicted) which is in agreement with data from experiments is monkeys. We will use two paradigms to activate habenular activity in sated, abstinent, and nonsmokers: passive learning using juice as reward, and a market task in which subjects gain and lose money. PUBLIC HEALTH RELEVANCE: Tobacco abuse is a behavioral pattern that is very difficult to break, mainly because of withdrawal symptoms. To help design better anti-tobacco abuse therapies, we will study which parts of the brain are involved in tobacco abuse behavior and withdrawal symptoms.