Role of Habenula in Tobacco Addiction

缰核在烟草成瘾中的作用

• 批准号: 8270527
• 负责人: RAMIRO SALAS
• 金额: $ 12.95万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8270527
• 关键词: Affinity; Americas; Area; Attention; Behavior; Behavioral; Brain; Brain Part; Brain region; Cessation of life; Coupled; Coupling; Cues; Data; Data Set; Developed Countries; Development; Drosophila acetylcholine receptor alpha-subunit; Environment; Faculty; Functional Magnetic Resonance Imaging; Future; Genes; Genetic; Genetic Polymorphism; Genetic Techniques; Genotype; Goals; Grant; Habenula; Health; Human; Image; Imaging Techniques; Individual; Juice; Learning; Light; Link; Malignant neoplasm of lung; Mammals; Mediating; Mediator of activation protein; Medical; Mentored Research Scientist Development Award; Methods; Microdialysis; Molecular Target; Monkeys; Mus; Mutation; Neurons; Neuropathy; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Antagonists; Nicotinic Receptors; Nucleus Accumbens; Paper; Pattern; Pharmaceutical Preparations; Pharmacology; Play; Population; Relapse; Research; Research Personnel; Research Project Grants; Rewards; Risk; Role; Series; Single Nucleotide Polymorphism; Smoker; Study Subject; Subgroup; Substance Withdrawal Syndrome; System; Time; Tobacco; Tobacco Dependence; Tobacco smoke; Tobacco use; Variant; Visual; Withdrawal; Withdrawal Symptom; Work; Writing; addiction; base; brain research; cost; design; experience; genetic variant; genome wide association study; improved; in vivo; insight; interpeduncular nucleus; member; neuroimaging; non-smoker; novel strategies; public health relevance; research study; reward processing; smoking cessation; tobacco abuse

DESCRIPTION (provided by applicant): Description of Applicant's goals and Environment My long term goal is to become an independent investigator and to study neuronal mechanisms of addiction and related neuropathies. I had a postdoctoral experience in which I worked on mice with mutations on nicotinic receptors (nAChR), using behavior, in vivo pharmacology, microdialysis, etc. My current goal is to verify that the conclusions of my mouse research are applicable to humans. I will study whether certain nicotinic receptors in specific brain areas are critical for nicotine withdrawal symptoms in humans, as they are in mice. To that end, I moved to the Human Neuroimaging Lab in Baylor. This center has state of the art imaging facilities, being the only center of its kind in the world with five scanners devoted solely to brain research. In addition, there are in Baylor several faculty members with expertise on both tobacco addiction research and in several imaging techniques. My short term goal is to use functional magnetic resonance imaging (fMRI) in human smokers and non- smokers to study brain mechanisms of tobacco withdrawal with special attention to the habenula, a small brain region that I showed that in mice, is critical for nicotine withdrawal. During the K01 award, I plan to become proficient in imaging and genetic techniques, and to collect enough data to write an R01 grant and at least 3 papers. Description of Research Project Tobacco addiction is the number one cause of preventable death in America. Recent studies have linked certain genetic variants in a subgroup of nicotinic acetylcholine receptor subunits (13, 15 and 24) to tobacco addiction risk. I will use functional magnetic resonance imaging (fMRI) to study patterns of brain activity during passive learning in non smokers and in sated and abstinent smokers. In the passive learning task, the activity of the reward system is modulated while subjects learn a cue-reward relationship. This task allows for the study of both learning and reward processing, which are compromised in abstinent smokers. The 13, 15 and 24 subunits are highly expressed in the habenula, an area which has been recently shown to be a critical part of the reward system in mammals. In addition, we have shown that the habenula is necessary for nicotine withdrawal in mice. The study of the habenula in humans has been hampered by its small size, which makes it difficult to image it in fMRI studies. We have developed a method to study habenular activity in humans during the passive learning paradigm, and we are now capable of studying habenular activity related to tobacco use and withdrawal. In addition, I will genotype a series of single nucleotide polymorphisms in all studied subjects to correlate genetic background and tobacco-dependent habenular activity. These experiments will provide a mechanism for the increased risk of tobacco addiction carried by those genetic variants. In summary, I will study brain activity during nicotine withdrawal in a genetically defined population, with special emphasis on the reward system, including the habenula and dopaminergic areas. I hope that this data will open new avenues to help design genetic background-specific drugs to treat tobacco addiction. 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 and which genes are involved in tobacco abuse behavior and withdrawal symptoms.

我的长期目标是成为一名独立的研究人员，研究成瘾的神经机制和相关的神经疾病。我有一次博士后工作经历，我在尼古丁受体(NAChR)突变小鼠身上工作，使用行为学、体内药理学、微透析等方法。我目前的目标是验证我的小鼠研究结论是否适用于人类。我将研究特定大脑区域的某些尼古丁受体是否像老鼠一样，对人类的尼古丁戒断症状起关键作用。为此，我搬到了贝勒的人类神经成像实验室。该中心拥有最先进的成像设备，是世界上唯一一个拥有五台专门用于脑研究的扫描仪的中心。此外，贝勒有几名教职员工，他们在烟草成瘾研究和几种成像技术方面都有专长。我的短期目标是在吸烟者和不吸烟者身上使用功能磁共振成像(FMRI)来研究烟草戒断的大脑机制，特别是缰核，这是我在老鼠身上展示的一个小大脑区域，对尼古丁戒断至关重要。在K01奖项期间，我计划精通成像和基因技术，并收集足够的数据来写一份R01奖金和至少3篇论文。研究项目简介在美国，烟草成瘾是可预防的死亡的头号原因。最近的研究将烟碱型乙酰胆碱受体亚基亚基(13、15和24)中的某些基因变异与烟草成瘾风险联系起来。我将使用功能磁共振成像(FMRI)来研究非吸烟者、满足吸烟者和戒烟者在被动学习过程中的大脑活动模式。在被动学习任务中，奖赏系统的活动在被试学习线索-奖赏关系的同时受到调节。这项任务允许研究学习和奖励过程，这两个过程在戒烟者身上都受到了影响。13、15和24亚基在缰核高度表达，这一区域最近被证明是哺乳动物奖励系统的关键部分。此外，我们还证明缰核是小鼠戒断尼古丁所必需的。人类缰核的研究因其体积较小而受到阻碍，这使得在功能磁共振研究中很难对其进行成像。我们已经开发了一种方法来研究被动学习范式中人类的缰核活动，现在我们有能力研究与烟草使用和戒断有关的缰核活动。此外，我将在所有研究对象中对一系列单核苷酸多态进行基因分型，以将遗传背景与烟草依赖的缰核活性联系起来。这些实验将为这些基因变异带来的烟草成瘾风险增加提供一种机制。综上所述，我将研究尼古丁戒断过程中的大脑活动，特别强调奖励系统，包括缰核和多巴胺能区。我希望这些数据将开辟新的途径，帮助设计针对遗传背景的药物来治疗烟草成瘾。 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以及哪些基因与烟草滥用行为和戒断症状有关。