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.

描述（由申请人提供）：申请人的目标和环境的描述我的长期目标是成为独立研究者，并研究成瘾和相关神经病的神经元机制。我有一种博士后经验，我在烟碱受体（NACHR），使用行为，体内药理学，微透析等的小鼠上工作。我目前的目标是验证我的小鼠研究的结论是否适用于人类。我将研究特定大脑区域的某些烟碱受体是否对人类中的尼古丁戒断症状至关重要。为此，我搬到了贝勒的人类神经影像实验室。该中心具有最先进的成像设施，是世界上唯一的同类中心，其中五个扫描仪仅专门用于大脑研究。此外，在贝勒（Baylor）中，有几位在烟草成瘾研究和多种成像技术方面具有专业知识的教职员工。我的短期目标是在人类吸烟者和非吸烟者中使用功能磁共振成像（fMRI）研究烟草戒断的大脑机制，并特别注意Habenula，这是我在小鼠中表明的一个小脑部区域，这对于尼古丁戒断至关重要。在K01奖励期间，我计划熟练成像和遗传技术，并收集足够的数据来撰写R01赠款和至少3篇论文。 研究项目的描述烟草成瘾是美国可预防死亡的第一原因。最近的研究已将烟碱乙酰胆碱受体亚基（13、15和24）亚组中的某些遗传变异与烟草成瘾风险联系起来。 我将使用功能性磁共振成像（fMRI）来研究非吸烟者和戒烟者中被动学习期间的大脑活动模式。在被动学习任务中，在受试者学习提示奖励关系的同时，调制了奖励系统的活动。这项任务允许研究学习和奖励处理，这些处理在戒烟者中受到损害。 13、15和24个亚基在Habenula中高度表达，该区域最近被证明是哺乳动物奖励系统的关键部分。此外，我们已经表明，在小鼠中，尼古丁戒断是必需的。对人类中的Habenula的研究受到其小规模的阻碍，这使得在fMRI研究中很难对其进行想象。我们已经开发了一种在被动学习范式期间研究人类中人类活性的方法，现在我们能够研究与烟草使用和戒断有关的Habenular活动。 此外，我还将在所有研究的受试者中基因型一系列单核苷酸多态性，以相关遗传背景和烟草依赖性的超单活性。这些实验将为这些遗传变异携带的烟草成瘾风险增加提供一种机制。 总而言之，我将在遗传定义的人群中研究尼古丁戒断期间的大脑活动，并特别着重于奖励系统，包括Habenula和Dobaminergic地区。我希望这些数据将开辟新的途径，以帮助设计遗传背景特异性药物来治疗烟草成瘾。 公共卫生相关性：烟草滥用是一种非常难以破坏的行为模式，这主要是由于戒断症状。为了帮助设计更好的抗烟科滥用疗法，我们将研究大脑的哪些部分以及哪些基因参与烟草滥用行为和戒断症状。