Role of Habenula in Tobacco Addiction

我的长期目标是成为一名独立的研究者，研究成瘾和相关神经病的神经元机制。我有一个博士后的经历，我研究了尼古丁受体（nAChR）突变的老鼠，使用行为学，体内药理学，微透析等。我目前的目标是验证我在小鼠研究中的结论是否适用于人类。我将研究大脑特定区域的某些尼古丁受体是否对人类的尼古丁戒断症状至关重要，就像它们在老鼠身上一样。为此，我搬到了贝勒大学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5台专门用于大脑研究的扫描仪的中心。此外，贝勒大学还有几位在烟草成瘾研究和几种成像技术方面都有专长的教员。我的短期目标是利用功能性磁共振成像（fMRI）在人类吸烟者和非吸烟者身上研究烟草戒断的大脑机制，特别关注habenula，一个小的大脑区域，我在老鼠身上展示过，对尼古丁戒断至关重要。在K01奖期间，我计划熟练掌握成像和遗传技术，并收集足够的数据来撰写R01基金和至少3篇论文。烟草成瘾是美国可预防性死亡的头号原因。最近的研究已经将尼古丁乙酰胆碱受体亚基（13、15和24）亚群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在被动学习期间的大脑活动模式。在被动学习任务中，当被试学习线索-奖励关系时，奖励系统的活动被调节。这项任务允许研究学习和奖励处理，这在戒烟者中是受损的。13,15和24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，我们已经证明缰对小鼠的尼古丁戒断是必要的。人类habenula的研究一直受到其小尺寸的阻碍，这使得在功能磁共振成像研究中难以成像。我们已经开发了一种方法来研究人类被动学习范式中的habenular活动，我们现在能够研究与烟草使用和戒断有关的habenular活动。此外，我将对所有研究对象的一系列单核苷酸多态性进行基因分型，以将遗传背景与烟草依赖的habenular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。总之，我将研究尼古丁戒断期间的大脑活动，在基因上确定的人群中，特别强调奖励系统，包括缰核和多巴胺能区域。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。

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.