Identifying nicotine withdrawal mechanisms hidden within habenular complexity

项目摘要 长期接触烟草制品中的尼古丁会导致许多健康后果（肺癌， 肺气肿、高血压等）每年有超过600万人因此死亡复发率很高， 那些试图戒烟的人，以及寻求促进戒烟的药物治疗， 有效性因此，对于治疗尼古丁依赖的更有效的策略存在显著未满足的需求。 尼古丁暴露会产生身体依赖性，身体和/或情绪上的尼古丁戒断 症状-与尼古丁的奖励作用相比-通常是最重要的贡献者， 复发不幸的是，很少有研究探讨了身体依赖这一重要问题， 尼古丁戒断机制事实上，在我们对以下问题的理解方面存在着重大的知识差距： 慢性尼古丁暴露如何建立身体依赖性，从而使吸烟者高度 容易复发在这个项目中，我们将使用小鼠模型来研究内侧缰（MHB），一个小的 上丘脑区域的大脑区域，最近与尼古丁戒断有关， 表达非常高水平的几种类型的烟碱乙酰胆碱受体（nAChR）。nAChRs 调节尼古丁的精神活性和成瘾作用，我们打算鉴定相关的nAChR， MHB回路参与尼古丁依赖和戒断。三个独立和互补的目标 提出，其中每一个探针的具体机制方面的反应，尼古丁在MHB。在 目的1，我们将使用生物物理和光学技术，以确定通过什么机制急性尼古丁 差异激活MHB中的特定细胞类型。在AIM 2中，我们将采用类似的技术来确定 慢性尼古丁如何选择性地增强戒断途径特定子回路中的神经元活动。 最后，在AIM 3中，我们将把生理学技术与一种新的行为/系统方法结合起来， 参与尼古丁摄入期间产生身体和/或情绪反应的重要MHB回路 戒断总之，这些目标将帮助我们解决问题，了解如何停止尼古丁 摄入会导致大脑产生令人厌恶的身体和情感戒断反应， 复发。解决这个问题可能会导致新的策略或药物来促进戒烟。

PROJECT SUMMARY Chronic exposure to nicotine in tobacco products results in numerous health consequences (lung cancer, emphysema, hypertension, etc.) and accounts for over 6 million deaths per year. Relapse rates are high among those who attempt to quit smoking, and pharmacotherapies that seek to foster smoking cessation have limited effectiveness. Thus, there is a significant unmet need for more effective strategies to treat nicotine dependence. Nicotine exposure produces physical dependence, and the physical and/or emotional nicotine withdrawal symptoms – as compared to the rewarding effects of nicotine – are often the most important contributors to relapse. Unfortunately, few research studies have probed the important question of physical dependence and nicotine withdrawal mechanisms. Indeed, a critical gap in knowledge exists regarding our understanding of how chronic nicotine exposure establishes physical dependence and therefore makes smokers highly susceptible to relapse. In this project, we will use mouse models to study the medial habenula (MHB), a small brain area in the epithalamic region that has recently been implicated in nicotine withdrawal, and which expresses extraordinarily high levels of several types of nicotinic acetylcholine receptors (nAChRs). nAChRs mediate the psychoactive and addictive action of nicotine, and we intend to identify the relevant nAChRs and MHB circuits involved in nicotine dependence and withdrawal. Three independent and complementary AIMs are proposed, each of which probes a specific mechanistic aspect of the response to nicotine in the MHB. In AIM 1, we will use biophysical and optical techniques to determine through what mechanisms acute nicotine differentially activates specific cell types in MHB. In AIM 2, we will employ similar techniques to determine how chronic nicotine selectively enhances neuronal activity in a specific sub-circuit of the withdrawal pathway. Finally, in AIM 3, we will couple physiology techniques with a novel behavioral/systems approach to identify important MHB circuits involved in generating physical and/or emotional responses during nicotine withdrawal. Together, these AIMs will help us solve the problem of understanding how cessation of nicotine intake causes the brain to generate aversive physical and emotional withdrawal responses that inevitably lead to relapse. Solving this problem could lead to new strategies or drugs to foster smoking cessation.