Identifying nicotine withdrawal mechanisms hidden within habenular complexity

项目总结 长期接触烟草产品中的尼古丁会导致许多健康后果(肺癌， 肺气肿、高血压等)每年造成600多万人死亡。复发率很高，在 那些试图戒烟的人和寻求促进戒烟的药物疗法都是有限的 有效性。因此，对治疗尼古丁依赖的更有效策略的需求仍未得到满足。 尼古丁暴露会产生身体依赖，身体和/或情感上的尼古丁戒断 症状--与尼古丁的有益效果相比--往往是导致 旧病复发。不幸的是，很少有研究探讨身体依赖和 尼古丁戒断机制。事实上，在我们对知识的理解方面存在着严重的差距 长期接触尼古丁如何建立身体依赖，从而使吸烟者高度依赖 易复发的易复发的在本项目中，我们将使用小鼠模型来研究内侧缰核(MHB)，一种小的 最近与尼古丁戒断有关的上丘脑区域，以及 表达非常高水平的几种类型的烟碱型乙酰胆碱受体(NAChRs)。NAChRs 调节尼古丁的精神活性和成瘾作用，我们打算确定相关的nAChRs和 MHB环路参与尼古丁依赖和戒断。三个独立相辅相成的目标 每一个都探讨了MHB中对尼古丁的反应的一个特定的机制方面。在……里面 目标1，我们将使用生物物理和光学技术来确定急性尼古丁通过什么机制 差异地激活MHB中的特定细胞类型。在AIM 2中，我们将使用类似的技术来确定 慢性尼古丁如何选择性地增强戒断路径特定亚回路中的神经元活性。 最后，在目标3中，我们将结合生理学技术和新的行为/系统方法来识别 在尼古丁过程中参与产生身体和/或情绪反应的重要MHB回路 戒烟。综合起来，这些目标将帮助我们解决理解尼古丁如何停止的问题 摄入会导致大脑产生令人厌恶的身体和情绪上的撤退反应，这不可避免地会导致 故态复萌。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.