The Role of Anxiety-Related Brain Circuits in Tobacco Dependence and Withdrawal

近5000万美国人吸烟，吸烟是过早死亡的主要原因， 残疾在美国。虽然从烟草使用到尼古丁依赖的转变与 在多种激励机制的持久变化中，大多数神经生物学研究都集中在奖励上， 相关系统。很少有人注意到大脑回路参与 戒断相关的负面影响这是不幸的-焦虑加剧是尼古丁的标志 有令人信服的证据表明，这种进化上保守的 戒断的特征强烈地激发尼古丁依赖和复发。啮齿类动物的机械工作， 我们小组的成像工作提出了一个假设，即退缩增强的焦虑反映了一个 神经回路包括终纹床核（BNST）、前腹核（AI）和中腹核。 扣带皮层（MCC）。但是，这种回路与人类戒断的相关性尚未得到探索， 未知利用我们团队独特的多学科专业知识，本提案的目标是使用 先进的功能磁共振成像分析技术与基于移动的手机的生态瞬间的创新结合 评估（EMA），以了解，第一次，焦虑相关的大脑回路的相关性，慢性 戒烟者的烟草使用和尼古丁急性戒断。功能磁共振成像将用于分析焦虑相关的 24小时戒烟组和非戒烟组的激活和功能连接 吸烟者（n=36/组;一半女性）。EMA将用于分析应激源暴露、负面影响、吸烟 冲动/渴望，酒精/物质使用和吸烟14天（5次/天），包括24小时内 在功能性磁共振成像会议之前立即退出。这些数据将使我们能够系统地了解 焦虑相关脑回路与以下因素的相关性：（1）急性尼古丁戒断和（2） 真实的世界中的情绪和行为。这些目标与NIDA战略计划密切一致。 实现第一个目标将提供一个前所未有的机会， 突出成瘾神经生物学模型的相关性，指导双向发展 尼古丁依赖的翻译模型，在电路水平上识别新的生物靶点，并告知 开发新的戒烟辅助工具。解决第二个目标将完善我们对病因学的理解， 为行为治疗提供新的目标，并为基于移动的电话的干预措施的发展提供信息。 了解焦虑相关的大脑回路在戒断中的作用，对于旨在减少焦虑的努力至关重要。 烟草依赖造成的巨大痛苦和经济负担。

Nearly 50 million Americans smoke tobacco and smoking is the leading cause of premature death and disability in the US. Although the transition from tobacco use to nicotine dependence is associated with enduring changes in multiple motivational mechanisms, most neurobiological research has focused on reward- related systems. Very little attention has been devoted to understanding the brain circuits involved in withdrawal-related negative affect in humans. This is unfortunate—heightened anxiety is a hallmark of nicotine deprivation in both rodents and humans and there is compelling evidence that this evolutionarily-conserved feature of withdrawal powerfully motivates nicotine dependence and relapse. Mechanistic work in rodents and imaging work by our group suggests the hypothesis that withdrawal-potentiated anxiety reflects alterations in a neural circuit encompassing the bed nucleus of the stria terminalis (BNST), anterior insula (AI), and mid- cingulate cortex (MCC). But the relevance of this circuitry to withdrawal in humans is unexplored and remains unknown. Leveraging our team's unique multi-disciplinary expertise, the goal of this proposal is to use an innovative combination of advanced fMRI analytic techniques and mobile phone-based ecological momentary assessment (EMA) to understand, for the first time, the relevance of anxiety-related brain circuits to chronic tobacco use and acute nicotine withdrawal in abstinent smokers. fMRI will be used to assay anxiety-related activation and functional connectivity in well matched groups of 24-hour abstinent and non-abstinent tobacco smokers (n=36/group; half female). EMA will be used to assay stressor exposure, negative affect, smoking urge/craving, alcohol/substance use, and smoking for 14 days (5x/day), including the 24-hour period of withdrawal immediately prior to the fMRI session. These data would enable us to systematically understand the relevance of anxiety-related brain circuits to: (1) acute nicotine withdrawal and (2) clinically-relevant features of mood and behavior in the real world. These objectives are closely aligned with the NIDA Strategic Plan. Addressing the first objective would afford an unprecedented opportunity to examine the translational relevance of prominent neurobiological models of addiction, guide the development of bidirectional translational models of nicotine dependence, identify new biological targets at the circuit level, and inform the develop of novel cessation aids. Addressing the second objective would refine our understanding of etiology, provide new targets for behavioral therapy, and inform the development of mobile phone-based interventions. Understanding the role of anxiety-related brain circuits in withdrawal is critical for efforts aimed at reducing the tremendous suffering and economic burden caused by tobacco dependence.