The mesointerpeduncular circuit in anxiety and nicotine withdrawal

焦虑和尼古丁戒断中的中脚间回路

• 批准号: 10087907
• 负责人: ANDREW R TAPPER
• 金额: $ 33.5万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10087907
• 关键词: Action Potentials; Affective; Anatomy; Anxiety; Behavior; Brain; Brain region; Cessation of life; Chronic; Cognitive deficits; Data; Development; Dopamine; Electrophysiology (science); Face; Foundations; Gene Delivery; Glutamates; Goals; Habenula; Halorhodopsins; Hand; Health; Label; Light; Link; Measures; Medial; Mediating; Mental Depression; Molecular; Molecular Biology; Mus; Neurons; Neurotransmitters; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Population; Psychological reinforcement; Publishing; Receptor Activation; Receptor Signaling; Relapse; Research; Reverse Transcriptase Polymerase Chain Reaction; Rewards; Rodent; Role; Slice; Smoker; Smoking; Smoking Cessation Intervention; Substance Withdrawal Syndrome; Sweating; Synapses; System; Testing; Tobacco use; Ventral Tegmental Area; Viral; Withdrawal Symptom; Work; anxiety treatment; anxiety-like behavior; biophysical techniques; cholinergic; dopaminergic neuron; driving force; environmental tobacco smoke exposure; experimental study; foot; insight; neural circuit; nicotine exposure; nicotine replacement; nicotine reward; novel; novel strategies; novel therapeutics; optogenetics; patch clamp; preventable death; receptor; receptor expression; recombinase-mediated cassette exchange; response; selective expression; smoking cessation

Project Summary/Abstract Chronic exposure to tobacco smoke accounts for ~6 million deaths per year making health complications from smoking the primary cause of preventable mortality in the world. Current smoking cessation aids including nicotine replacement therapy and medication that target nicotinic receptors are minimally effective. Thus, a better understanding of brain regions, neural circuits, and neurotransmitter systems that underlie nicotine withdrawal syndrome is needed to facilitate the development of new therapies for smoking cessation. While dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) that project to the nucleus accumbens are critical for nicotine reward and reinforcement, recent studies have identified the habenulo-interpeduncular (Hb- IPN) axis as a critical circuit in nicotine withdrawal symptoms. In particular, the IPN is implicated in increased anxiety during nicotine withdrawal in rodents and receives inputs from cholinergic/glutamatergic medial habenula neurons associated with affective behavior. Interestingly, we have identified a novel circuit consisting of VTA neurons that project to the IPN, the mesointerpeduncular pathway. Our data indicate that DA from VTA afferents may innervate the IPN to modulate neuronal activity and anxiety-like behavior via DA receptor signaling. In addition, DA receptor expression in the IPN appears to be regulated by chronic nicotine exposure. These observations provide the foundation for this application. We propose to test the hypothesis that VTA DAergic neurons that project to the IPN modulate anxiety and are critical for increased anxiety during nicotine withdrawal. In Aim 1, we propose to use molecular and biophysical approaches to test the hypothesis that DA controls IPN neuronal activity through activation of DA receptors that are regulated by nicotine. In Aim 2, we will use pharmacology, optogenetics, and biophysical approaches to test the hypothesis that the IPN receives DA input from the VTA. Finally, in Aim 3 we will use pharmacology, optogenetics, and behavior to test the hypothesis that the mesointerpeduncular circuit modulates anxiety-like behavior at baseline and during nicotine withdrawal. It is anticipated that understanding the role of the mesointerpeduncular circuit in anxiety and nicotine withdrawal will provide novel strategies to alleviate anxiety and nicotine withdrawal symptoms.

项目摘要/摘要 长期暴露在烟草烟雾中每年造成约600万人死亡，造成健康并发症 吸烟是世界上可预防的死亡的主要原因。目前的戒烟辅助工具包括 尼古丁替代疗法和针对尼古丁受体的药物效果微乎其微。因此，一个 更好地了解尼古丁背后的大脑区域、神经回路和神经递质系统 戒断综合症是促进戒烟新疗法的发展所必需的。而当 投射到伏核的腹侧被盖区(VTA)中的多巴胺(DA)能神经元是 对尼古丁奖赏和强化至关重要的是，最近的研究发现，缰核-脚间(HB- IPN)轴是尼古丁戒断症状的关键回路。特别是，IPN牵涉到增加 啮齿类动物尼古丁戒断过程中的焦虑与胆碱能/谷氨酸能中枢神经传入 缰核神经元与情感行为有关。有趣的是，我们发现了一种新的电路 由投射到IPN的VTA神经元组成，IPN是脚间中通路。我们的数据表明 来自VTA传入的DA可能通过DA支配IPN来调节神经元的活动和焦虑样行为 受体信号。此外，IPN中DA受体的表达似乎受慢性尼古丁的调节 曝光。这些观察结果为本应用程序提供了基础。我们建议检验这一假设 投射到IPN的VTA能神经元调节焦虑，并对焦虑增加至关重要。 尼古丁戒断。在目标1中，我们建议使用分子和生物物理方法来检验这一假说。 DA通过激活受尼古丁调节的DA受体来控制IPN神经元的活动。在AIM 2，我们将使用药理学、光遗传学和生物物理学的方法来检验IPN的假设 从VTA接收DA输入。最后，在目标3中，我们将使用药理学、光遗传学和行为学来 检验脚间系膜环路调节焦虑样行为的假设 尼古丁戒断。预计了解脚间系膜环路在焦虑中的作用 尼古丁戒断将提供新的策略来缓解焦虑和尼古丁戒断症状。