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.

项目概要/摘要 长期接触烟草烟雾每年导致约 600 万人死亡，并导致健康并发症 吸烟是世界上可预防死亡的主要原因。目前的戒烟辅助措施包括 尼古丁替代疗法和针对烟碱受体的药物的效果甚微。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 需要戒断综合症来促进新的戒烟疗法的开发。尽管 腹侧被盖区 (VTA) 中投射到伏隔核的多巴胺能 (DAergic) 神经元是 对于尼古丁奖励和强化至关重要，最近的研究已经确定了缰核-脚间（Hb- IPN）轴作为尼古丁戒断症状的关键回路。特别是，IPN 涉及增加 啮齿类动物尼古丁戒断期间的焦虑，并接受来自胆碱能/谷氨酸能内侧的输入 与情感行为相关的缰核神经元。有趣的是，我们发现了一种新颖的电路 由投射到 IPN（中脚间通路）的 VTA 神经元组成。我们的数据表明 来自 VTA 传入神经的 DA 可能会支配 IPN，通过 DA 调节神经元活动和焦虑样行为 受体信号传导。此外，IPN 中的 DA 受体表达似乎受到慢性尼古丁的调节 接触。这些观察结果为本应用奠定了基础。我们建议检验假设 投射到 IPN 的 VTA DAergic 神经元可调节焦虑，并且对于在 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假设 DA 通过激活受尼古丁调节的 DA 受体来控制 IPN 神经元活动。瞄准 2、我们将利用药理学、光遗传学和生物物理方法来检验IPN的假设 接收来自 VTA 的 DA 输入。最后，在目标 3 中，我们将利用药理学、光遗传学和行为学来 检验中脚间回路在基线和期间调节焦虑样行为的假设 尼古丁戒断。预计了解中脚间回路在焦虑中的作用 尼古丁戒断将为缓解焦虑和尼古丁戒断症状提供新策略。