Nicotinic acetylcholine receptor function in the mesolimbic dopamine system

中脑边缘多巴胺系统中烟碱乙酰胆碱受体的功能

基本信息

批准号：
10397392
负责人：
Ryan Michael Drenan
金额：
$ 8.56万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10397392
关键词：
Acetylcholine Acute Address Affect Alkaloids Animal Behavior Animals Area Arousal Attention Award Axon Behavior Behavioral Benchmarking Biological Brain Cell Communication Cell Nucleus Cells Cessation of life Chronic Communication Complement Complex Coupled Data Dendrites Development Dopamine Effectiveness Electrophysiology (science)Fiber Fostering Funding Gene Expression Profiling Glean Glutamates Goals Health Heterogeneity Hypertension Image Individual Knowledge Lead Location Malignant neoplasm of lung Maps Measures Mediating Methods Midbrain structure Molecular Moods Muscarinic Acetylcholine Receptor Neurodevelopmental Disorder Neurons Neurosciences Neurotransmitters Nicotine Nicotine Dependence Nicotine Withdrawal Nicotinic Receptors Output Parkinson Disease Pathway interactions Pattern Pharmacotherapy Photometry Population Process Prosencephalon Publications Pulmonary Emphysema Relapse Reporting Research Research Personnel Resolution Rewards Schizophrenia Signal Transduction Site Slice Solid Structure Synapses Synaptic Transmission System Techniques Tobacco smoke United States Ventral Tegmental Area Work addiction awake base cell type cholinergic cognitive function conditioned place preference desensitization dopaminergic neuron experimental study gamma-Aminobutyric Acid innovation insight mRNA Expression mesolimbic system motivated behavior motor learning nervous system disorder neurochemistry neuronal cell body neuroregulation neurotransmission nicotine exposure nicotine reward nicotine seeking behavior novel novel therapeutic intervention optogenetics presynaptic receptor receptor function response smoking cessation tobacco products tool transmission process two photon microscopy two-photon vesicular glutamate transporter 2

项目摘要

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 moderate effectiveness. Thus, there is a significant unmet need for more effective strategies to treat nicotine dependence. Development of such strategies requires a more detailed understanding of the biological mechanisms leading to nicotine addiction. An essential goal related to mechanistic studies on nAChRs is gaining a better understanding of the location and activity of nAChRs in discrete sites within individual nerve cells. It is also critical that we connect this location/activity information to the various neurochemically-defined (e.g. dopamine, GABA, glutamate) cell types within the brain reward pathways. For these specific cell types in the reward pathway, recent research points to a highly complex input/output relationship. We identified nAChR expression in glutamate-producing neurons in the ventral tegmental area (VTA), and have demonstrated that these receptors enable nicotine- or ACh-mediated alterations in synaptic transmission within the VTA. However, several gaps in knowledge remain, which we will address in this project. First (in Aim 1), we will identify the location within VTA glutamate neurons where nAChRs show the greatest functional activity. This will be done using electrophysiological recordings during 2-photon imaging of neurons in brain slices. This approach will be coupled with studies using a novel photoactivatable nicotine, which we recently introduced. Directly connecting this structural and functional information is critical to fully understanding how nAChRs modulate glutamate transmission in the VTA. In Aim 2, we will answer questions related to nAChR modulation of cell-cell communication within the VTA. Glutamate neurons in this nucleus directly impinge on local DA/GABA neurons, activity which is modulated by nAChR activity on glutamate cells. We will investigate the mechanisms underlying this synaptic communication using optogenetics, photostimulation techniques, and 2-photon microscopy. In Aim 3, we move our queries to the behaving animal to determine which of the components investigated in Aims 1-2 are most important during animal behavior. Using fiber photometry, we will image Ca2+ activity in VTA neurons during acute nicotine exposure and during acquisition/expression of nicotine conditioned reward behavior. To complement these experiments, we will also use chemogenetics to determine whether VTA glutamate neurons are important for nicotine reward-like behavior. By determining how cholinergic mechanisms map onto the complexity (neurochemical and connectivity) of cell types in the VTA, this project will significantly advance our understanding of cholinergic neurotransmission. These studies could also lead to novel treatments for addiction or novel hypotheses about reward system function/activity.

项目概要长期接触烟草制品中的尼古丁会导致多种健康后果（肺癌、肺气肿、高血压等），每年导致超过 600 万人死亡。其中复发率很高那些试图戒烟的人以及旨在促进戒烟的药物疗法效果中等。因此，对治疗尼古丁的更有效策略的需求尚未得到满足依赖性。制定此类策略需要更详细地了解生物学导致尼古丁成瘾的机制。与 nAChR 机制研究相关的一个基本目标是更好地了解个体神经内离散部位中 nAChR 的位置和活性细胞。将位置/活动信息与各种神经化学定义的信息联系起来也很重要（例如多巴胺、GABA、谷氨酸）大脑奖励通路内的细胞类型。对于这些特定的细胞类型在奖励途径中，最近的研究指出了一种高度复杂的输入/输出关系。我们确定了 nAChR 在腹侧被盖区 (VTA) 产生谷氨酸的神经元中表达，并具有证明这些受体能够尼古丁或乙酰胆碱介导的突触传递改变在 VTA 内。然而，仍然存在一些知识空白，我们将在本项目中解决这些空白。第一（在目标 1)，我们将确定 VTA 谷氨酸神经元内 nAChRs 显示出最大功能的位置活动。这将通过大脑神经元的 2 光子成像过程中的电生理记录来完成切片。这种方法将与使用新型光活化尼古丁的研究相结合，我们最近介绍了。直接连接这些结构和功能信息对于充分理解如何 nAChR 调节 VTA 中的谷氨酸传输。在目标 2 中，我们将回答与 nAChR 相关的问题 VTA 内细胞间通讯的调节。该核中的谷氨酸神经元直接影响局部 DA/GABA 神经元的活性受谷氨酸细胞上的 nAChR 活性调节。我们将调查使用光遗传学、光刺激技术和 2 光子显微镜。在目标 3 中，我们将查询转移到行为动物身上，以确定哪一个是目标 1-2 中研究的成分在动物行为过程中最为重要。使用光纤光度测定法，我们将在急性尼古丁暴露期间和获取/表达过程中对 VTA 神经元中的 Ca2+ 活性进行成像尼古丁条件奖励行为。为了补充这些实验，我们还将使用化学遗传学来确定 VTA 谷氨酸神经元对于尼古丁奖励样行为是否重要。通过确定胆碱能机制如何映射到细胞类型的复杂性（神经化学和连接性） VTA，这个项目将显着增进我们对胆碱能神经传递的理解。这些研究还可能导致新的成瘾治疗方法或关于奖励系统功能/活动的新假设。