Synaptic Mechanisms of Addiction-Related Behaviors in the Nucleus Accumbens

伏核成瘾相关行为的突触机制

• 批准号: 8637959
• 负责人: Brad Alan Grueter
• 金额: $ 24.9万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637959
• 关键词: Abstinence; Academia; Acute Pain; Address; Affect; Area; Bacterial Artificial Chromosomes; Behavior; Behavioral; Belief; Biological Process; Brain; Cells; Cocaine; Communication; Complex; Development; Disease; Disease model; Doctor of Medicine; Doctor of Philosophy; Dopamine D2 Receptor; Drug Exposure; Drug abuse; Exposure to; Foundations; Future; Glutamate Receptor; Goals; In Vitro; Institutes; Interneurons; Knowledge; Label; Learning; Mental disorders; Mentors; Metabotropic Glutamate Receptors; Minnesota; Modeling; Modification; Molecular; Mus; Names; National Institute of Drug Abuse; Neurons; Nucleus Accumbens; Output; Paper; Patch-Clamp Techniques; Pathway interactions; Pharmaceutical Preparations; Phase; Physiology; Process; Property; Publications; Publishing; Recording of previous events; Recruitment Activity; Research; Rewards; Rhodopsin; Role; Running; Scientist; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Training; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Viral; Whole-Cell Recordings; addiction; behavior influence; career; cholinergic; chronic pain; cocaine exposure; drug of abuse; effective therapy; expectation; experience; in vivo; interest; learned behavior; light effects; meetings; mesolimbic system; motivated behavior; nerve supply; neural circuit; neuroregulation; optogenetics; post-doctoral training; postsynaptic; promoter; research study; synaptic function; tool; transmission process

Early in my career as a scientist, I decided that communication was the key to all biological processes. This ideology has evolved into a keen interest in the study of synaptic transmission. In the lab of Danny G. Winder, Ph.D. I began my training in synaptic physiology publishing many papers on modulation of excitatory synaptic transmission by metabotropic glutamate receptors and their in vivo recruitment by cocaine. During my postdoctoral training, I have continued to study synaptic transmission in reward related circuitry in the lab of Robert C. Malenka, M.D., Ph.D. Dr. Malenka is a renowned synaptic physiologist and has trained many prominent figures in the synaptic physiology and addiction fields, Antonello Bonci (NIDA), Karl Deisseroth (Stanford), Dan Feldman (UC Berkeley), Pablo Castillo (Albert Einstein), John Isaac (NIH, now Lilly), Anatol Kreitzer (UCSF), Michael Crair (Yale), and Mark Thomas (Univ. Minnesota) to name a few. It is my goal to continue this tradition by obtaining an independent lab in academia studying the role of synaptic transmission in rewarding and aversive behaviors. My area of study differs from Dr. Malenka in that in addition to excitatory transmission, I am also interested in studying inhibitory and neuromodulatory transmission onto NAc interneurons as well as primary output neurons. Eventually, I plan to expand disease models and study effects of aversive states, such as acute and chronic pain, on NAc synaptic circuitry. To do this I am utilizing state of the art techniques and sophisticated yet simple approaches to address these issues in the Nucleus Accumbens (NAc). The ultimate goal of this project is to gain a better understanding of synaptic function in the NAc circuitry and to begin to address how these circuits are recruited to elicit addiction related behaviors. The NAc, as part of the mesolimbic dopamine system, integrates a complex mix of excitatory, inhibitory and modulatory inputs to optimize adaptive motivated behaviors. Dynamic alterations in synaptic transmission within this circuitry are strongly implicated in the development and expression of addictive disorders. The specific aims involve using whole-cell recordings from in vitro slices to define basic properties of NAc neurons and how these are modified by in vivo cocaine exposure. In this proposal, the effects of in vivo cocaine exposure on synaptic properties of NAc output neurons and local microcircuit interneurons (INs) will be delineated utilizing bacterial artificial chromosome (BAC) transgenic marker mice that specifically label direct and indirect pathway medium spiny neurons (MSNs), GABAergic and cholinergic INs. Also, the synaptic properties of three distinct excitatory inputs onto NAc, MSNs and INs will be characterized and the consequences of in vivo cocaine experience on these specific inputs will be determined using virally expressed channel rhodopsin (ChR2). The objectives for the mentored phase of this proposal are: (1) to examine the synaptic properties of direct and indirect MSNs following in vivo cocaine experience, and (2) to determine if specific excitatory synaptic inputs onto these MSNs are differentially altered following in vivo cocaine experience utilizing optogenetic approaches. The independent phase will address: (1) afferent specific basal and drug-induced alterations in excitatory synaptic properties of NAc INs, (2) basal and drug-induced changes in synaptic connectivity between INs and MSNs and (3) behavioral effects of light-induced (ChR2) activation of NAc INs in drug related context, all of which utilize state-of-the-art optogenetic approaches. The results of the proposed experiments will provide a fundamental knowledge of the changes in the synaptic circuitry of the NAc in a pathophysiological state and have implications on future targets for treatment of addiction related behaviors. Additionally, the careful detailed approach of this study provides the foundation for the study of other drugs of abuse and addiction models, as well as additional affirmative disorders associated with maladaptive processes in the NAc. It is my expectation that upon completion of the mentored project I will have the technical and intellectual expertise to successfully run my own independent lab at a respected institute of higher learning. I will have developed to tools to effectively communicate these findings at meetings and in publications. Additionally, it is my belief that upon completion of these projects, I will be able to successfully compete for an R01. Ultimately, this will allow me to continue to contribute to the field of addiction research both by producing quality research and mentoring young scientists.

在我作为一名科学家的早期职业生涯中，我认为交流是所有生物过程的关键。这 意识形态已经演变成对突触传递研究的浓厚兴趣。在丹尼·G·温德的实验室里 博士。我开始了突触生理学的训练，发表了许多关于兴奋性突触调制的论文 代谢性谷氨酸受体的传播及其可卡因体内募集。在我的 在博士后培训期间，我继续研究奖赏相关回路中的突触传递。 罗伯特·C·马伦卡，医学博士，博士。马伦卡博士是一位著名的突触生理学家，他培养了许多 突触生理学和成瘾领域的杰出人物，安东内洛·邦奇(NIDA)，卡尔·戴瑟罗斯 (斯坦福)，丹·费尔德曼(加州大学伯克利分校)，巴勃罗·卡斯蒂略(阿尔伯特·爱因斯坦)，约翰·艾萨克(NIH，现为礼来公司)，阿纳托尔 Kreitzer(加州大学旧金山分校)、Michael Crair(耶鲁大学)和Mark Thomas(大学明尼苏达州)仅举几例。我的目标是 通过在学术界获得一个独立的实验室来研究突触传递的作用，来延续这一传统 在奖励和厌恶行为中。我的研究领域与马伦卡博士的不同之处在于，除了兴奋之外 传递，我也有兴趣研究抑制和神经调节传递到NAC 中间神经元以及初级输出神经元。最终，我计划扩展疾病模型并研究其影响 NAC突触回路上的厌恶状态，如急性和慢性疼痛。为此，我正在利用状态 在《核》中解决这些问题的艺术技术和复杂而简单的方法 伏隔草(NAC)。 这个项目的最终目标是更好地了解NAC电路中的突触功能，并 开始解决这些回路是如何被招募来引发与成瘾有关的行为的。新来港儿童，作为 中脑边缘多巴胺系统，整合了兴奋、抑制和调制输入的复杂组合，以 优化适应性激励行为。该回路内突触传递的动态变化是 与成瘾障碍的发展和表达密切相关。具体目标包括使用 来自体外切片的全细胞记录以确定NAC神经元的基本特性以及这些特性是如何被修饰的 通过体内可卡因暴露。在这项研究中，体内可卡因暴露对大鼠脑内神经元突触特性的影响 NAC输出神经元和局部微路间神经元(INS)将利用细菌人工神经来描绘 染色体(BAC)转基因标记小鼠，特异性标记直接和间接途径培养基刺 神经元(MSN)、GABA能和胆碱能INS。此外，三种不同兴奋性神经元的突触特性 对NAC、MSNS和INS的输入将被表征，体内可卡因经验的后果将在 这些特定的输入将使用病毒表达的通道视紫红质(ChR2)来确定。 本提案指导阶段的目标是：(1)研究直接和间接突触的特性。 体内可卡因经验后的间接MSN，以及(2)确定特定的兴奋性突触输入 根据体内可卡因的经验，利用光遗传方法对这些MSN进行不同的改变。 独立阶段将解决：(1)兴奋性传入、特异性基础和药物诱导的改变。 NAC-INS的突触特性，(2)基础和药物诱导的INS和INS之间突触连接的变化 MSNS和(3)药物相关环境中光诱导(ChR2)激活NAC INS的行为效应，所有 它利用了最先进的光遗传方法。建议的实验结果将提供一个 NAC在病理生理状态下突触回路变化的基础知识和 对成瘾相关行为的未来治疗目标有影响。此外，细心的 本研究的详细方法为其他药物滥用和成瘾的研究提供了基础 模型，以及与NAC中的适应不良进程相关的其他积极障碍。 这是我的期望，在完成指导项目后，我将拥有技术和智力 在一所受人尊敬的高等学府成功运营自己的独立实验室的专业知识。我要一杯 发展成为在会议和出版物中有效传达这些调查结果的工具。此外，它是 我相信，在完成这些项目后，我将能够成功地竞争一辆R01。最终， 这将使我能够继续为成瘾研究领域做出贡献，通过生产高质量的研究 以及指导年轻的科学家。