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: 8585390
• 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/8585390
• 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.

在我作为科学家的职业生涯的早期，我认为沟通是所有生物过程的关键。这 意识形态已经发展成为对突触传播研究的浓厚兴趣。在Danny G. Winder的实验室中 博士我开始在突触生理学方面的培训，发表了许多有关兴奋性突触调节的论文 代谢性谷氨酸受体的传播及其在可卡因的体内募集。在我期间 博士后培训，我继续研究与奖励相关电路中的突触传输 罗伯特·C·马伦卡（Robert C. Malenka），医学博士，博士Malenka博士是一位著名的突触生理学家，已经培训了许多 突触生理和成瘾领域的突出数字，Antonello Bonci（NIDA），Karl Deisseroth （斯坦福），丹·费尔德曼（UC Berkeley），Pablo Castillo（Albert Einstein），John Isaac（NIH，现在是Lilly），Anatol 克雷兹（UCSF），迈克尔·克莱尔（Michael Crair）（耶鲁大学）和马克·托马斯（Mark Thomas）（明尼苏达州大学）列举了一些。这是我的目标 通过在研究突触传播的作用的学术界中获得独立实验室来继续这一传统 在奖励和厌恶行为方面。我的研究领域与马伦卡博士不同，除了兴奋性 传播，我也有兴趣研究抑制性和神经调节性传播到NAC 中间神经元和主要输出神经元。最终，我计划扩大疾病模型和研究效果 NAC突触回路上的厌恶状态，例如急性和慢性疼痛。为此，我正在利用 艺术技术和精致而简单的方法来解决核中这些问题 伏anc（NAC）。 该项目的最终目标是更好地了解NAC电路中的突触功能 开始如何招募这些电路以引起与成瘾有关的行为。 NAC，作为 中唇多巴胺系统，将兴奋性，抑制性和调节性输入的复杂混合物整合到 优化适应性动机行为。该电路内突触传输的动态变化为 与成瘾性疾病的发展和表达强有关。具体目的涉及使用 从体外切片中的全细胞记录来定义NAC神经元的基本特性，以及如何修改它们 通过体内可卡因暴露。在此提案中，体内可卡因暴露对 NAC输出神经元和局部微电路中间神经元（INS）将使用细菌人工来划定 染色体（BAC）转基因标记小鼠，该小鼠专门标记直接和间接途径培养基 神经元（MSN），GABA能和胆碱能INS。另外，三种不同兴奋性的突触特性 将对NAC，MSN和INS的输入进行表征，并在体内可卡因经验的后果 这些特定输入将使用病毒表达的通道视紫红质（CHR2）确定。 该提案的指导阶段的目标是：（1）检查直接和 在体内可卡因经验之后的间接MSN和（2）确定特定兴奋性突触输入是否 在使用光遗传学方法的体内可卡因经验之后，在这些MSN上进行了差异改变。 独立阶段将解决：（1）传入的特异性基础和药物诱导的兴奋性改变 NAC INS的突触特性（2）基础和药物诱导的INS和药物之间突触连通性的变化 MSN和（3）光诱导的NAC INS激活在药物相关的环境中的行为效应， 利用最先进的光遗传学方法。提出的实验的结果将提供 对病理生理状态和NAC突触电路变化的基本知识 对与成瘾相关行为的未来目标有影响。另外，小心 这项研究的详细方法为研究其他虐待和成瘾药物奠定了基础 模型以及与NAC中适应不良过程相关的其他肯定性疾病。 我期望完成指导项目后，我将拥有技术和知识分子 在受人尊敬的高等教育学院成功运营我自己的独立实验室的专业知识。我会的 开发到工具，以有效地在会议和出版物中传达这些发现。另外，是 我相信这些项目完成后，我将能够成功竞争R01。最终， 这将使我能够通过产生质量研究来继续为成瘾研究领域做出贡献 并指导年轻科学家。