Cellular Mechanisms Regulating VTA Dopamine Neurons

调节 VTA 多巴胺神经元的细胞机制

• 批准号: 7490509
• 负责人: ARTHUR C RIEGEL
• 金额: $ 12.29万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7490509
• 关键词: Adenylate Cyclase; Animals; Applications Grants; Arts; Axon; Behavior; Brain; Calcium; Calcium-Activated Potassium Channel; Chronic; Confocal Microscopy; Country; Data; Dendrites; Dependence; Development; Development Plans; Dopamine; Drug abuse; Electric Stimulation; Elements; Environment; Experimental Models; Exposure to; Fire - disasters; Forskolin; Glutamate Receptor; Glutamates; Goals; Health; Human; Image; Imaging Techniques; Individual; Institutes; Instruction; Iontophoresis; Laboratories; Lead; Life; Localized; Location; Maps; Measures; Mediating; Mediator of activation protein; Mentored Research Scientist Development Award; Mentors; Metabotropic Glutamate Receptors; Microscopy; Morphine; Neurons; Neurosciences; Opiates; Opioid; Pattern; Photons; Physiology; Public Health; Regulation; Research; Research Personnel; Resources; Self Administration; Signal Transduction; Site; Solid; Techniques; Testing; Tissues; Training; Up-Regulation; Whole-Cell Recordings; Work; addiction; base; career; design; dopaminergic neuron; innovation; neuroadaptation; neuroimaging; novel; novel strategies; opioid abuse; optical imaging; photolysis; programs; research study; response; skills; therapeutic target; tool

DESCRIPTION (provided by applicant): The applicant's long-term career goal is to develop into an independent investigator studying the mechanisms underlying drug abuse and addiction. In order to achieve this objective, the applicant (Dr. Arthur Riegel) has prepared a Mentored Research Scientist Development Award (K01) designed to: 1) acquire important technical and theoretical training in state-of-the-art neuroimaging techniques, while investigating the dendritic physiology of dopamine neurons; and 2) prepare a competitive R01 grant proposal in order to establish an independent research program. The training proposed in this K01 application will be conducted in the context of a Career Development Plan. This Career Plan incorporates mentoring from an established neurophysiologist (Dr. John Williams), as well as important training opportunities for practical career development skills, didactic instruction and Responsible Conduct of Research. The applicant has the commitment of resources and expertise from the Vollum Institute, one of the finest cellular neuroscience environments in the country. The research element of the Career Plan investigates neuroadaptations in dendritic physiology following chronic exposure to morphine. Dr. Riegel's immediate goals are to develop an expertise in 2-photon microscopy, spinning confocal microscopy, photolysis, focal electrical stimulation, focal iontophoresis, and experimental models of chronic opioid administration. These techniques will be used to investigate preliminary data demonstrating that forskolin-activation of adenylyl cyclase (AC) enhances the mGluR-mediated activation of the sK-channel. The proposed specific aims will test the hypothesis that there exists a novel AC/PKA-dependent signaling cascade, which regulates the sK-channel current and is upregulated during chronic morphine treatment. The results from these experiments are expected to increase our understanding of the impact of sK-channel function on dopamine neuron excitability during addiction. With regard to public health, the relevance for the proposed research is that a better understanding of the cellular mechanisms underlying sK-channel function will lead to the development of neuropharmacological tools to exploit this channel as a therapeutic target. The training incorporated in this Career Plan will provide a solid basis upon which to develop a R01 proposal in Year-3.

描述（由申请人提供）：申请人的长期职业目标是发展为研究药物滥用和成瘾机制的独立研究人员。为了实现这一目标，申请人（Arthur Riegel博士）准备了一项指导的研究科学家发展奖（K01），旨在：1）在研究最先进的神经影像学技术中获得重要的技术和理论培训，同时研究了多巴胺神经元的树突状生理； 2）准备有竞争力的R01赠款提案，以建立独立的研究计划。本K01申请中提出的培训将在职业发展计划的背景下进行。该职业计划纳入了既定的神经生理学家（约翰·威廉姆斯博士）的指导，以及实践职业发展技能，教学教学和负责任的研究的重要培训机会。申请人拥有Vollum Institute的资源和专业知识的承诺，Vollum Institute是该国最好的细胞神经科学环境之一。职业计划的研究因素研究了长期暴露于吗啡后的树突状生理中的神经照顾。 Riegel博士的近期目标是在2光子显微镜，旋转共聚焦显微镜，光解，局灶性电刺激，局灶性离子噬菌体和慢性阿片类药物的实验模型方面发展专业知识。这些技术将用于研究初步数据，以表明对腺苷酸环化酶（AC）的Forskolin激活增强了MGLUR介导的SK通道激活。提出的特定目的将检验存在一种新型的AC/PKA依赖性信号级联的假设，该级联级联对SK通道电流进行了调节，并在慢性吗啡处理过程中被上调。预计这些实验的结果将增加我们对成瘾过程中SK通道功能对多巴胺神经元兴奋性的影响的理解。关于公共卫生，与拟议的研究的相关性是，对SK通道功能的细胞机制有更好的了解将导致神经药理学工具的开发，以利用该渠道作为治疗靶点。本职业计划中的培训将提供扎实的基础，以在3年级制定R01提案。