Cellular Mechanisms Regulating VTA Dopamine Neurons

描述（由申请人提供）：申请人的长期职业目标是发展成为一名独立的研究者，研究药物滥用和成瘾的机制。为了实现这一目标，申请人（Arthur Riegel博士）准备了一个指导研究科学家发展奖（K01），旨在：1)在研究多巴胺神经元的树突生理学的同时，获得最先进的神经成像技术的重要技术和理论培训；2)准备一个有竞争力的R01拨款提案，以建立一个独立的研究计划。本K01申请中建议的培训将在职业发展计划的背景下进行。该职业规划包括来自知名神经生理学家（John Williams博士）的指导，以及实用职业发展技能、教学指导和负责任的研究行为的重要培训机会。申请人拥有Vollum研究所的资源和专业知识，该研究所是美国最好的细胞神经科学环境之一。职业计划的研究内容是研究长期接触吗啡后树突生理中的神经适应性。Riegel博士的近期目标是在双光子显微镜、旋转共聚焦显微镜、光解、焦电刺激、焦离子导入和慢性阿片类药物给药的实验模型方面发展专业知识。这些技术将用于研究证明福斯克林活化腺苷酸环化酶（AC）增强mglur介导的sk通道激活的初步数据。提出的具体目标将验证存在一种新的AC/ pka依赖性信号级联的假设，该信号级联调节sk通道电流，并在慢性吗啡治疗期间上调。这些实验的结果有望增加我们对成瘾时sk通道功能对多巴胺神经元兴奋性的影响的理解。就公共卫生而言，拟议研究的相关性在于，更好地了解sk通道功能的细胞机制将导致神经药理学工具的发展，以利用该通道作为治疗靶点。本职业规划中包含的培训将为第三学年制定R01提案提供坚实的基础。

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.