Mechanism of Action of Deep Brain Stimulation

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，用于发展神经外科的学术生涯。该计划将促进电生理学，电化学，脑成像和立体定向和功能神经外科的命令。生理学和生物医学工程主席加里西克博士将担任主要导师。一个由脑成像、电分析化学、神经工程和神经外科专家组成的导师团队将帮助申请人阐明脑深部电刺激（DBS）治疗帕金森病的机制。我们最近的工作表明，底丘脑核（DBS）DBS可能激活神经末梢释放神经递质，包括多巴胺。拟议的实验将需要电生理，电化学和荧光显微镜记录在DBS。具体目的包括证明1）DBS导致纹状体中神经元动作电位放电和多巴胺释放的变化。2)在帕金森病的6-OH DA损伤大鼠模型中，多巴胺释放介导了DBS的治疗益处。3)DBS通过星形胶质细胞囊泡释放机制导致脑内谷氨酸的释放。这项研究将是第一次详细分析DBS的机制，因为它涉及DBS对星形胶质细胞谷氨酸释放和纹状体多巴胺释放的影响。该项目的成功将开启医疗诊断和干预的新时代，提供DBS电极的精确定位和神经递质的调节，这些神经递质与DBS的治疗效果密切相关。申请人肯德尔·李医学博士哲学博士、是马约诊所罗切斯特的一名新的研究者和神经外科医生，具有神经病学、神经外科和神经科学的多学科背景。他展示了形成独特而有效的合作的能力。为了最大限度地提高成功的可能性，申请人已经招募了一个高技能的研究团队作为顾问：查尔斯·布拉哈博士。（电流分析法专家），Paul Garris博士（帕金森病动物模型和快速扫描循环伏安法专家），Eric纽曼，博士（星形胶质细胞研究专家）和Demetrius Maragonore，医学博士。（帕金森病神经学家和研究人员）。此外，Fredric Meyer，M.D.（主席，神经外科马约诊所罗切斯特）将担任职业发展顾问，以确保在学术神经外科的申请人成功的职业生涯。

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in neurosurgery. This program will promote the command of electrophysiology, electrochemistry, brain imaging and stereotactic and functional neurosurgery. Dr. Gary Sieck, Chair of Physiology and Biomedical Engineering, will serve as the primary mentor. A mentorship team of experts in brain imaging, electroanalytical chemistry, neuroengineering and neurosurgery will help the applicant elucidate the mechanisms by which Deep Brain Stimulation (DBS) treats Parkinson's disease. Our recent work demonstrates that subthalamic nucleus (STN) DBS may activate nerve endings to release neurotransmitters, including dopamine. The proposed experiments will entail electrophysiologic, electrochemical, and fluorescent microscopic recordings during DBS. The specific aims include the demonstration of 1) DBS results in changes in neuronal action potential firing and release of dopamine in the striatum. 2) The therapeutic benefit of STN DBS is mediated by dopamine release in the 6-OH DA lesioned rat model of Parkinson's disease. 3) STN DBS results in release of glutamate in the STN via astrocytic vesicular release mechanism. This study will be the first detailed analysis of the mechanism of DBS as it relates to DBS effect on astrocytic glutamate release and striatal dopamine release. Success in this project will open a new era in medical diagnosis and intervention, providing precise targeting of DBS electrodes and regulation of neurotransmitter that are critically involved in the therapeutic effectiveness of DBS. The applicant, Kendall Lee, M.D., Ph.D., is a new investigator and a neurosurgeon at the Mayo Clinic Rochester with a multidisciplinary background in neurology, neurosurgery, and neuroscience. He has demonstrated the ability to form unique and effective collaborations. To maximize the likelihood of success, the applicant has enlisted as advisors a highly skilled team of researchers: Charles Blaha, Ph.D. (expert in amperometry), Paul Garris, Ph.D. (expert in Parkinson's disease animal models and fast scan cyclic voltammetry), Eric Newman, Ph.D. (expert in astrocyte research), and Demetrius Maragonore, M.D. (Parkinson's disease Neurologist and researcher). In addition, Fredric Meyer, M.D. (Chair, Neurosurgery Mayo Clinic Rochester) will serve as career development advisor, to make certain a successful career in academic neurosurgery for the applicant.