Mechanism of Action of Deep Brain Stimulation

描述（由申请人提供）：此提案描述了一个为期5年的神经外科学术生涯发展培训计划。该计划将促进对电生理学，电化学，脑成像以及立体定向和功能神经外科的掌握。生理学和生物医学工程主席Gary Sieck博士将担任主要导师。由脑成像、电分析化学、神经工程和神经外科专家组成的指导团队将帮助申请人阐明深部脑刺激（DBS）治疗帕金森病的机制。我们最近的工作表明，丘脑下核（STN） DBS可能激活神经末梢释放神经递质，包括多巴胺。拟议的实验将包括电生理，电化学和荧光显微镜记录在DBS期间。具体目的包括：1)DBS导致纹状体神经元动作电位放电和多巴胺释放的变化。2) STN DBS在6-OH DA损伤大鼠帕金森病模型中的治疗作用是通过多巴胺释放介导的。3) STN DBS通过星形细胞囊泡释放机制释放STN中的谷氨酸。本研究首次详细分析了DBS对星形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学诊断和干预的新时代，提供DBS电极的精确靶向和神经递质的调节，这对DBS的治疗效果至关重要。申请人Kendall Lee，医学博士，是罗切斯特梅奥诊所的一名新研究员和神经外科医生，具有神经病学，神经外科和神经科学的多学科背景。他展示了形成独特和有效合作的能力。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：Charles Blaha博士（电流测量专家），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 Newman博士（星形胶质细胞研究专家）和Demetrius Maragonore医学博士（帕金森病神经科医生和研究员）。此外，Fredric Meyer医学博士（罗切斯特梅奥诊所神经外科主席）将担任职业发展顾问，以确保申请人在学术神经外科方面取得成功。

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.