In Vivo Fluorescent Microscopy Analysis of Motor Cortex Activation by STN DBS

STN DBS 对运动皮层激活的体内荧光显微镜分析

• 批准号: 10023233
• 负责人: Charles Blaha
• 金额: $ 4.65万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023233
• 关键词: Address; Adoption; Animal Model; Animals; Apomorphine; Attenuated; Behavior; Behavioral Paradigm; Biomedical Engineering; Brain region; Calcium; Cells; Chronic; Clinical; Clinical Research; Complex; Computer Simulation; Deep Brain Stimulation; Denervation; Disease; Disease model; Electrochemistry; Electrophysiology (science); Evaluation; Excitatory Amino Acid Antagonists; Fluorescence; Functional Imaging; Globus Pallidus; Glutamates; Head; Hyperactive behavior; Image; Imaging Techniques; Interruption; Lesion; Measures; Mediating; Microscope; Microscopy; Modeling; Molecular; Motion; Motor Cortex; Movement; Neural Pathways; Neuroglia; Neurons; Operative Surgical Procedures; Optics; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathology; Pathway interactions; Pattern; Pharmacology; Photons; Play; Population; Rattus; Refractory; Reporting; Resolution; Role; Rotation; STN stimulation; Structure of subthalamic nucleus; Substantia nigra structure; System; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Treatment Efficacy; awake; behavior test; behavioral outcome; behavioral response; cohesion; free behavior; in vivo; kinematics; multidisciplinary; neurochemistry; novel; preclinical study; relating to nervous system; response; spatiotemporal; success; temporal measurement; theories; time use; tool; treatment response; two photon microscopy

PROJECT SUMMARY Subthalamic nucleus (STN) deep brain stimulation (DBS) is a common surgical treatment for Parkinson’s disease (PD). Despite over 20 years of clinical success, the therapeutic mechanisms of STN DBS remain elusive. However, it has become clear that DBS acts at the molecular, cellular, and systems levels in complex and sometimes contradictory ways. Current techniques such as electrophysiology, electrochemistry, and functional imaging commonly used to study pieces of this puzzle are limited in either resolution or behavioral paradigms these can be applied to, and have thus not provided all the information needed to parse out the complicated relationships between stimulation and evoked effects. Here, we propose the use of fluorescence calcium microscopy in GCaMP6f-expressing rats using a head-mounted miniature single photon system as a novel tool to bridge the gap between cellular and system level understanding of DBS in awake behaving animal models of PD. To this end, we will analyze neural activity changes in motor cortex evoked by stimulation of the STN during open field, stepping, cylinder tests, and apomorphine-induced rotations, all of which are stereotypical tests that have shown predictive validity for evaluation of movement and therapeutic efficacy in parkinsonian animals. The techniques proposed here provide a unique approach for answering questions about DBS mechanisms such as whether DBS-induced activation or pharmacologic inhibition of excitatory STN glutamatergic neuronal projections to the globus pallidus internus / substantia nigra reticulata produces detectable changes in motor cortex activity associated with changes in behavioral outcomes (e.g., open field, kinematic assessment of stepping, cylinder, and apomorphine-induced rotation tests).

项目摘要 丘脑下核（STN）深脑刺激（DBS）是帕金森氏病的常见手术治疗 （PD）。尽管超过20年的临床成功，但STN DBS的治疗机制仍然难以捉摸。 但是，很明显，DB在复合物和复合物中的分子，细胞和系统水平作用 有时矛盾的方式。当前技术，例如电生理学，电化学和功能 通常用于研究此难题部分的成像受到分辨率或行为范式的限制 这些可以应用于，因此没有提供分析复杂所需的所有信息 刺激与诱发作用之间的关系。在这里，我们建议使用荧光钙 使用头部安装的微型单光子系统作为一种新工具，在GCAMP6F表达大鼠的显微镜表达大鼠 弥合细胞和系统级别对DBS的差距，在清醒的行为动物模型中 PD。为此，我们将分析通过刺激STN在 开放场，垫脚，圆柱测试和叠磷型诱导的旋转，所有这些都是刻板的测试 已经显示出用于评估帕金森动物运动和治疗效率的预测有效性。 这里提出的技术为回答有关DBS机制的问题提供了一种独特的方法 DBS诱导的激活或药物抑制兴奋性STN谷氨酸能神经元 投影到Globus pallidus internus / siveia nigra reticulata会产生可检测的电动机变化 与行为结果变化相关的皮质活性（例如，开放式，运动学，运动学评估 步进，圆柱和磷灰碱诱导的旋转测试）。