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).

项目概要 丘脑底核 (STN) 深部脑刺激 (DBS) 是帕金森病的常见手术治疗方法 (PD) 尽管 STN DBS 的临床成功已有 20 多年，但其治疗机制仍然难以捉摸。 然而，很明显，DBS 在复杂且复杂的分子、细胞和系统水平上发挥作用。 当前的技术，如电生理学、电化学和功能学，有时是相互矛盾的。 通常用于研究这个难题的各个部分的成像在分辨率或行为范式方面受到限制 这些可以应用于，因此没有提供解析出复杂的所需的所有信息 在这里，我们建议使用荧光钙。 使用头戴式微型单光子系统作为新工具对表达 GCaMP6f 的大鼠进行显微镜检查 弥合在清醒行为动物模型中对 DBS 的细胞水平和系统水平理解之间的差距 为此，我们将分析 STN 刺激引起的运动皮层神经活动变化。 开放场地、步进、圆柱测试和阿朴吗啡诱导的旋转，所有这些都是典型的测试 已显示出评估帕金森病动物的运动和治疗效果的预测有效性。 这里提出的技术提供了一种独特的方法来回答有关 DBS 机制的问题，例如 DBS 诱导的兴奋性 STN 谷氨酸能神经元的激活还是药物抑制 投射到苍白球内部/黑质网状体会产生可检测到的运动变化 与行为结果变化相关的皮层活动（例如，开放领域、运动学评估） 步进、圆柱和阿扑吗啡引起的旋转测试）。