Miniature, Integrated Fluorescence Microscopes for In Vivo Brain Imaging

用于体内脑成像的微型集成荧光显微镜

基本信息

批准号：
8393431
负责人：
Kunal Ghosh
金额：
$ 32.33万
依托单位：
INSCOPIX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8393431
关键词：
Adult American Animal Behavior Animals Area Autistic Disorder Behavior Boxing Brain Brain Diseases Brain imaging Cells Chronic Communities Computer software Core Facility Corpus striatum structure Custom Data Data Set Devices Disease Electronics Elements Exhibits Extravasation Feedback Fluorescence Microscopy Foundations Goals Head Hippocampus (Brain)Home environment Housing Human Image Imagery Imaging technology Individual Intellectual Property Knowledge Letters Licensing Life Light Location Magnetism Marketing Medicine Mental Depression Methods Microcirculation Microscope Monitor Mus National Institute of Mental Health Nature Neurons Neurosciences Neurosciences Research Neurotransmitters Optics Pathologic Pathway interactions Pattern Performance Peripheral Phase Preparation Problem Solving Production Publishing Rattus Research Personnel Resolution Rodent Role Schizophrenia Scientist Sea Shapes Small Business Innovation Research Grant Solutions Source Speed Staging Stream Technology Testing Therapeutic Time Universities Validation awake base brain research commercialization computerized data processing cost data acquisition design digital disease phenotype electronic data flexibility fluorescence microscope graphical user interface image registration improved in vivo innovation interest lens member miniaturize mouse model neural circuit neural patterning neurochemistry neuropsychiatry news novel therapeutics prototype relating to nervous system research study seal sensor spatiotemporal technological innovation theories user-friendly

项目摘要

DESCRIPTION (provided by applicant): There is a rising emphasis today on the role of neural circuitry in neuropsychiatric disease. However we still lack crucial knowledge of both normal patterns of neural activity and how these patterns go awry in disease. Although brain researchers have already created mouse models of many human brain diseases, presently there is no technology that can visualize the activity of large numbers of individual, neurons of genetically identified types in the brains of behaving mice - ideally in multiple mice in parallel. The capacity to obtain such large-scale data sets is important towards identifying neurophysiologic signatures of brain disease and is a prerequisite for developing therapeutic means of re-tuning aberrant activity patterns. Fluorescence microscopy has key advantages for tracking neural activity. However, while conventional fluorescence microscopes offer the spatiotemporal resolution needed for imaging the brain's cellular dynamics, they neither permit studies in freely behaving mice nor are scalable for studies of large numbers of animal subjects. If fluorescence microscopes could be made small, portable, and cheap, then in principle large numbers of behaving mice could be studied in parallel. Inscopix, Inc. has spun-out of Stanford University to commercialize miniature, integrated fluorescence microscopes - imaging technology that helps neuroscientists visualize neural circuit dynamics in awake behaving mice and rats. Prototype microscopes at Stanford are already enabling imaging of cerebellar microcirculation and permitting visualization of Ca2+ dynamics within hundreds of individual neurons (over weeks in some experiments) as the animal behaves freely in a naturalistic manner. The core miniature, integrated microscope technological innovation and its promise for studying the brain and its diseases was recently featured in Nature, MIT Technology Review, and several media outlets. In Phase I Inscopix aims to develop and test a new set of prototype microscopes that are significantly higher-performing, robust and part of a user-friendly end-to-end solution for in vivo brain imaging in freely behaving rodents. Specifically, we will: (1) Desig and create a new version of our miniaturized, integrated microscope. We will further develop the core technology and incorporate several improvements to significantly enhance imaging performance and extend the capabilities for in vivo brain imaging, including: (a) Attaining spatial resolution finer than 1 ¿m over fields-of-view up to 1 mm2; (b) Developing a digital, high-speed rotary commutator enabling unsupervised, imaging studies of brain activity; (c) Creating a robust and reliable microscope housing suitable for low-cost manufacturing in large volumes. (2) Develop accompanying hardware and software for data acquisition and processing. We will create a compact and user-friendly USB-compatible box for image acquisition and microscope control along with an easy-to-use Graphical User Interface (GUI). (3) Fabricate and test 10 new miniature microscopes with accompanying peripherals. We will fabricate and internally test our new designs before distributing 10 prototypes to carefully chosen beta labs for in vivo testing and validation. By the end of Phase I we expect to have received considerable in vivo usage feedback from beta labs, laying the foundation for volume production and roll-out of a market-ready product in Phase II. PUBLIC HEALTH RELEVANCE: Modern understanding of brain disease is currently undergoing a sea change, gradually shifting away from theories that emphasize a dearth or excess of neurotransmitter, and towards more sophisticated theories in which neurons of specific types exhibit improper patterns of ensemble activity underlying aberrant human behavior. This shift is especially important for disorders such as autism, which defy simple neurochemical explanations and appear to arise from circuit-level abnormalities; for disorders for which there has been much evidence to support roles for altered neurochemistry, such as schizophrenia or depression, there is rising appreciation for the equally important roles of pathologic neural circuit dynamics in causing disease phenotypes. Inscopix will develop and commercialize an innovative imaging technology for visualizing neural activity in behaving mice - and in principle, across large numbers of subjects in parallel - helping researchers obtain some of the missing knowledge about normal and aberrant neural activity patterns in mouse models of human brain disease, a key step towards developing novel therapeutics and corrective strategies.

描述（由申请人提供）：如今，人们越来越重视神经回路在神经精神疾病中的作用，然而，尽管大脑研究人员已经了解了神经活动的正常模式以及这些模式如何在疾病中出错，但我们仍然缺乏重要的知识。建立了许多人类大脑疾病的小鼠模型，目前还没有技术可以可视化行为小鼠大脑中大量个体、基因识别类型的神经元的活动——最好是在多只小鼠中并行进行。获得如此大规模的数据集的能力对于识别脑部疾病的神经生理学特征非常重要，并且是开发重新调整异常活动模式的治疗方法的先决条件。然而，荧光显微镜在跟踪神经活动方面具有关键优势。显微镜提供了大脑细胞动力学成像所需的时空分辨率，但它们既不允许对自由行为的小鼠进行研究，也无法扩展以研究大量动物受试者。 Inscopix, Inc. 已从斯坦福大学分离出来，将微型集成荧光显微镜商业化，这种成像技术可帮助神经科学家可视化清醒行为下的神经回路动态。斯坦福大学的原型显微镜已经能够对小脑微循环进行成像，并允许在动物以自然方式自由活动时对数百个单个神经元内的 Ca2+ 动态进行可视化（在某些实验中需要数周时间）。核心微型集成显微镜技术创新及其对研究大脑及其疾病的承诺最近在《自然》、《麻省理工学院技术评论》和多家媒体上进行了专题报道，Inscopix 的第一阶段旨在开发和测试一套新的原型显微镜，这些显微镜具有显着的效果。具体来说，我们将：（1）设计并创建新版本的微型集成显微镜。进一步发展核心技术以及显着增强成像性能并扩展体内脑成像能力的多项改进，包括：分辨率优于 1 ¿ m 视场达 1 mm2； (b) 开发数字高速旋转换向器，实现对大脑活动进行无人监督的成像研究； (c) 创建适合低成本制造的坚固可靠的显微镜外壳； (2) 开发用于数据采集和处理的配套硬件和软件我们将创建一个紧凑且用户友好的 USB 兼容盒，用于图像采集和显微镜控制以及易于使用的图形用户界面 (GUI) (3)。制造和测试 10 个新型微型显微镜及配套外围设备我们将制造并内部测试我们的新设计，然后将 10 个原型分发给精心挑选的 beta 实验室进行体内测试和验证。到第一阶段结束时，我们预计将收到大量的体内测试结果。来自测试实验室的使用反馈，为第二阶段的批量生产和推出市场就绪产品奠定了基础。公共健康相关性：现代对脑部疾病的理解正在经历巨大的变化，逐渐从强调神经递质缺乏或过量的理论转向更复杂的理论，在这些理论中，特定类型的神经元表现出异常人类背后的不正确的整体活动模式这种转变对于自闭症等疾病尤其重要，这种疾病无法用简单的神经化学解释来解释，并且似乎是由回路水平异常引起的，而有大量证据支持神经化学的作用，例如无论是精神分裂症还是抑郁症，人们越来越认识到病理性神经回路动力学在疾病表型中同样重要的作用，Inscopix 将开发并商业化一种创新的成像技术，用于可视化大量受试者的行为小鼠的神经活动以及其致病原理。平行 - 帮助研究人员获得一些关于人脑疾病小鼠模型中正常和异常神经活动模式的缺失知识，这是开发新疗法和纠正策略的关键一步。