Modular nanophotonic probes for dense neural recording at single-cell resolution

用于单细胞分辨率密集神经记录的模块化纳米光子探针

• 批准号: 9077841
• 负责人: MICHAEL L ROUKES
• 金额: $ 10万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9077841
• 关键词: 3-Dimensional; Biological Neural Networks; Brain; Brain imaging; Brain region; Calcium; Caliber; Cells; Cognition; Collaborations; Communities; Computer Analysis; Cortical Column; Custom; Development; Disease; Electrophysiology (science); Elements; Engineering; Fluorescence; Foundations; Functional Imaging; Genetic Engineering; Gold; Head; Health; Human; Image; Individual; Laser Scanning Microscopy; Length; Light; Measurement; Measures; Methodology; Methods; Microscope; Microscopy; Monitor; Mus; Nanotechnology; Neocortex; Neurons; Neurosciences; Optical reporter; Perception; Population; Positioning Attribute; Production; Property; Protocols documentation; Reporter; Research Personnel; Resolution; Role; Site; Source; Specificity; Specimen; Speed; Staging; Structure; Surface; Technology; Testing; Thick; Time; Tissues; Visual Cortex; Work; absorption; base; brain research; brain tissue; cell assembly; cell type; density; detector; drug discovery; extracellular; high throughput screening; in vivo; information processing; light scattering; nanoprobe; nanosystems; nervous system disorder; neuronal cell body; neuropsychiatry; new technology; novel; optical imaging; patch clamp; photon-counting detector; photonics; prototype; relating to nervous system; scale up; screening; temporal measurement; two-photon

DESCRIPTION (provided by applicant): Our understanding of the properties of individual neurons and their role in brain computations has advanced significantly during the last few decades. However, we are still very far from understanding how large assemblies of cells interact to process information. Electrophysiology is the gold standard with unmatched temporal resolution, but is currently limited in terms of its ability record from every single neuron withina volume with cell-type specificity. Optical imaging provides a powerful alternative method, which enables localization of neurons in anatomical space and cell-type specificity via genetically encoded fluorescent markers. The current state-of-the-art in functional brain imaging is two-photon fluorescence laser-scanning microscopy. But this approach works best only on the surface of the brain, or transparent tissues and is not easily scalable. More generally, light scattering and absorption in tissue impose significant fundamental limits: in mammalian brains, accessible depths in vivo are restricted to superficial cortical regions, d1mm. Endoscopic methods developed to circumvent such restrictions impart significant damage to tissue above the imaging site given the large probe diameter (0.3 to >1 mm) and thus are quite limited (e.g. cannot be used to study cortical columns). Here we propose a novel paradigm for functional optical imaging that surmounts these limitations. It permits function- al imaging with cellular resolution in highly scattering brain tissue, enables complete coverage of all neurons within a target volume, and has long-term prospects for human applications. Our approach, which we term integrated neurophotonics, is based on distributing a dense 3-D lattice of emitter and detector pixels within the brain itself. These pixel arrays are embedded onto neurophotonic probes, realized as implantable, ultra narrow shanks that leverage recent advances in both integrated nanophotonics. Used with functional optical reporters (e.g. GCaMP6), one 25-shank probe module will be capable of recording the activity of all neurons within a 1- mm3 volume (~100,000 neurons) with single cell resolution. The methodology is scalable; multiple modules can be tiled to densely cover extended regions deep within the brain. It will ultimately permit simultaneous recording from millions of neurons at arbitrary positions and depths in the brain, to unveil the dynamics of complete neural networks - with single-cell resolution and cell-type specificity. Ultra-narrow neurophotonic probes will perturb brain tissue minimally, imposing negligible tissue displacement and minute local power dissipation. Importantly, they are readily producible though existing wafer-scale foundry (factory) based methods and thus will be widely available for use by the community. They will transform studies of circuit- level mechanisms of brain computation and neuropsychiatric disorders, and will accelerate drug discovery via high throughput in vivo screening. Our multi-disciplinary team spans all requisite expertise: nanotechnology and large-scale-integration for development of neurophotonic probe arrays (Roukes, Shepard), and in vivo testing and computational analysis (Tolias, Siapas).

描述（由申请人提供）：在过去的几十年中，我们对单个神经元的特性及其在大脑计算中的作用的理解有了显著的进步。然而，我们离理解细胞的大集合如何相互作用来处理信息还很远。电生理学是具有无与伦比的时间分辨率的金标准，但目前在具有细胞类型特异性的体积内的每个单个神经元的能力记录方面受到限制。光学成像提供了一种强大的替代方法，它能够通过遗传编码的荧光标记物在解剖空间和细胞类型特异性中定位神经元。目前最先进的脑功能成像技术是双光子荧光激光扫描显微镜。但这种方法只在大脑表面或透明组织上效果最好，而且不容易扩展。更一般地说，组织中的光散射和吸收施加了重要的基本限制：在哺乳动物大脑中，体内可达深度仅限于表层皮层区域，d1 mm。为规避这种限制而开发的内窥镜方法在给定大探头直径（0.3至>1 mm）的情况下对成像部位上方的组织造成显著损伤，因此非常有限（例如，不能用于研究皮质柱）。在这里，我们提出了一种克服这些限制的功能光学成像新范式。它允许在高度散射的脑组织中以细胞分辨率进行功能成像，能够完全覆盖目标体积内的所有神经元，并且具有人类应用的长期前景。我们的方法，我们称之为集成神经光子学，是基于分布在大脑本身的发射器和检测器像素的密集的3-D网格。这些像素阵列嵌入到神经光子探针上，实现为可植入的超窄柄，利用集成纳米光子学的最新进展。与功能性光学报告分子（例如GCaMP 6）一起使用，一个25柄探针模块将能够以单细胞分辨率记录1 mm 3体积（约100，000个神经元）内所有神经元的活动。该方法是可扩展的;多个模块可以平铺以密集覆盖大脑深处的扩展区域。它最终将允许同时记录大脑中任意位置和深度的数百万个神经元，以揭示完整神经网络的动力学-具有单细胞分辨率和细胞类型特异性。超窄的神经光子探针将最小限度地干扰脑组织，造成可忽略的组织位移和微小的局部功耗。重要的是，它们通过现有的基于晶圆级铸造（工厂）的方法很容易生产，因此将被社区广泛使用。它们将改变大脑计算和神经精神疾病的回路级机制的研究，并将通过高通量体内筛选加速药物发现。我们的多学科团队涵盖了所有必要的专业知识：纳米技术和大规模集成开发神经光子探针阵列（Roukes，谢泼德），以及体内测试和计算分析（Tolias，Siapas）。