High density chronic optogenetic interface for primate brains

灵长类大脑的高密度慢性光遗传学接口

• 批准号: 10706899
• 负责人: Alessandra Angelucci
• 金额: $ 49.64万
• 依托单位: BLACKROCK MICROSYSTEMS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10706899
• 关键词: Acceleration; Acute; Address; Anesthesia procedures; Animals; Area; BRAIN initiative; Behavioral; Biological Models; Brain; Brain Diseases; Cerebral cortex; Chronic; Color; Coupled; Development; Device Designs; Devices; Electrodes; Electronics; Electrophysiology (science); Encapsulated; Engineering; Environment; Epilepsy; Failure; Foundations; Functional disorder; Funding; Future; Gene Expression; Generations; Geometry; Goals; Human; Immediate-Early Genes; Investigation; Learning; Light; Link; Macaca; Measurable; Medical; Methods; Morphologic artifacts; Names; Neurologic; Neurons; Neurophysiology - biologic function; Neurosciences; Optics; Output; Pattern; Penetration; Performance; Periodicals; Phase; Physiologic pulse; Population; Primates; Printing; Process; Schizophrenia; Shapes; Side; Signal Transduction; Site; Small Business Technology Transfer Research; Surface; Target Populations; Technology; Temperature; Testing; Therapeutic Intervention; United States National Institutes of Health; Universities; Update; Utah; Validation; Visual Cortex; Work; autism spectrum disorder; cell type; density; design; ex vivo imaging; experimental study; fabrication; implantation; improved; in vivo; in vivo evaluation; layered ceramics; manufacture; nervous system disorder; neural; neural circuit; neural patterning; neuroregulation; new technology; nonhuman primate; novel; operation; optogenetics; performance tests; process optimization; prosthesis control; response; sensor; spatiotemporal; tool

PROJECT SUMMARY Understanding the function of neural circuits in the cerebral cortex of the non-human primate (NHP), the model system closest to human, is crucial to understanding normal cortical function and the circuit-level basis of human brain disorders. Optogenetics has become a powerful tool for studying neural circuit function, but challenges remain in its application to NHPs. Large volume manipulations are essential in the large NHP brain in order to observe measurable electrophysiological or behavioral effects and understand the encoding of information across multiple brain areas. Under previous NIH BRAIN Initiative funding, an interdisciplinary team led by the University of Utah has developed and tested in vivo the Utah Optrode Array (UOA). This is a 10x10 array of penetrating transparent light guides, bonded to a µLED array, for large-volume, spatiotemporally patterned optogenetic modulation of neural circuits in large brains. In vivo testing of the UOA in NHP visual cortex demonstrated that the device allows for selective activation of deep cortical layers, as well as for both focal and large-scale photostimulation by simply varying the number of simultaneously activated µLEDs and/or their light irradiance These results establish the UOA as a powerful tool for studying local and large-volume targeted neuronal populations in large brains. Led by Blackrock Neurotech, the goal of this STTR is to transition the UOA into a commercializable device by combing the best features of its current ‘LED Stim’ optogenetic surface stimulation array with the UOA. Thus, the goal of Phase I is to engineer the first iteration of this new device, termed ‘OA2’ for development purposes: Aim 1: Integration of blue stimulation array, in which redesign, fabrication, and integration of the two-level stimulation device will be performed using independent 10×10 and 9×9 arrays of blue µLEDs for deep-layer and surface stimulation, respectively. Aim 2: Device encapsulation and packaging, in which robust encapsulation processes will be developed and tested, suitable for acute in vivo use. Aim 3: Development of matrix driver, in which a new driver and firmware will be developed in order to independently control the deep and surface stimulation arrays for spatially-multiplexed operation. The project includes a Go-NoGo to phase II paradigm which requires >90% of the stimulation sites to remain active >2.8 mW/mm2 following acute soak testing with 50% simultaneous operation at 10% duty cycle, artifact-free. Phase II will consist of four Aims: Aim 4: Device optimization for multi-color stimulation, in which the active µLED component will be modified to facilitate placement and hard encapsulation of µLEDs onto the topside of the device, allowing multi-color stimulation at each deep/surface site. Both single and two-color devices will be produced in Phase II. Aim 5: Device encapsulation and packaging, will build upon the work of Aim 2 to include hard encapsulation of the active components of the device in order to increase device in vivo reliability. Processes will be developed and tested suitable for chronic in vivo use. Aim 6: Development of dual-color matrix driver, in which the matrix driver will be updated to bipolar drive signals to enable multiplexed control of two µLEDs per stimulation site. Aim 7: In vivo testing in NHP, in which both acute and chronic testing of the OA2 device will be performed in macaque for periods up to 6 months.

项目摘要 了解神经回路在非人类灵长类动物（NHP）的大脑皮层中的功能，该模型 最接近人类的系统对于理解正常皮质功能和人类的电路级别至关重要 脑疾病。光遗传学已成为研究神经电路功能的强大工具，但挑战 保留在NHP的应用中。在大型NHP大脑中，大容量的操作至关重要 观察可测量的电生理或行为效应，并了解信息的编码 多个大脑区域。在先前的NIH Brain Initiative资金下，由该团队领导的跨学科团队 犹他大学在体内开发和测试了犹他州的Optrode Array（UOA）。这是一个10x10阵列 穿透透明的轻轨，粘合到µLED阵列，用于大容量的时空图案 大脑中神经回路的光遗传学调节。 NHP Visual Cortex中UOA的体内测试 证明该设备允许选择性激活深层皮质层，以及焦点和焦点 通过简单地改变易于激活的µLED和/或它们的光线数量，大规模的光刺激 辐照度这些结果将UOA建立为研究本地和大批量的有力工具 大脑中的神经元种群。在贝莱德神经技术领导的领导下，该STTR的目标是过渡UOA 通过结合其当前“ LED刺激”光遗传表面的最佳功能，进入可商业化的设备 用UOA刺激阵列。这是第一阶段的目标是设计这种新设备的第一次迭代， 为开发目的称为“ OA2”：目标1：蓝色刺激阵列的整合，其中重新设计， 将使用独立的10×10和 9×9的蓝色µLED阵列分别用于深层和表面刺激。 AIM 2：设备封装和 包装，其中将开发和测试强大的封装过程，适用于体内急性使用。 目标3：矩阵驱动程序的开发，其中将开发新的驱动程序和固件以便为了 独立控制深层和表面刺激阵列，以用于空间旋转的操作。项目 包括一个go-nogo到II期范式，该范式需要> 90％的刺激位点保持活跃> 2.8 急性浸泡测试后的MW/MM2，在10％占空比时进行50％的简单操作，无伪影。阶段 II将由四个目标组成：目标4：用于多色刺激的设备优化，其中有源µLED 将修改组件以促进将µLED的放置和硬包裹在 设备，可以在每个深/表面位点进行多色刺激。单彩和两色设备将是 在第二阶段产生。 AIM 5：设备封装和包装，将建立在AIM 2的工作之上 对设备的活动组件的硬封装，以增加体内可靠性的设备。过程 将开发和测试适合慢性体内使用。目标6：开发双色矩阵驱动程序， 矩阵驱动器将被更新到双极驱动信号，以实现每次两个µLED的多路复用控制 刺激部位。 AIM 7：在NHP中进行体内测试，其中OA2设备的急性和慢性测试将是 在猕猴中进行长达6个月的时间。