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.

项目概要 了解非人类灵长类动物 (NHP) 大脑皮层神经回路的功能，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基础至关重要 光遗传学已成为研究神经回路功能的有力工具，但也面临挑战。 仍然在 NHP 的应用中，大容量操作对于大型 NHP 大脑至关重要。 观察可测量的电生理或行为效应，并了解信息的编码 在先前的 NIH BRAIN Initiative 资助下，由 NIH 领导的跨学科团队 犹他大学开发并测试了犹他光极阵列 (UOA)，这是一个 10x10 阵列。 穿透式透明光导，粘合到 µLED 阵列，用于大体积、时空图案化 大脑神经回路的光遗传学调节 NHP 视觉皮层 UOA 的体内测试。 证明该设备可以选择性激活深层皮质层，以及局部和局部区域 通过简单地改变同时激活的 µLED 和/或其光的数量来实现大规模光刺激 这些结果使 UOA 成为研究局部和大体积目标的强大工具。 由 Blackrock Neurotech 领导的大大脑中的神经元群体，该 STTR 的目标是转变 UOA。 通过结合当前“LED Stim”光遗传学表面的最佳特性，将其转化为可商业化的设备 因此，第一阶段的目标是设计这个新设备的第一次迭代， 出于开发目的，称为“OA2”：目标 1：整合蓝色刺激阵列，其中重新设计、 两级刺激装置的制造和集成将使用独立的 10×10 和 9×9 蓝色 µLED 阵列分别用于深层和表面刺激 目标 2：器件封装和 包装，其中将开发和测试稳健的封装工艺，适合急性体内使用。 目标3：开发矩阵驱动程序，其中将开发新的驱动程序和固件，以便 独立控制深层和表面刺激阵列以进行空间复用操作。 包括 Go-NoGo 到 II 期范例，需要 >90% 的刺激位点保持活跃 >2.8 mW/mm2 经过急性浸泡测试，在 10% 占空比下同时运行 50%，无伪影相位。 II 将包含四个目标： 目标 4：多色刺激的设备优化，其中有源 µLED 组件将被修改，以方便将 µLED 放置和硬封装到顶部 设备，允许在每个深层/表面部位进行多色刺激。单色和双色设备都将是。 目标 5：器件封装和封装，将建立在目标 2 的工作基础上，包括 对设备的活性部件进行硬封装，以提高设备体内工艺的可靠性。 将开发并测试适合长期体内使用的目标 6：开发双色矩阵驱动器。 矩阵驱动器将更新为双极驱动信号，以实现每个两个 µLED 的多路复用控制 目标 7：NHP 体内测试，其中将对 OA2 装置进行急性和慢性测试。 在猕猴身上进行了长达 6 个月的实验。