Head-mounted miniature microscopes for combined calcium imaging and electrophysiological measurement of neural circuit function in deep brain regions of behaving macaques

项目摘要 在过去的十年里，神经科学界已经就以下问题达成了共识： 在神经回路的层面上理解大脑功能。这样的理解可以帮助我们跨越 调查规模，以提供一个更全面的模型，大脑功能，同时也提供了一个更 与神经系统疾病相关的功能障碍有直接联系。Insopix通过其旗舰产品 nVista，部分由先前授予的NIH/NIMH脑倡议SBIR赠款，现在提供 全球300多个实验室的神经科学家，能够监测细胞分辨率，大规模的钙离子， 自由行为的啮齿动物的动态，导致对神经回路机制的突破性研究 基本行为的基础。然而，为了推进我们对高级认知功能的理解， 行为和心理健康，迫切需要将这种能力转化为使用非人类的研究 灵长类动物（NHP），一种具有与人类相似的行为库和大脑结构的模型。 在这个快速通道提案中，我们将建立在我们之前成功的SBIR和nVista在啮齿动物中的成功基础上， 并开发和商业化NHP神经电路研究的首个同类平台，使大型 将光学和电生理（ephys）记录深入并分布在大脑中，关键是， 因此，通过简化的手术工作流程和即插即用操作， 世界，创造新的能力，研究人类相关的认知，行为和精神障碍。同相 我们将设计和制造新探针和植入硬件的原型，其中包括病毒涂层 晶状体、集成基板和颅腔系统，用于简化手术工作流程（目标1）， 与用于更深脑成像的较长透镜一起，用于相同部位成像的电极集成透镜， ephys，和一个新的基板支持神经元的纵向跟踪（目标2）。我们，沿着两个测试实验室 合作伙伴将验证这些原型在NHP中的性能（目标3）。在第二阶段，我们将设计和 制造一个完全集成的硬件和软件NHP平台，用于多系统，同时成像， ephys（目标4），并制作15个完整的，用户友好的系统，结合第一阶段的反馈， 增强关键功能，以支持更大的科学用例集（目标5）。我们将在体内进行广泛的 在更大的测试网站上进行实验，以证明所有功能的科学价值（目标6）。年底 在第二阶段，我们将有一个新的平台，用于简化，完全集成的钙成像和ephys， 行为正常的脑区该平台将是NHP神经回路研究的首个此类平台， 经过充分设计和验证，以满足NHP神经科学研究社区的独特需求。这将 允许他们提出关于感知的神经回路机制的新问题， 功能和复杂的行为，以及神经回路异常潜在的神经退行性疾病， 神经精神疾病，这将大大促进我们对人类心理健康的理解。

PROJECT SUMMARY A consensus has emerged in the Neurosciences over the last decade regarding the critical importance of understanding brain function at the level of neural circuits. Such an understanding can help us bridge across scales of investigation to provide a more comprehensive model of brain function, while also providing a more direct link to the dysfunctions associated with neurological disease. Inscopix, through its flagship product, nVista, in part facilitated by previously awarded NIH/NIMH Brain Initiative SBIR grants, is now providing neuroscientists in over 300 labs worldwide with the ability to monitor cellular-resolution, large-scale calcium dynamics in freely behaving rodents, leading to breakthrough research on the neural circuit mechanisms underlying basic behaviors. Nevertheless, to advance our understanding of higher-cognitive function, complex behavior and mental health, a critical need remains to translate such capabilities to research using non-human primates (NHPs), a model with a behavioral repertoire and brain structure similar to that of humans. In this Fast-Track proposal, we will build on our prior successful SBIRs and the success of nVista for rodents, and develop and commercialize a first-of-its-kind platform for NHP neural circuits research, enabling large- scale optical and electrophysiological (ephys) recordings deep and distributed in the brain and, critically, doing so with a streamlined surgical workflow and plug-n-play operation to aid mass adoption in labs across the world, creating new capabilities for studying human-relevant cognition, behavior and mental disorder. In Phase 1 we will design and fabricate prototypes of new probes and implant hardware, which will include virus-coated lenses, integrated baseplates and a cranial chamber system for a streamlined surgical workflow (Aim 1), together with longer lenses for deeper brain imaging, electrode-integrated lenses for same-site imaging and ephys, and a new baseplate supporting longitudinal tracking of neurons (Aim 2). We, along with two beta lab partners, will validate performance of these prototypes in NHPs (Aim 3). In Phase 2, we will design and fabricate a fully integrated hardware and software NHP platform for multi-system, simultaneous imaging and ephys (Aim 4) and fabricate 15 complete, user-friendly systems, incorporating feedback from Phase 1 and enhancing key features to enable a larger set of scientific use cases (Aim 5). We will perform extensive in vivo experiments with a larger set of beta sites to demonstrate the scientific value of all features (Aim 6). At the end of Phase 2, we will have a new platform for streamlined, fully integrated calcium imaging and ephys in deep brain regions of behaving NHPs. This platform will be the first-of-its-kind for neural circuits research in NHPs, fully designed and validated to meet the unique needs of the NHP neuroscience research community. This will allow them to ask new questions about the neural circuit mechanisms underlying perception, higher-cognitive function and complex behavior, as well as the neural circuit abnormalities underlying neurodegenerative and neuropsychiatric disease, which together will greatly advance our understanding of human mental health.