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

项目总结 在过去的十年里，神经科学中已经出现了一种共识，即 在神经回路水平上了解大脑功能。这样的理解可以帮助我们跨越 调查量表提供了更全面的大脑功能模型，同时也提供了更多 与神经系统疾病相关的功能障碍有直接联系。Inscope ix通过其旗舰产品， NVista在一定程度上得到了之前授予NIH/NIMH Brain Initiative SBIR赠款的帮助，现在正在提供 全球300多个实验室的神经科学家能够监测细胞分辨率、大规模钙离子 自由行为啮齿动物的动力学，导致神经回路机制的突破性研究 潜在的基本行为。然而，为了提高我们对高等认知功能的理解，复杂 行为和心理健康，一个迫切的需求仍然是将这种能力转化为使用非人类的研究 灵长类动物(NHP)，一种行为模式和大脑结构与人类相似的模型。 在这份快速通道提案中，我们将建立在我们之前成功的SBIRS和啮齿动物nVista成功的基础上， 并开发和商业化首个用于NHP神经电路研究的平台，使大型 刻度光学和电生理(EFYS)记录深入并分布在大脑中，关键是，做 因此，通过简化的手术工作流程和即插即用操作，帮助全球各地的实验室大规模采用 世界，为研究人类相关的认知、行为和精神障碍创造了新的能力。同相 1我们将设计和制造新的探针和植入硬件的原型，其中将包括病毒涂层 镜片、集成底板和用于简化手术工作流程的颅腔系统(目标1)， 与更长的镜片一起用于更深层次的脑成像，电极集成镜片用于同位成像和 Ephys，以及支持神经元纵向跟踪的新底板(目标2)。我们，以及两个测试版实验室 合作伙伴将在国家卫生计划(目标3)中验证这些原型的性能。在第二阶段，我们将设计和 构建硬件和软件完全集成的NHP平台，实现多系统、同时成像和 Ephys(目标4)并制造15个完整的、用户友好的系统，纳入来自第一阶段和 加强关键功能，使更多的科学用例成为可能(目标5)。我们将在活体内进行广泛的 用更多的测试版站点进行实验，以证明所有功能的科学价值(目标6)。在最后 在第二阶段，我们将拥有一个新的平台，用于简化、完全集成的钙成像和深度Ephys 表现为NHP的大脑区域。该平台将是首个用于NHP神经回路研究的平台， 经过充分设计和验证，可满足NHP神经科学研究界的独特需求。这将是 允许他们就认知、高级认知基础的神经回路机制提出新的问题 功能和复杂的行为，以及神经退行性变和 神经精神疾病，这将极大地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.