Neuropixels Opto: Integrated Silicon Probes for Cell-Type-Specific Electrophysiology

项目总结 在每个大脑区域内，神经元可以分为数十种或数百种不同的细胞类型，每种类型都具有独特的功能和对疾病状态的独特影响。传统上，活体电生理记录--它为我们理解行为的神经基础做出了宝贵的贡献--无法区分基因定义的细胞类型的活动。尽管最近我们在同时测量多个神经元的动作电位方面取得了进展，但仍然很难将这些棘波序列与潜在的细胞类型以及所有关于它们的形态、连接模式和内在特性的已知联系起来。在这里，我们建议通过创建一种能够同时进行高密度电生理记录和多色光传输的探头版本来扩展广泛使用的神经像素平台。这种被称为神经像素光学标记的设备可以用来通过一种被称为“光学标记”的方法来识别细胞类型，同时还可以促进对遗传定义的神经种群的精确操作。我们将与拥有世界一流制造设施的纳米电子研发组织IMEC合作，设计和制造一种完全集成的植入式记录设备，拥有1280个电子读出点，多达48个红光发射器和62个蓝光发射器。该探测器的概念验证版本已经交付给艾伦研究所，在那里它成功地用于光学标记实验。然而，需要做更多的工作来开发一种可以规模化制造并以大约2500美元/探头的价格出售的设备，以促进其在整个系统神经科学界的传播。我们将与三个外部测试地点合作，验证NeuroPixus Opto在四个大脑区域：视觉皮质、内嗅觉皮质、纹状体和腹侧被盖区执行特定细胞类型记录和操作的有效性。此外，我们将通过开发控制这些探针的模块来扩展流行的数据采集程序包，以及创建新的转基因小鼠品系，使用户更容易进行双色光遗传操作。总而言之，这些努力将使NeuroPixels Opto成为了解不同细胞类型在活着的大脑中所起作用的强大、可访问和不可或缺的工具。

PROJECT SUMMARY Within every brain region, neurons can be classified into dozens or hundreds of different cell types, each with unique functional roles and unique impacts on disease states. Traditionally, in vivo electrophysiological recordings—which have made invaluable contributions to our understanding of the neural basis of behavior— have not been able to distinguish the activity of genetically defined cell types. Despite recent advances in our ability to measure action potentials from many neurons simultaneously, it remains difficult to connect these spike trains to underlying cell types and all that is known about their morphology, connectivity patterns, and intrinsic properties. Here, we propose to extend the widely used Neuropixels platform by creating a version of these probes that is capable of both high-density electrophysiological recording and multi-color light delivery. This device, called Neuropixels Opto, could be used to identify cell types through an approach known as “optotagging,” while also facilitating precise manipulations of genetically defined neural populations. We will work with IMEC, a nanoelectronics R&D organization with exclusive access to world-class fabrication facilities, to design and build a fully integrated implantable recording device with 1280 electrical readout sites, up to 48 red light emitters, and up to 62 blue light emitters. A proof-of-concept version of this probe has already been delivered to the Allen Institute, where it was successfully used in an optotagging experiment. However, more work is required to develop a device that can be manufactured at scale and sold for around $2500/probe, in order to facilitate its dissemination throughout the systems neuroscience community. In collaboration with three external test sites, we will validate the efficacy of Neuropixels Opto for performing cell-type-specific recordings and manipulations in four brain regions: the visual cortex, entorhinal cortex, striatum, and the ventral tegmental area. In addition, we will extend popular data acquisition packages by developing modules for controlling these probes, as well as create new transgenic mouse lines that make it much simpler for users to carry out dual-color optogenetic manipulations. Taken together, these efforts will make Neuropixels Opto a powerful, accessible, and indispensable tool for understanding the role that different cell types play in living brains.