An optical-genetic toolbox for reading and writing neural population codes in functional maps

用于在功能图中读取和写入神经群体代码的光学遗传工具箱

• 批准号: 9355717
• 负责人: WILSON S GEISLER
• 金额: $ 57.83万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9355717
• 关键词: Address; Affect; Animal Behavior; Behavior; Behavior assessment; Code; Complement; Discrimination; Foundations; Generations; Genetic; Goals; Human; Image; Imaging Techniques; Light; Link; Macaca; Mammals; Maps; Measurement; Measures; Methods; Microscope; Modeling; Molecular Genetics; Monitor; Monkeys; Neurons; Optical Methods; Optics; Pathway interactions; Patients; Pattern; Perception; Peripheral; Population; Primates; Reading; Reporter; Resolution; Rodent; Sensory; Signal Transduction; Specificity; Stimulus; System; Techniques; Testing; Transgenes; Viral; Vision; Visual; Visual Cortex; Writing; area striata; awake; calcium indicator; cell type; member; neural circuit; neural patterning; neurophysiology; optogenetics; orientation columns; relating to nervous system; response; selective expression; sensory cortex; sensory neuroscience; success; tool; transgene expression; two-photon; voltage sensitive dye

The overarching goal of this proposal is to develop an optical-genetic toolbox for reading and writing neural population codes in functional maps of awake, higher mammals. Such tools could ultimately be used to restore perceptual capabilities in patients with damage to peripheral sensory pathways by direct stimulation of early sensory cortex. Advanced optical methods for reading and writing neural codes using genetically-encoded reporters and actuators have become powerful tools for studying neural circuits in rodents. However, rodents are a suboptimal model for human perception because of their vastly different sensory representations and perceptual capabilities. For example, rodents' primary visual cortex (V1) lacks the functional columnar organization which is a hallmark of primate vision. In contrast to rodents, the macaque monkeys' sensory representations and perceptual capabilities are highly similar to those of humans. Furthermore, the behaving macaque provides a unique opportunity to develop and test tools for reading and writing neural codes at the level of functional domains such as the orientation columns in V1. However, multiple technical hurdles remain before the optical-genetic methods currently available in rodents could be readily applied in larger, non- transgenic mammals. Here we propose to take advantage of the unique expertise of our team members to develop optical techniques that utilize virally delivered transgenes for monitoring and manipulating neural population codes in behaving macaques. Specifically, we will address three technical goals. First, we will develop and test new genetic methods that will provide long-term expression of transgenes in primates with cell-type and activity- dependent specificity. Second, we will develop a two-photon microscope for behaving monkeys that will allow one to monitor these signals with cellular resolution and complement current imaging techniques with larger coverage but coarser resolution. Finally, we will develop methods for writing neural population codes in functional maps by combining patterned light stimulation that target specific functional domains and selective expression of actuators. We will validate and optimize these techniques by linking V1 responses (elicited by both visual and direct patterned optogenetic stimulation) and monkeys' behavior in visual discrimination tasks. The tools that we will develop will enable a deeper understanding of the neural code and a better characterization of the capabilities and limitations of methods for reading and writing neural population codes in functional maps in humans.

这项提案的首要目标是开发一个光学遗传工具箱，用于阅读和书写神经系统。 在清醒的高等哺乳动物的功能地图中的种群代码。这些工具最终可以用来恢复 早期直接刺激外周感觉通路损害患者的感知能力 感觉皮层使用遗传编码的神经编码进行阅读和写入的高级光学方法 报告器和致动器已经成为研究啮齿动物神经回路的有力工具。然而，啮齿动物 是人类感知的次优模型，因为它们的感官表现截然不同， 感知能力例如，啮齿类动物的初级视觉皮层（V1）缺乏功能性柱状视皮层。 这是灵长类视觉的标志。与啮齿类动物相比，猕猴的感官 表征和感知能力与人类高度相似。此外，行为 猕猴提供了一个独特的机会，开发和测试工具，阅读和编写神经代码在 功能域的水平，如V1中的方向列。然而，仍然存在多个技术障碍 在目前可用于啮齿动物的光学遗传学方法可以很容易地应用于更大的，非 转基因哺乳动物 在这里，我们建议利用我们团队成员的独特专业知识， 利用病毒递送的转基因来监测和操纵神经群体代码的技术， 举止优雅的猕猴具体而言，我们将解决三个技术目标。首先，我们将开发和测试新的 遗传学方法，将提供长期表达的转基因在灵长类动物与细胞类型和活性- 依赖特异性第二，我们将开发一种双光子显微镜， 一种是以细胞分辨率监测这些信号， 覆盖范围，但分辨率较粗糙。最后，我们将开发出在计算机中编写神经种群代码的方法。 通过结合针对特定功能域的图案化光刺激和选择性光刺激， 执行器的表达。我们将通过连接V1响应（由以下因素引发）来验证和优化这些技术 视觉和直接模式光遗传学刺激）和猴子在视觉辨别任务中的行为。 我们将开发的工具将使我们能够更深入地了解神经代码， 表征阅读和写入神经群体代码的方法的能力和局限性 人类的功能地图