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

这项提议的首要目标是开发一个读写神经的光学遗传工具箱 清醒高等哺乳动物功能图谱中的种群编码。这样的工具最终可以用来恢复 早期直接刺激周围感觉通路受损患者的知觉能力 感觉皮层。使用遗传编码读取和写入神经代码的高级光学方法 记者和执行器已经成为研究啮齿动物神经回路的强大工具。然而，啮齿动物 是人类感知的次优模型，因为它们的感官表征和 感知能力。例如，啮齿动物的初级视皮层(V1)缺乏功能柱 组织，这是灵长类视力的标志。与啮齿动物相比，猕猴的感官 表征和感知能力与人类高度相似。此外，他的行为 Macaque为开发和测试读取和写入神经代码的工具提供了一个独特的机会 功能域级别，如V1中的方向栏。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能够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来开发光学 利用病毒传递的转基因来监测和操纵神经种群编码的技术 举止乖巧的猕猴。具体地说，我们将解决三个技术目标。首先，我们将开发和测试新的 基因方法将使转基因在灵长类动物中的长期表达具有细胞类型和活性- 依存性专一性。其次，我们将开发一种用于猴子行为的双光子显微镜，这将允许 一种用细胞分辨率来监测这些信号，并用更大的 覆盖范围较广，但分辨率较低。最后，我们将开发编写神经种群代码的方法 通过组合针对特定功能域的图案化光刺激和选择性的功能图 执行机构的表达。我们将通过链接V1响应验证和优化这些技术(由 视觉和直接模式光遗传刺激)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理解神经代码，并更好地 中读取和写入神经种群代码的方法的能力和局限性的表征 人类的功能图。

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.