Novel Platforms for Systematic Optical Control of Complex Neural Circuits In Vivo

描述（由申请人提供）：用于体内复杂神经回路的系统光学控制的新型平台哺乳动物大脑中神经回路的关键特征是它们的三维性和几何复杂性。 为了了解正常和病理性的大脑功能是如何从这些复杂的回路中产生的，我们建议发现新的试剂，并发明能够扰乱这些结构中的活动的新设备，以其真正的三维复杂性，从而使我们能够理解这些回路中的每一个对神经和精神疾病的因果贡献，以及大脑的强大功能，如感觉，情感，认知，和行动。 使用我们已经开发的分子敏化剂，如channelrhodopsin-2和halorhodopsin，以及我们计划开发的用于强大的神经回路沉默的新分子（目标1），我们可以使用光来打开和关闭神经元，从而能够快速评估它们在完整回路中的功能。 然而，到目前为止，还不可能在完整的大脑中操纵三维复杂的神经回路。 我们将开发微加工的，可定制的结构和技术，能够将光传递到大脑中的任意结构（目标2和3），从而实现真实的-时间分析复杂形状的神经回路如何在正常和异常的大脑中运作。 我们的发明可以直接实现新的疗法，通过辅助能够使用光来治疗神经和精神疾病的新一代光学修复术。 公共卫生相关性：解析复杂的三维神经回路--如弯曲的海马体或分布式的额杏仁核投射--如何因果地影响正常和病理性的大脑功能，对于理解精神障碍（如药物成瘾）是如何从大脑中受损的神经回路中产生的至关重要。 我们的提案将产生第一个试剂和设备，能够激活和沉默这些结构在其真正的三维复杂性，单独和组合，从而使新的理解如何不同的大脑结构和神经回路，复杂的解剖电路的复杂性，有助于正常和异常的大脑功能。 此外，我们的发明可以通过转化工作直接实现改善人类健康的新疗法。 1

DESCRIPTION (provided by applicant): Novel Platforms for Systematic Optical Control of Complex Neural Circuits In Vivo A key feature of neural circuits in the mammalian brain is their 3-dimensionality and geometric complexity. In order to understand how normal and pathological brain functions emerge from these complex circuits, we propose to discover new reagents and invent new devices capable of perturbing activity in these structures, in their true 3-D complexity, thus enabling us to understand the causal contribution of each of these circuits to neurological and psychiatric disorders, and to powerful functions of the brain such as sensation, emotion, cognition, and action. Using molecular sensitizers that we have developed, such as channelrhodopsin-2 and halorhodopsin, as well as new molecules that we plan to develop for powerful neural silencing of circuits (Aim 1), we can use light to turn neurons on and off, enabling rapid assessment of their function in intact circuits. However, to date it has not been possible to manipulate neural circuits in their 3-D complexity, in the intact brain. We will develop micromachined, custom-fabricatable structures and technologies capable of delivering light to arbitrary structures in the brain (Aims 2 and 3), thus enabling real- time parsing of how complexly-shaped neural circuits operate in the normal and abnormal brain. Our inventions may directly enable new therapies, by subserving a new generation of optical prosthetics capable of using light to treat neurological and psychiatric disorders. PUBLIC HEALTH RELEVANCE: The ability to parse out how complex, 3-D neural circuits - such as the curved hippocampus, or the distributed frontoamygdala projection - causally contribute to normal and pathological brain functions is essential for the understanding of how mental disorders such as drug addiction arise from corrupted neural circuits in the brain. Our proposal will yield the first reagents and devices capable of activating and silencing these structures in their true 3-D complexity, alone and in combination, thus enabling new understandings of how different brain structures and neural circuits, of complex anatomical circuit complexity, contribute to normal and aberrant brain function. In addition, our inventions may directly enable new therapies for improving human health, through translational work. 1