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

描述(申请人提供)：用于在活体内对复杂神经回路进行系统光学控制的新平台哺乳动物大脑中神经回路的关键特征是其三维和几何复杂性。为了了解大脑如何从这些复杂的环路中产生正常和病理的功能，我们建议发现新的试剂和发明新的设备，能够干扰这些结构中的活动，以其真正的3-D复杂性，从而使我们能够了解这些环路中的每一个对神经和精神疾病以及对大脑的强大功能(如感觉、情感、认知和动作)的因果贡献。使用我们已经开发的分子敏感剂，如通道视紫红质-2和卤视紫红质，以及我们计划开发的用于强大的神经电路沉默的新分子(目标1)，我们可以用光来开启和关闭神经元，从而能够快速评估它们在完整电路中的功能。然而，到目前为止，还不可能在完整的大脑中操纵3D复杂的神经电路。我们将开发微机械、定制制造的结构和技术，能够向大脑中的任意结构提供光(目标2和3)，从而能够实时解析复杂形状的神经电路在正常和异常大脑中的工作方式。我们的发明可能直接使新的疗法成为可能，通过替代能够利用光来治疗神经和精神疾病的新一代光学假体。 与公共健康相关：能够解析复杂的三维神经回路--如弯曲的海马体或分布的额叶杏仁核投射--对正常和病理的大脑功能有何因果影响的能力，对于理解吸毒等精神障碍是如何由大脑中的神经回路受损引起的至关重要的。我们的提议将产生第一种试剂和设备，能够单独或联合激活和沉默这些结构的真正3D复杂性，从而使人们能够对复杂的解剖电路的不同大脑结构和神经回路如何促进正常和异常的大脑功能有新的理解。此外，通过翻译工作，我们的发明可能直接使改善人类健康的新疗法成为可能。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