Optogenetic modulation of neuronal and behavioral responses in the primate

描述（由申请人提供）：光遗传学是指一套前沿的分子方法，允许在完整的大脑中基于光控制目标神经元。这些方法具有巨大的潜力，可以作为确定特定神经元群在健康和异常脑功能中的作用的基础研究工具。此外，这些方法的进一步发展可能会导致神经和精神疾病的新型治疗，以及为那些有感觉障碍的人提供一类新的假肢。本项目旨在进一步发展这些方法，使它们能够发挥其基础研究和临床潜力。本提案介绍了分子方法的关键改进，以及它们在高阶感知和认知功能研究中的应用的基本改进。关键的是，这项建议的方法是微创的，因此，不像以前的方法，造成很少或没有组织损伤。此外，这一建议提出的改进允许更精确地靶向神经元和更有效地控制这些神经元的反应。本建议使用这些方法系统地确定它们在神经元和行为水平上的功效。这种方法的一个关键创新是“光遗传窗口”的发展。这一窗口期将允许皮层的长期健康，在分子药物递送之前的功能定位，分子药物对特定功能部位的精确靶向，以及用已建立的光学成像、电生理和行为方法进行评估。这一建议将允许神经元调节模式（抑制性和兴奋性）与特定的感知和行为效应相关。这个项目的成功完成将为高阶感知和认知功能的基础研究带来巨大的好处，并将为开发新的治疗方法提供坚实的基础，用于治疗感觉障碍以及那些患有精神或神经疾病的人。

DESCRIPTION (provided by applicant): Optogenetics refers to a cutting-edge set of molecular methods that allows for light-based control of targeted neurons in intact brains. These methods have immense potential as a basic research tool to determine the role of specific neuronal populations in healthy and abnormal brain function. In addition, further development of these methods may lead to new types of treatments for neurological and psychiatric disorders, as well as a new class of prostheses for those with sensory impairments. This project is aimed at further developing these methods so that they can achieve their basic research and clinical potential. This proposal introduces key improvements in the molecular methods as well as fundamental improvements in their application to the study of higher-order perceptual and cognitive functions. Critically, the approach of this proposal is minimally invasive and hence, unlike previous methods, causes little to no tissue damage. In addition, the improvements introduced by this proposal allow for more precise targeting of neurons and more potent control of the responses of those neurons. This proposal uses these methods to systematically determine their efficacy at both the neuronal and the behavioral levels. A key innovation of this approach is the development of an "optogenetic window". This window will permit long-term health of the cortex, functional mapping prior to delivery of molecular agents, precise targeting of molecular agents to specific functional sites, and assessment with established optical imaging, electrophysiological, and behavioral methods. This proposal will allow patterns of neuronal modulation (both inhibitory and excitatory) to be related to specific perceptual and behavioral effects. The successful completion of this project will have enormous benefits for basic research into higher-order perceptual and cognitive functions, and will provide a solid foundation for the development of new treatments for the sensory impaired as well as those with psychiatric or neurological disorders. PUBLIC HEALTH RELEVANCE: The long-term goal of this project is to provide insight into the neuronal mechanisms that underlie perception and cognition. This project will provide methods and knowledge that will aid in the treatment and prevention of neurological and psychiatric disorders. These aims are also directly relevant to the development of prostheses for the visually handicapped.