Optogenetic modulation of neuronal and behavioral responses in the primate

描述(申请人提供)：光遗传学是指一套尖端的分子方法，允许对完整大脑中的目标神经元进行基于光的控制。这些方法作为确定特定神经元群体在健康和异常脑功能中的作用的基础研究工具具有巨大的潜力。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类型的治疗，以及为那些感觉障碍的人提供一种新的假体。本项目旨在进一步发展这些方法，以实现其基础研究和临床潜力。这项建议介绍了分子方法的主要改进，以及它们在高阶知觉和认知功能研究中的应用的根本改进。最重要的是，这种方法是微创的，因此，与以前的方法不同，它几乎不会造成组织损伤。此外，这一提议带来的改进允许更精确地定位神经元，并更有效地控制这些神经元的反应。这项建议使用这些方法来系统地确定它们在神经元和行为水平上的有效性。这一方法的一个关键创新是开发了一个“光遗传窗口”。这一窗口将允许对大脑皮层的长期健康进行评估，在分子药物输送之前进行功能映射，将分子药物精确定位到特定的功能部位，并使用已建立的光学成像、电生理和行为方法进行评估。这一提议将允许神经元调制模式(抑制性和兴奋性)与特定的知觉和行为影响有关。该项目的成功完成将对高阶知觉和认知功能的基础研究产生巨大的好处，并将为开发针对感觉受损以及精神或神经障碍的新疗法奠定坚实的基础。

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.