Optogenetic modulation of neuronal and behavioral responses in the primate

描述（由申请人提供）：光遗传学是指一组尖端的分子方法，允许在完整的大脑中对靶神经元进行基于光的控制。这些方法作为基础研究工具具有巨大的潜力，可以确定特定神经元群体在健康和异常脑功能中的作用。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新型假肢。该项目旨在进一步开发这些方法，使其能够实现基础研究和临床潜力。 该提案介绍了分子方法的关键改进以及其应用于高阶感知和认知功能研究的根本改进。重要的是，该提议的方法是微创的，因此，与以前的方法不同，几乎不会造成组织损伤。此外，该提议引入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。该提案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功效。 这种方法的一个关键创新是“光遗传学窗口”的开发。该窗口将允许皮质的长期健康，在递送分子剂之前的功能映射，将分子剂精确靶向至特定功能位点，以及用已建立的光学成像、电生理和行为方法进行评估。这一建议将允许模式的神经元调制（抑制和兴奋）相关的特定的感知和行为的影响。该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好处，并将为开发针对感觉障碍以及精神或神经障碍患者的新疗法提供坚实的基础。 公共卫生相关性：该项目的长期目标是深入了解感知和认知的神经机制。该项目将提供有助于治疗和预防神经和精神疾病的方法和知识。这些目标也直接关系到为视力残疾者研制假肢。

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.