Large-scale calcium and voltage imaging to illuminate neural mechanisms of visual experience

项目摘要： 大部分的生活经验依赖于神经活动来传递关于世界的感觉信息。 神经创伤和中风是昏迷和空间忽视等疾病的主要原因， 损害视觉体验，并且没有可行的治疗方案。同样，挽救生命的医疗 依赖于全身麻醉暂时切断患者与感官世界的联系。电流 麻醉剂通过抑制包括脑干在内的整个大脑来实现这一点，这是一个重大的健康风险。甚至 因此，由于未知的原因，全身麻醉有时无法防止手术期间的经验， 严重创伤的病人。这些问题持续存在，造成负面的健康结果，部分原因是 尽管对感觉编码的机制进行了大量的研究，特别是在视觉方面， 神经活动如何将感官信息转化为意识体验。有很多理论，每一个 表明了不同的机制。视觉体验可能来自高阶神经元的活动， 或者依赖于网络结构中隐藏的复杂交互。经验可能涉及 局部的、周期性的网络交互、远程计算或全局事件，这些事件可使网络得以持续和统一 活动不幸的是，支持这些理论的具体证据是有限的。现有技术缺乏 或者是识别单个神经元和亚型的微观编码特性的特异性，或者是 必要的范围，以检测活动，同时在相当大的视觉网络。新兴技术在 Schnitzer实验室克服了这些技术限制。先进的显微镜和免费的光学 现在的技术可以同时记录整个视觉网络中的数千个神经元， Ca ~（2+）显像显示与神经放电有关的活动，电压显像显示阈下波 与神经通讯相关的动态。在这个项目中，我们将1。制定一项任务， 小鼠模型中的视觉体验，以优化神经记录技术的益处; 2.）使用国家的 艺术光学仪器来解决成千上万的特定类型的单个神经元的动力学， 所有视觉皮层区域，表征区分可见和不可见感知的活动模式; 3）使用 化学发生学操作，通过抑制枕，一个皮质下区域， 调节视觉网络。这项工作的结果，作为初步的数据支持，将揭示详细的证据 与有意识的视觉感知相关的神经机制， 目前的理论这将推动该领域达成数据驱动的共识，并阐明将 有助于治疗疾病

Project Summary: The majority of lived experience depends on neural activity conveying sensory information about the world. Neural trauma and stroke are leading causes of disorders such as coma and spatial neglect, which severely damage visual experience, and there are no viable treatment options. Similarly, life saving medical treatments depend on the ability for general anesthesia to temporarily disconnect patients from the sensory world. Current anesthetics do so by inhibiting the entire brain, including the brainstem, which is a significant health risk. Even so, for unknown reasons, general anesthesia sometimes fails to prevent experiences during surgery, resulting in severe trauma for patients. These problems persist, creating negative health outcomes, in part because despite substantial research into the mechanisms of sensory encoding, particularly in vision, it remains unclear how neural activity transforms sensory information into conscious experience. There are many theories, each suggesting different mechanisms. Visual experience may emerge from the activity of higher-order neural ensembles, or depend on hidden, complex interactions built into network structures. Experience may involve local, recurrent network interactions, long-range computations, or global events that subsume and unify network activity. Unfortunately, concrete evidence supporting any of these theories is limited. Existing technologies lack either the specificity to identify the microscopic encoding properties of individual neurons and subtypes, or the necessary scope to detect activity simultaneously across sizable visual networks. New emerging technology in the Schnitzer lab overcomes these technical limitations. Advanced microscopes and complimentary optical techniques now make it possible to simultaneously record thousands of neurons across the entire visual network, with Ca2+ imaging revealing activity related to neural firing, and voltage imaging revealing subthreshold wave dynamics associated with neural communication. In this project, we will 1.) develop a task designed to isolate visual experience in mouse models to optimize the benefits of neural recording techniques; 2.) use state-of-the- art optical instrumentation to resolve the dynamics of thousands of individual neurons of specific types across all visual cortical areas, characterizing activity patterns that differentiate seen from unseen percepts; 3) use chemogenetic manipulations to test mechanisms of perception by inhibiting the pulvinar, a subcortical area that modulates visual networks. The results of this work, as preliminary data supports, will reveal detailed evidence of neural mechanisms associated with conscious visual perception that can differentiate predictions made by current theories. This will drive the field towards a data-driven consensus and illuminate mechanisms that will be instrumental in treating disorders.