Virtual Realty Systems for Neural Circuit Dynamics

描述（由申请人提供）：该申请涉及广泛的挑战领域06：使能技术。具体的挑战题目是06-NS-103：神经科学的突破性技术。虚拟现实（VR）是一种允许用户与计算机模拟环境进行交互的技术。环境可以是真实世界的模拟，也可以是想象的世界，可以实时修改以提供一种新的认知探索。广泛应用于人类行为和神经成像实验，我们现在建议将这项技术应用于啮齿动物细胞分辨率的神经回路研究的不同领域。我们将开发VR仪器和软件，可以与体内双光子激光扫描显微镜和体内全细胞贴片记录协同工作，为系统神经科学提供新的能力。这项技术是利用头部受限的啮齿动物在悬浮球体表面行走和奔跑。我们最近证明，这种球形跑步机可以与双光子激光扫描显微镜一起使用，以细胞分辨率测量清醒、活动的小鼠皮质神经元群（~100）的钙瞬态。为了增加视觉虚拟现实能力，一个环形的屏幕，跨越啮齿动物的视野围绕着球。这个屏幕显示了一个投影的计算机生成的图像，该图像经过几何变换，从鼠标的角度提供了虚拟环境的真实图像。检测由受试者运动产生的球运动的传感器向计算机提供在环境中转弯和前进的控制信号。最近完成的使用该装置的试点实验表明，在工具条件反射范式中，小鼠学会在虚拟竞技场和迷宫中导航以获得水奖励。单单元记录显示了虚拟环境中的位置细胞。此外，该系统提供了在导航过程中应用体内全细胞细胞内记录方法的能力，并演示了位置细胞的第一次细胞内记录。通过将VR与双光子成像相结合，还证明了在导航过程中监测海马锥体细胞群的能力。以这些结果为基础，由神经科学不同领域的研究人员组成的团队将共同努力，扩大啮齿动物虚拟现实系统的开发，作为一项新的突破性技术。一是在积累第一代系统经验的基础上，研发改进型显示器、球形跑步机、运动传感器、视觉虚拟现实软件等。这将提高现有视觉VR系统的总体性能，并使其易于被更广泛的神经科学界采用。将构建用于表征位置细胞和网格细胞的VR环境，并将这些细胞的特征与在真实环境中观察到的特征进行比较。其次，我们将开发一种球形跑步机和相关仪器，用于头部受限大鼠VR，这一物种广泛用于导航研究，以及最近的执行控制。第三，我们将开发仪器，以增加新的感官模式和反馈能力。将开发vr控制的嗅觉和听觉刺激。为了研究小脑在运动控制中的作用，将开发一种计算机控制的阻力跑步机，它可以实时提供本体感觉反馈。在所有情况下，VR仪器将被优化用于体内双光子激光扫描显微镜和全细胞细胞内贴片记录。一旦完成，这套新仪器将为系统神经科学界提供新的能力来分析清醒行为的啮齿动物的细胞电路。这项研究将开发用于神经科学研究的虚拟现实系统。当受试者在虚拟环境中导航时，该系统将能够测量大脑中一个或多个单个神经元的电子和化学过程。这种能力在比较大脑的正常和患病状态方面是有价值的。开发的方法将适用于小鼠，这是健康研究中领先的哺乳动物遗传模型。它还将用于大鼠，一种在行为研究中广泛使用的物种。

Description (provided by applicant): This application addresses broad Challenge Area 06: Enabling Technologies. The specific Challenge Topic is 06-NS-103: Breakthrough Technologies in Neuroscience. Virtual reality (VR) is a technology that allows a user to interact with a computer- simulated environment. The environment can represent a simulation of the real world or an imaginary world that can be modified in real time to provide a novel probe of cognition. Widely used in human behavior and neuro-imaging experiments, we now propose to bring this technology to bear on diverse areas in the study of neural circuits at cellular resolution in rodents. We will develop VR instrumentation and software that can work in a synergistic way with both in vivo two photon laser scanning microscopy and in vivo whole cell patch recording to provide new capabilities in systems neuroscience. The technology revolves around the use of head-restrained rodents walking and running on the surface of a levitated sphere. We have recently demonstrated that this spherical treadmill can be used with two-photon laser scanning microscopy to provide measurements of calcium transients at cellular resolution from populations (~100) of cortical neurons in awake, mobile, mice. To add visual VR capability, a toroidal screen that spans the rodent visual field surrounds the ball. This screen displays a projected computer generated image that has been geometrically transformed to provide a realistic image of the virtual environment from the mouse's perspective. Sensors that detect the motion of the ball produced by movements of the subject provide a control signal to a computer for both turning and forward motion within the environment. Recently completed pilot experiments using this apparatus demonstrate that mice, in an instrumental conditioning paradigm, learn to navigate in virtual arenas and mazes for water rewards. Single unit recordings demonstrate place cells in the virtual environments. Furthermore, the system provides the capability to apply in vivo whole cell intracellular recording methods during navigation and the first intracellular recordings of place cells are demonstrated. By combining VR with two-photon imaging, the capability for monitoring populations of hippocampal pyramidal cells during navigation is also demonstrated. Based on these results, a team of investigators working in diverse areas of neuroscience will work together to expand the development of VR systems for rodents as a new breakthrough technology. First, we will develop improved displays, spherical treadmills, motion sensors, and visual VR software based on experience with the first generation system. This will improve the performance of the existing visual VR system in general and also allow it to be easily adopted by the wider neuroscience community. VR environments for the characterization of place cells and grid cells will be constructed and the characteristics of these cells will be compared to that observed in real environments. Second, we will develop a spherical treadmill and associated instrumentation for head restrained rat VR, a species widely used in studies of navigation and, more recently, executive control. Third, we will develop instrumentation for adding new sensory modalities and feedback capabilities. VR-controlled olfactory and auditory stimuli will be developed. For studies of the role of the cerebellum in motor control, a computer-controlled resistance treadmill will be developed that provides proprioceptive feedback in real-time. In all cases, the VR instrumentation will be optimized for use with in vivo two-photon laser scanning microscopy and whole cell intracellular patch recording. When completed, the suite of new instrumentation will provide the systems neuroscience community with new capabilities for cellular analysis of circuits in awake behaving rodents. This study will develop virtual reality systems for use in neuroscience research. The system will enable the measure of electrical and chemical processes in one or many individual neurons in the brain while the subject is navigating in a virtual environment. This capability would be valuable in comparing normal and diseased states in the brain. The methods developed will be applicable to the mouse, which is the leading mammalian genetic model in health research. It will also be developed for the rat, a species widely used in behavioral studies.