Octopus microscopy for imaging multiple brain areas concurrently

描述（由申请人提供）：迄今为止，研究人员已经获得了大量关于大脑微观组成部分的知识，如蛋白质、细胞和微电路，以及关于人类大脑区域在各种任务中激活的宏观模式。然而，研究哺乳动物大脑的神经科学家目前缺乏可靠的解释，无法解释数万到数千个细胞（通常分布在大脑的多个遥远区域）如何协同作用，形成哺乳动物的认知和行为。这种理解上的差距是由于缺乏关于多个大脑区域的细胞协调其尖峰动态的机制的数据，而这反过来又源于缺乏可以可视化细胞如何在大脑区域之间相互作用的技术。我们寻求新的技术来观察信息是如何在大脑区域之间转换的，例如从感觉区域到运动区域。如果我们要理解大脑的整体动态和紊乱，发明观察细胞如何在大脑区域相互作用的方法是必不可少的。对大脑功能障碍的理解正转向越来越复杂的观点，其中特定类型的神经元表现出不适当的集合活动模式。原则上，针对纠正神经回路活动异常模式的新疗法有巨大的机会。一个关键的困境是，我们不能充分利用这些机会，除非我们知道大脑区域的正常活动模式是什么，以及这些模式在疾病或紊乱中是如何出错的。有许多啮齿动物的人类大脑疾病模型，但我们还不能可视化细胞如何在这些模型的大脑区域相互作用。获得如此大规模的数据集是识别大脑功能障碍的神经生理特征的关键，也是开发治疗方法以重新调整异常活动模式的先决条件。为了研究神经元如何在多个大脑区域相互作用，我们将建造一个机器人显微镜，“章鱼”，它有8个光学臂，每个光学臂都是双光子显微镜，可以灵活地定位在大脑周围，同时记录多达8个大脑区域的神经动力学，头部受限，清醒行为的啮齿动物。章鱼成像将首次提供在动物行为过程中，多个区域的神经系统如何协调其动态的一瞥。我们将第一次能够同时观察计算处理和信息通过多个大脑区域的流动。观察到的8个区域包括多个感觉或运动新皮质区、小脑皮质区和皮层下区。我们将能够同时可视化感觉运动转换的多个阶段，不同的区域如何促进认知决策，或者大脑区域如何在不同的生命阶段或不同的大脑状态下以不同的方式协同工作。W还将能够在数周和数月的时间内跟踪8个区域的单个细胞，观察神经编码和可塑性的长期动态。总的来说，章鱼显微镜是一种改变游戏规则的新方法，非常适合于EUREKA计划。

DESCRIPTION (provided by applicant): To date, researchers have gained substantial knowledge about microscopic components of the brain, such as proteins, cells and microcircuits, and about macroscopic patterns of human brain area activation across a wide variety of tasks. However, neuroscientists studying the mammalian brain presently lack credible explanations for how tens to thousands of cells - typically distributed across multiple, distant regions of the brain - act in concert to create mammalian cognition and behavior. This gap in understanding is due to the lack of data regarding the mechanisms by which cells in multiple brain areas coordinate their spiking dynamics, which in turn stems from a lack of technology that can visualize how cells interact across brain regions. We seek novel technology to watch how information is transformed between brain areas, e.g. from sensory to motor areas. Inventing ways to observe how cells interact across brain areas is essential if we are to comprehend global brain dynamics and disorders thereof. Understanding of brain malfunction is shifting towards increasingly sophisticated views, in which neurons of specific types exhibit improper patterns of ensemble activity. In principle, there are enormous opportunities for new therapies aimed at correcting aberrant patterns of circuit activity. A key dilemma is that we cannot take ful advantage of these opportunities until we know what are normal patterns of activity across brain areas and how these patterns go awry in disease or disorder. There are many rodent models of human brain disorders, but we cannot yet visualize how cells interact across brain areas in these models. Obtaining such large-scale data sets is key to identifying neurophysiologic signatures of brain malfunction and is a prerequisite for developing therapeutic ways to re-tune aberrant activity patterns. To study how large ensembles of neurons interact across multiple brain areas, we will build a robotic microscope, the 'Octopus', with 8 optical arms, each a two-photon microscope that can be flexibly positioned around the brain, to record neural dynamics in up to 8 brain areas concurrently in a head-restrained, awake behaving rodent. Octopus imaging will provide the first glimpses of how neural ensembles in multiple areas coordinate their dynamics during animal behavior. For the first time, we will be able to watch computational processing and the flow of information through multiple brain areas concurrently. The 8 regions under view could include multiple sensory or motor neocortical regions, cerebellar cortex, and sub-cortical areas. We will be able to visualize simultaneously the multiple stages of a sensorimotor transformation, how different regions contribute to a cognitive decision, or how brain areas work differently together across various stages of life or in different brain states. W will also be able to follow individual cells in the 8 areas over weeks and months, to observe the long-term dynamics of neural coding and plasticity. Overall, Octopus microscopy is a game-changing new approach and ideally suited for the EUREKA program.