New Optical Strategies to Unlock the Neural Basis of Perception

描述（由申请人提供）：大脑皮层是一台计算机器。尽管进行了深入的研究，但它的许多基本工作原理仍然未知，它的语言--动作电位在空间和时间上的模式--在很大程度上仍然无法解释。因此 要了解大脑的功能，我们必须建立皮质回路如何编码感官刺激以产生感知和指导行为的基本逻辑。正如破译遗传密码彻底改变了我们对基础生物学的理解和我们治疗遗传疾病的能力一样，破译神经密码将大大提高我们对神经功能的理解和我们治疗神经系统疾病的能力。然而，现有的方法不足以充分解决这一问题。因此，本提案的目标是开发新的实验范例，以帮助破译代码，并确定皮层回路产生感知的机制。我们将利用结构光显微镜1和光遗传学工具2，3来设计新的方法，使我们能够以前所未有的精度控制完整大脑中皮层神经元的时空活动。在第一种方法中，我们将双向控制单个皮质层和柱的活动-皮质的两个主要细分-通过将数字化装置与光遗传神经激活剂和沉默剂的细胞类型特异性靶向相结合。这将使我们能够确定这些细分如何合作，以提取感知的核心感官刺激的基本特征。在第二种方法中，我们将使用双光子结构光显微镜在单细胞分辨率下控制皮质神经元的高度特异性局部集合的活动。这将使我们能够评估皮层回路如何通过神经活动的精确时空模式产生感知。最终，我们设想这些技术的应用将帮助我们解释感知的神经代码。这不仅将导致对皮层功能的更机械的理解，而且它应该帮助我们理解神经系统疾病的原因，并帮助设计更有效的神经假体。

DESCRIPTION (provided by applicant): The cerebral cortex is a computational machine. Despite intense investigation, many of its basic operating principles remain unknown, and its language - patterns of action potentials in space and time - is still largely uninterpretable. Thus to understand brain function, it is critical that we establish the fundamental logic of how cortica circuits encode sensory stimuli to generate perceptions and guide behavior. Just as deciphering the genetic code revolutionized our understanding of basic biology and our ability to treat genetic disorders, deciphering the neural code will dramatically enhance our understanding of neural function and our ability to treat neurological disease. Existing approaches, however, are not sufficient to adequately address this problem. Therefore the goal of this proposal is to develop new experimental paradigms to help decipher the code and identify the mechanisms by which cortical circuits generate perceptions. We will leverage structured light microscopy1 and optogenetic tools 2,3 to design new approaches that will allow us to control the spatiotemporal activity of cortical neurons in the intact brain with unprecedented precision. In the first approac we will bi-directionally control the activity of individual cortical layers and columns - the two major subdivisions of the cortex - by combining a digital micromirror device with cell-type specific targeting of optogenetic neural activators and silencers. This will allow us to determine how these subdivisions cooperate to extract basic features of sensory stimuli that are central to perception. In the second approach we will control the activity of highly specific local ensembles of cortical neurons at single cell resolution using two-photon structured light microscopy. This will allow us to assess how cortical circuits generate perceptions through precise spatiotemporal patterns of neural activity. Ultimately, we envision that the application of these techniques will help us interpret the neural codes for perception. Not only will this lead to a much more mechanistic understanding of cortical function, but it should help us understand the causes of neurological disorders and aid in the design of more effective neural prostheses.