Establishing a Comprehensive and Standardized Cell Type Characterization Platform

 描述(申请人提供)：大脑回路是一个错综复杂的网络，由大量具有不同分子、解剖和生理特性的神经元组成。神经细胞类型是神经回路的基本构件。为了理解大脑回路中信息处理的原理，有必要有一个系统的 了解每个组件的共同和独特属性--单元类型、它们如何相互连接，以及它们在电路中的作用。从对大量电路的研究中，已经提出了关于不同类型的细胞在信号处理中的作用的许多类型的机制。然而，尽管很重要，我们还远没有全面了解大脑或特定回路中细胞的数量和类型。我们确实有关于每个地区主要细胞类型的丰富知识，以及许多特定类型的例子。但在很大程度上，由于缺乏系统的努力，我们不知道大多数电路的完整细胞类型组成，我们对单个细胞之间的变异程度和异质性知之甚少，无论是在给定的类型内还是在不同类型之间。为了解决这个问题，我们建议建立一个全面和标准化的细胞类型表征平台，该平台可以扩大到系统地检查大脑中任何神经回路中细胞类型组件的属性和功能。为了实现这一点，我们提出了一个学术实验室/中心和艾伦研究所之间合作的模型，用于表征特定大脑回路中的细胞类型，所有通过QC的DAA都进入艾伦研究所细胞类型数据库并公开可用。我们将测试一系列实验方法，包括分子、解剖和生理测量及其在单细胞水平上的整合。我们的原理研究的证据是基于对小鼠大脑中三个主要的脑神经回路的比较：两个密切相关的皮质回路-初级视觉皮质(V1)和初级体感皮质(S1)，以及一个更独特的回路-下丘脑/杏仁核情绪通路。这两个比较轴在评估我们将要测试的细胞类型表征方法的可靠性和一般性方面应该非常有用。因此，我们希望确定在神经元功能的指导下，将神经元分类为离散细胞类型所需的关键参数和度量标准。因此，我们预计该项目及其产生的资源将对研究大脑回路功能和功能障碍的科学界产生广泛的影响和催化作用。

 DESCRIPTION (provided by applicant): The brain circuit is an intricately interconnected network of a vast number of neurons with diverse molecular, anatomical and physiological properties. Neuronal cell types are fundamental building blocks of neural circuits. To understand the principles of information processing in the brain circuit, it is essential to have a systematic understanding of the common and unique properties for each of its components - the cell types, how they are connected to each other, and what are their functions in the circuit. From the study of numerous circuits, many types of mechanisms have been proposed regarding the roles of different cell types in signal processing. However, despite of the importance, we are far from a comprehensive understanding of the number and kinds of cell types in the brain or a given circuit. We do have a wealth of knowledge on the major cell types in each region, and many examples of specific types. But for the most part, due to the lack of systematic efforts, we don't know the complete cell type composition of most circuits, and we have very little idea about the degree of variation and heterogeneity among single cells, both within a given type and between different types. To address this issue, we propose to establish a comprehensive and standardized cell type characterization platform that can be scaled up to systematically examine the properties and function of cell type components in any neural circuits throughout the brain. To implement this, we propose a model for collaboration between academic labs/centers and Allen Institute for characterizing cell types in specific brain circuits, with all the QC-passed daa going into the Allen Institute Cell Types Database and becoming publicly available. We will test a range of experimental approaches, encompassing molecular, anatomical and physiological measurements and their integration at the single cell level. Our proof of principle studies are based on comparison of three major brain neural circuits in the mouse brain: two closely related cortical circuits - primary visual cortex (V1) and primary somatosensory cortex (S1), and a more distinct circuit - the hypothalamus/amygdala emotional pathway. These two axes of comparison should be very informative in assessing the reliability and generality of the cell type characterization approaches we will be testing. We thereby hope to determine the critical parameters and metrics necessary to classify neurons into discrete cell types, guided by their functions. Thus, we anticipate that this project and the resources it produces will have a broad impact and catalytic effect on the scientific community studying brain circuitry function and dysfunction.