The Role of Cell Lineage in Determining Tuning Preferences in Visual Cortex

描述（由申请人提供）：大脑皮层可能是大脑中最复杂的结构，由数十亿个神经元和数万亿个连接组成。这种高度的复杂性是大脑皮层巨大计算能力的基础，使我们能够感知周围的世界并组织适当的行动。为了理解大脑皮层作为一个整体是如何发挥作用的，神经科学家们试图研究大脑皮层中更小的功能单元。有人提出，皮质的最小计算单元可能是个体发育柱-来自单个神经祖细胞的锥体神经元的垂直柱。最近的研究表明，细胞谱系是一个重要的预测发展的功能特性的新皮层。然而，研究之间效应量的巨大差异导致了围绕细胞谱系在决定功能方面的重要性的争议。本项目将使用体内双光子钙成像来表征小鼠初级视皮层（V1）中克隆相关神经元的视觉反应特性。一个他莫昔芬诱导的Cre-loxP系统将用于稀疏标记神经祖细胞与荧光标记在神经发生的开始。他莫昔芬给药的剂量和时间将针对单个微柱的空间隔离进行优化。V1中相关和附近不相关神经元的钙响应将用于计算单个细胞的方向调谐。我们将系统地改变成像时的年龄和克隆大小（在以前的研究中没有控制的两个变量），以确定这些参数是否有助于研究之间的变异性。此外，这些实验将导致重要的见解发展的时间过程中调谐性能的克隆相关的神经元。虽然拟议中的研究将直接解决个体发育微柱编码视觉刺激的意义，结果将进行微柱单位作为一个一般原则的皮质处理的作用的影响。拟议的实验可能会提供一个电路水平的基础，研究神经发育障碍，如自闭症和精神分裂症。

DESCRIPTION (provided by applicant): The cerebral cortex is perhaps the most complex structure in the brain, consisting of billions of neurons with trillions of connections. This high level of complexity underlies the massive computational power of the cortex and allows us to perceive the world around us and organize appropriate actions. In an effort to understand how the cortex as a whole functions neuroscientists have attempted to study smaller functional units within the cortex. It has been proposed that the smallest computational unit of the cortex may be the ontogenetic column - vertical columns of pyramidal neurons derived from a single neural progenitor cell. Recent studies suggest that cell lineage is an important predictor for development of functional properties in the neocortex. However, large differences in effect size between studies have led to controversy surround how important cell lineage is in determining function. This project will use in vivo two-photon calcium imaging to characterize visual response properties of clonally- related neurons in mouse primary visual cortex (V1). A tamoxifen-inducible Cre-loxP system will be used to sparsely label neural progenitor cells with a fluorescent marker at the beginning of neurogenesis. The dose and timing of tamoxifen administration will be optimized for spatial isolation of single microcolumns. Calcium responses of related and nearby unrelated neurons in V1 will be used to calculate orientation tuning for individual cells. We will systematically vary age at imaging and clonal size (two variables that have not been controlled for in previous studies) to determine whether these parameters contribute to the variability between studies. In addition, these experiments will lead important insights into the developmental time course of tuning properties of clonally related neurons. While the proposed studies will directly address the significance of ontogenetic microcolumns for encoding visual stimuli, the results will carry implications for the role of microcolumnar unit as a general principle of cortical processing. The proposed experiments may provide a circuit level foundation to study neurodevelopmental disorders such as autism and schizophrenia.