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。这种高度的复杂性奠定了大脑皮层巨大的计算能力的基础，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运作的，神经科学家试图研究大脑皮层中更小的功能单元。有人提出，皮层中最小的计算单位可能是个体发生柱——由单个神经祖细胞衍生的锥体神经元组成的垂直柱。最近的研究表明，细胞谱系是新皮层功能特性发展的重要预测因子。然而，研究之间效应大小的巨大差异导致了围绕细胞谱系在决定功能中的重要性的争议。本项目将利用体内双光子钙成像技术表征小鼠初级视觉皮层（V1）克隆相关神经元的视觉反应特性。他莫昔芬诱导的Cre-loxP系统将用于在神经发生开始时用荧光标记物稀疏标记神经祖细胞。优化他莫昔芬给药剂量和给药时间，以实现单微柱的空间分离。V1中相关和附近不相关神经元的钙反应将用于计算单个细胞的定向调谐。我们将系统地改变成像年龄和克隆大小（这两个变量在以前的研究中没有得到控制），以确定这些参数是否有助于研究之间的可变性。此外，这些实验将为了解克隆相关神经元的调谐特性的发育时间过程提供重要的见解。虽然提出的研究将直接解决个体发生微柱编码视觉刺激的重要性，但结果将对微柱单元作为皮层处理的一般原则的作用产生影响。本实验可为孤独症、精神分裂症等神经发育障碍的研究提供电路水平的基础。

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.