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

描述(申请人提供)：大脑皮层可能是大脑中最复杂的结构，由数十亿个神经元组成，这些神经元之间有数万亿个连接。这种高度的复杂性是大脑皮层强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。为了了解大脑皮层作为一个整体的功能，神经学家试图研究大脑皮层中较小的功能单位。有人提出，大脑皮质最小的计算单位可能是来自单个神经前体细胞的个体发育柱--锥体神经元的垂直柱。最近的研究表明，细胞谱系是新皮质功能特性发展的重要预测因子。然而，不同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。该项目将使用体内双光子钙成像来表征小鼠初级视觉皮质(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稀疏地标记神经前体细胞。他莫昔芬的给药剂量和给药时机将进行优化，以实现单个微柱的空间隔离。V1中相关和附近无关神经元的钙反应将被用来计算单个细胞的取向调节。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被控制)，以确定这些参数是否有助于研究之间的变异性。此外，这些实验将引导对克隆相关神经元调谐特性的发育时间过程的重要见解。虽然拟议的研究将直接解决个体发育微柱对编码视觉刺激的重要性，但结果将对微柱单位作为皮质加工的一般原则的作用产生影响。拟议的实验可能为研究自闭症和精神分裂症等神经发育障碍提供电路层面的基础。

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.