Clonal origin of visual cortical microcircuitry

描述(由申请人提供)：哺乳动物的新大脑皮层在各种认知功能中起着重要作用，了解大脑皮层回路对于预防和治疗精神障碍至关重要。大脑皮层的一个突出特征是，具有相似功能特性的神经元以柱状组织。然而，柱状结构是如何在发育过程中产生的，人们仍然知之甚少。我们最近对小鼠视皮层的研究表明，在大脑发育早期，起源于共同前体细胞的姊妹神经元在定向调节方面表现出很强的相似性，这可能是初级视皮层最重要的功能特性。这一发现首次证明了个体发生柱和功能柱之间的直接对应关系，并为研究大脑皮层回路开辟了新的途径。这项拟议的研究旨在利用双光子成像、电生理记录、神经元标记和重组病毒载体的分子扰动等技术组合，解决有关皮质微电路发育起源的几个基本问题。通过测试姐妹神经元之间的功能相似性是否以及如何取决于它们的谱系和物理距离，我们将定义皮质的基本处理单位(目标1)。通过控制选定神经元的兴奋性和NMDA受体的表达以及动物的视觉体验，我们将阐明发育谱系、电活动和视觉体验之间的相互作用，以塑造皮质神经元的功能特性(目标2和3)。最后，使用谷氨酸去化的高速电路映射，我们将检测克隆相关姊妹神经元的共同输入，以了解它们功能相似的突触基础。这些实验代表着连接发育和系统神经科学的重要一步，它们可能为皮质微电路的发展和组织原理提供前所未有的见解。

DESCRIPTION (provided by applicant): The mammalian neocortex is instrumental in a variety of cognitive functions, and understanding cortical circuitry is essential for prevention and treatment of mental disorders. A prominent feature of the cortex is that neurons with similar functional properties are organized in columns. However, how the columnar structure arises during development remains poorly understood. Our recent study in mouse visual cortex has shown that sister neurons originating from a common progenitor cell during early brain development exhibit strong similarity in orientation tuning, arguably the most important functional property in the primary visual cortex. This finding demonstrated, for the first time, a direct correspondence between the ontogenetic and functional columns, and it opened new avenues for studying cortical circuitry. The proposed study aims to address several basic questions concerning the developmental origin of cortical microcircuits, using a combination of techniques including two-photon imaging, electrophysiological recording, neuronal labeling, and molecular perturbation with recombinant viral vectors. By testing whether and how the functional similarity between sister neurons depends on their lineage and physical distances, we will define the basic processing unit of the cortex (Aim 1). By manipulating the excitability and NMDA receptor expression in selected neurons and visual experience of the animal, we will elucidate the interactions between developmental lineage, electrical activity, and visual experience in shaping the functional properties of cortical neurons (Aims 2 and 3). Finally, using high-speed circuit mapping with glutamate uncaging, we will detect common inputs to clonally related sister neurons in order to understand the synaptic basis for their functional similarity. These experiments represent a major step to bridge developmental and systems neuroscience, and they are likely to provide unprecedented insights into the development and organizational principle of cortical microcircuits.