Clonal origin of visual cortical microcircuitry

描述（由申请人提供）：哺乳动物的新皮层有助于各种认知功能，了解皮层回路对于预防和治疗精神障碍至关重要。皮层的一个显著特征是具有相似功能特性的神经元被组织成列。然而，柱状结构如何在发育过程中出现仍然知之甚少。我们最近对小鼠视觉皮层的研究表明，在早期大脑发育过程中，来自共同祖细胞的姐妹神经元在方向调节方面表现出很强的相似性，这可以说是初级视觉皮层中最重要的功能特性。这一发现首次证明了个体发育和功能柱之间的直接对应关系，并为研究皮层回路开辟了新的途径。这项研究的目的是解决几个基本问题，皮质微电路的发育起源，使用的技术，包括双光子成像，电生理记录，神经元标记，和重组病毒载体的分子扰动的组合。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，我们将定义皮层的基本处理单元（目标1）。通过操纵选定的神经元和视觉经验的动物的兴奋性和NMDA受体的表达，我们将阐明发育谱系，电活动和视觉经验之间的相互作用，在塑造皮层神经元的功能特性（目标2和3）。最后，使用谷氨酸释放的高速电路映射，我们将检测克隆相关的姐妹神经元的共同输入，以了解其功能相似性的突触基础。这些实验代表了连接发育和系统神经科学的重要一步，它们可能为皮层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.