视觉皮层功能柱的谱系发育基础

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, neuronal labeling with viral injection and electrophysiological recording. By testing whether and how the functional similarity between sister neurons depends on their lineage and physical distances, we will define the basic information processing unit of the cortex (Aim 1). By manipulating the visual experience of the animals, we will elucidate the interactions between developmental lineage and visual experience in shaping the functional properties of cortical neurons (Aim 2). 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.

大脑皮层的一个突出特点是具有相似功能的神经元集群形成功能柱结构。但功能柱结构在发育过程中是如何形成的还不甚了解。在哺乳动物的视觉皮层（V1），神经元对视觉刺激的空间朝向有着高度的选择性。我们发现：小鼠V1在胚胎发育中来自同一神经祖细胞的姊妹神经元具有相似的朝向选择性。这是第一次直接证明由姊妹神经元组成的同源发生柱就是功能柱的发育基础。在这项研究中，我们将双光子钙成像和细胞发育学方法相结合，在多细胞水平上同时观察姊妹神经元的功能变化。主要探索同源发生柱中V1姊妹神经元的功能相似度对细胞间谱系距离，物理距离以及视觉经验的依赖性。发育过程中异常的神经环路连接已牵涉各种神经精神疾病，了解发育过程中功能柱的发生机制以及影响功能柱形成的内外因素有助于我们了解病理条件下神经系统功能异常的可能机制，从而为提供有效治疗提供新的思路和策略。

在啮齿类动物上，单个皮层神经元的强选择性和其群体神经元功能结构的强随机性（即“Salt and Pepper”结构）共存，这一事实对神经功能图（Neural map）的“起源”和“重要性”提出了基本科学问题。我们报到发现神经元之间的复杂亲属相关性（kinship）及其突触连接关系很好的解释了小鼠视觉皮层的Salt and Pepper”功能组织结构。起源于不对称分裂的径向胶质祖细胞（RGPs）的姐妹兴奋神经元（sister neurons）优先形成相互的垂直和水平突触连接，并具有相似的方位选择性（orientation selectivity）。相反，对称分裂的增殖性RGPs产生的表亲兴奋性神经元（cousin neurons）不仅不优先形成垂直的突触联系，而且还形成水平上的拮抗突触连接。根据突触连接性，表亲神经元之前在功能的相似度比姐妹神经元的方位选择性上表现出更多的差异。综上所述，这些结果表明亲属关系显著影响兴奋性神经元突触连接的模式和程度，从而决定了新皮质的精确功能组织结构。