DEVELOPMENT OF LOCAL CONNECTIONS IN CEREBRAL CORTEX

在发育过程中，神经系统内的年轻神经元 必须形成与本地和长途的特定连接 目标。在大脑皮层内，大部分突触 连接是由局部投射的神经元形成的；因此 这种连接的畸形很可能会牵连到 在这一代人中，至少有一些童年时期的癫痫患者。 事实上，高分辨率核磁共振的使用已经使它越来越多地 显然，许多癫痫是由皮质引起的。 畸形。我们需要更多地了解这些规则 通过它在正常皮质中形成连接，以便 了解并可能治疗皮质内的缺陷 导致癫痫的畸形。当地的规则是什么 在开发过程中建立的连接似乎使用 高度特异的层状识别机制。主要目标是 这项研究提案的目的是了解通过什么过程 哺乳动物新皮质中的年轻神经元形成局部(固有) 脑内与适当靶神经元的轴突联系 受限制的层集合。我们会探讨如何发展 神经元在皮层2/3层细胞的局部投射 在第2/3层和项目内形成广泛的互联 至深层第5层和第6层；第5层的神经元，它们 投射到第2/3层和深层；最后是 皮质层6，向层4发送反馈投影。 具体目标如下：1)我们将使用 器官型培养的发育中的视皮层切片问 本地电路形成是否以切片形式概括，以及 轴突是否需要活动来确定其层特异性 轴突侧支的图案。2)通过将神经元置于异位 层状位置，我们会问是否形成局部 投射出一个涉及特定识别的活动过程 特定于层的线索。3)使用膜试条分析，其中 不同层的神经元可以选择 生长底物，我们将探索分子线索的性质 指导局部轴突的生长和在皮质中萌发。

During development, young neurons within the nervous system must form specific connections to both local and long distance targets. Within the cerebral cortex, the majority of synaptic connections are formed by locally-projecting neurons; thus it seems likely that the malformation of such connections will be implicated in the generation of at least some of the epilepsies of childhood. Indeed, use of high resolution MRI has made it increasingly apparent that a number of the epilepsies are caused b cortical malformations. We need to understand much more about the rules by which connections form in the normal cortex, in order to understand and possibly treat the defects within cortical malformations that lead to epilepsy. The rules by which local connections are established during development appear to employ highly specific mechanisms of laminar recognition. The major aim of this research proposal is to understand the processes by which young neurons in the mammalian neocortex form local (intrinsic) axonal connections with appropriate sets of target neurons in restricted sets of layers. We will explore the development of the local projections of neurons the cells of cortical layer 2/3, which form extensive interconnections within layer 2/3 and also project to the deep layers 5 and 6; those of neurons in layer 5, which projects up to layer 2/3 and to the deep layers; and finally those of the cortical layer 6, which sends a feedback projection to layer 4. The following specific aims are outlined: 1) We will use organotypic cultured slices of the developing visual cortex to ask whether local circuit formation be recapitulated in slices, and whether axons require activity to establish their layer-specific patterns of axon collaterals. 2) By placing neurons in ectopic laminar positions, we will ask whether the formation of local projections an active process that involves the specific recognition of layer-specific cues. 3) Using membrane stripe assays in which neurons of the different layers are presented with a choice of growth substrates, we will explore the nature of the molecular cues that direct local axonal growth and sprouting in the cortex.