The central nervous system is composed of highly ordered cell architecture and precise neuronal connections, which are essential for the sophisticated functions of the brain. The development of complex neural circuits encompasses a series of critical steps, including the production of neurons from progenitor cells (neurogenesis), the determination of discrete neuronal phenotypes (neuronal differentiation), the migration of young neurons from their birth place into appropriate positions, the pathfinding of growing axons and dendrites, and the final formation of specific synaptic connections. The goal of our research is to understand how the functional neural circuits in neocortex and cerebellum are generated. Studies will be focused on the molecular mechanisms for neuronal migration, formation of neuonal polarity and axon/dendrite pathfinding. Through combined approaches including the in vivo gene transfer using electroporation, in vitro growth cone turning assay, fluorescence imaging in cultured brain slice and pharmacology methods, we will address the following questions:

(1) Which factors/receptors guide the radial migration of new born neurons and determine their final lamination in the rat neocortex?
(2) How the projecting axons of cortical layer 2/3 pyramidal neurons are guided to innervate the contralateral cortex?
(3) How the axon branches of layer 2/3 neurons are controlled to extend toward difference layers (2/3 and 5 layers) and form local circuits within the same column or between columns?
(4) How extracellular factors influence the formation of neuronal polarity in the neocortex and hippocampus?
(5) What factors control the cerebellar granule cells to migrate from the external germinal layer into the internal granule cell layer during postnatal development?
(6) How the axons of cerebellar granule cells (parallel fiber) are guided to grow in molecular layer of cerebellum cortex?


      So far, we have demonstrated that the in vivo and in vitro assays work well and some preliminary observations have been obtained. We found that electroporation of siRNAs of some guidance receptors dramatically perturbed the cell layering in neocortex, suggesting that axon guidance molecules may also direct the "in-side-out" migration pattern of new born neurons in cortex.

中枢神经系统由规则的细胞群落和精细的神经连接组成，而这些对于脑的各项高级功能是必需的。复杂的神经回路发育过程包括了一系列关键步骤：神经元的产生、神经元的分化、神经元从出生地向将要起功能脑区的迁移、轴突和树突的导向，以及最终神经元之间形成特异的突触连接。我们的研究目标是理解在大脑皮层以及小脑的发育过程中，其中的神经环路是如何建立的。研究主要集中在了解神经元的定向迁移、神经细胞极性的形成、以及轴 / 树突的导向机理。目前，我们已经成功建立了在体和离体的实验系统，并且获得了初步的观察结果。我们发现通过电转一些导向因子受体的 siRNAs 可以显著的破坏大脑皮层中的细胞层次。提示在皮层发育中，轴突导向分子也可能参与引导新生神经元的迁移和层次定位。 通过一系列实验方法,包括在体电场转基因、离体生长锥转向分析、和培养脑片的荧光成像及药理学方法等，我们将试图回答以下几个问题：

1. 哪些因子/受体参与引导新生神经元的迁移和它们在大脑皮层中的最终定位？
2. 皮层2/3层神经元的投射轴突是如何被引导穿越中线并支配对侧皮层的？
3. 皮层2/3层神经元的轴突分支是如何被控制延伸到不同的层次，并且如何与同一功能柱或不同功能柱的神经元形成局部回路的？
4. 在出身后的发育过程中，哪些因子控制小脑颗粒细胞从 EGL 向 IGL 的迁移？
5. 什么细胞外因子引导小脑颗粒细胞的轴突（平行纤维）在小脑皮层的分子层中生长的？